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Sample records for node-positive triple negative

  1. DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients.

    Science.gov (United States)

    Mathe, Andrea; Wong-Brown, Michelle; Locke, Warwick J; Stirzaker, Clare; Braye, Stephen G; Forbes, John F; Clark, Susan J; Avery-Kiejda, Kelly A; Scott, Rodney J

    2016-09-27

    Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Our previous study identified 38 TNBC-specific genes with altered expression comparing tumour to normal samples. This study aimed to establish whether DNA methylation contributed to these expression changes in the same cohort as well as disease progression from primary breast tumour to lymph node metastasis associated with changes in the epigenome. We obtained DNA from 23 primary TNBC samples, 12 matched lymph node metastases, and 11 matched normal adjacent tissues and assayed for differential methylation profiles using Illumina HumanMethylation450 BeadChips. The results were validated in an independent cohort of 70 primary TNBC samples. The expression of 16/38 TNBC-specific genes was associated with alteration in DNA methylation. Novel methylation changes between primary tumours and lymph node metastases, as well as those associated with survival were identified. Altered methylation of 18 genes associated with lymph node metastasis were identified and validated. This study reveals the important role DNA methylation plays in altered gene expression of TNBC-specific genes and lymph node metastases. The novel insights into progression of TNBC to secondary disease may provide potential prognostic indicators for this hard-to-treat breast cancer subtype.

  2. Glutaminase expression is a poor prognostic factor in node-positive triple-negative breast cancer patients with a high level of tumor-infiltrating lymphocytes.

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    Kim, Joo Young; Heo, Sun-Hee; Choi, Seul Ki; Song, In Hye; Park, In Ah; Kim, Young-Ae; Park, Hye Seon; Park, Suk Young; Bang, Won Seon; Gong, Gyungyub; Lee, Hee Jin

    2017-04-01

    Glutamine metabolism is emerging as one aspect of dysregulated metabolism of tumors. Triple-negative breast cancer (TNBC) cells are glutamine dependent, whereas luminal-type cells tend to be glutamine independent. Therefore, TNBC patients might benefit from therapies targeting glutamine metabolism. To investigate the clinical significance of glutamine metabolism, we examined expression and prognostic significance of glutaminase in tumor cells and tumor-infiltrating lymphocytes (TILs) in TNBC. We retrieved 658 surgically resected TNBCs and analyzed glutaminase expression in tumor cells and TILs by immunohistochemical staining. Glutaminase expression was observed in 237 cases (36.0%) in tumor cells and 104 cases (15.5%) in TILs. Although glutaminase expression in tumor cells was significantly associated with a low level of TILs (p = 0.018), glutaminase expression in TILs was significantly higher in cases with a high level of TILs (p = 0.031). Glutaminase expression in tumor cells was significantly associated with poor disease-free survival in patients with lymph node metastasis and high levels of TILs (p = 0.020). In addition, it was an independent poor prognostic factor (hazard ratio = 10.643, 95% confidence interval = 1.999-56.668; p = 0.006). Glutaminase expression in tumor cells was observed in a subset of TNBC patients. It was significantly associated with a low level of TILs and poor disease-free survival in TNBCs presenting with lymph node metastasis and high levels of TILs.

  3. Prognostic factors in patients with node-negative gastric carcinoma: A comparison with node-positive gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Dong Yi Kim; Kyeung Won Seo; Jae Kyoon Joo; Young Kyu Park; Seong Yeob Ryu; Hyeong Rok Kim; Young Jin Kim; Shin Kon Kim

    2006-01-01

    AIM: To identify the clinicopathological characteristics of lymph node-negative gastric carcinoma, and also to evaluate outcome indicators in the lymph node-negative patients.METHODS: Of 2848 gastric carcinoma patients, 1524(53.5%) were lymph node-negative. A statistical analysis was performed using the Cox model to estimate outcome indicators.RESULTS: There was a significant difference in the recurrence rate between lymph node-negative and lymph node-positive patients (14.4% vs 41.0%, P<0.001).The 5-year survival rate was significantly lower in lymph node-positive than in lymph node-negative patients (31.1% vs 77.4%, P<0.001). Univariate analysis revealed that the following factors influenced the 5-year survival rate: patient age, tumor size, depth of invasion,tumor location, operative type, and tumor stage at initial diagnosis. The Cox proportional hazard regression model revealed that tumor size, serosal invasion, and curability were independent, statistically significant, prognostic indicators of lymph node-negative gastric carcinoma.CONCLUSION: Lymph node-negative patients have a favorable outcome attributable to high curability, but the patients with relatively large tumors and serosal invasion have a poor prognosis. Curability is one of the most reliable predictors of long-term survival for lymph nodenegative gastric carcinoma patients.

  4. Histologic changes associated with false-negative sentinel lymph nodes after preoperative chemotherapy in patients with confirmed lymph node-positive breast cancer before treatment.

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    Brown, Alexandra S; Hunt, Kelly K; Shen, Jeannie; Huo, Lei; Babiera, Gildy V; Ross, Merrick I; Meric-Bernstam, Funda; Feig, Barry W; Kuerer, Henry M; Boughey, Judy C; Ching, Christine D; Gilcrease, Michael Z

    2010-06-15

    A wide range of false-negative rates has been reported for sentinel lymph node (SLN) biopsy after preoperative chemotherapy. The purpose of this study was to determine whether histologic findings in negative SLNs after preoperative chemotherapy are helpful in assessing the accuracy of SLN biopsy in patients with confirmed lymph node-positive disease before treatment. Eighty-six patients with confirmed lymph node-positive disease at presentation underwent successful SLN biopsy and axillary dissection after preoperative chemotherapy at a single institution between 1994 and 2007. Available hematoxylin and eosin-stained sections from patients with negative SLNs were reviewed, and associations between histologic findings in the negative SLNs and SLN status (true negative vs false negative) were evaluated. Forty-seven (55%) patients had at least 1 positive SLN, and 39 (45%) patients had negative SLNs. The false-negative rate was 22%, and the negative predictive value was 67%. The negative SLNs from 17 of 34 patients with available slides had focal areas of fibrosis, some with associated foamy parenchymal histiocytes, fat necrosis, or calcification. These histologic findings occurred in 15 (65%) of 23 patients with true-negative SLNs and in only 2 (18%) of 11 patients with false-negative SLNs (P = .03, Fisher exact test, 2-tailed). The lack of these histologic changes had a sensitivity and specificity for identifying a false-negative SLN of 82% and 65%, respectively. Absence of treatment effect in SLNs after chemotherapy in patients with lymph node-positive disease at initial presentation has good sensitivity but low specificity for identifying a false-negative SLN.

  5. Triple-Negative Breast Carcinoma.

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    Livasy, Chad A

    2009-06-01

    Triple-negative breast carcinomas (TNBCs) comprise approximately 15% to 20% of breast cancers. Accurate assessment of tumor estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status is an essential part of classifying tumors into this group. As a group, these tumors are associated with poor clinical outcomes and have been shown to exhibit an increased propensity for hematogenous metastasis to the brain and lungs. Many TNBCs, particularly ductal, not otherwise specified (NOS), and metaplastic carcinomas, show an overlapping characteristic gene expression pattern when evaluated by cDNA microarrays. This group has been termed basal-like because of the similarity with normal breast basal/myoepithelial cells including basal cytokeratin expression and lack of hormone receptor and HER2 expression. The array data have been used to develop multiple immunohistochemical surrogates to identify basal-like tumors in formalin-fixed, paraffin-embedded tissues, most employing basal cytokeratins and epidermal growth factor receptor. Currently, there is no international consensus on biomarkers used to identify tumors as basal-like, and the routine use of the term basal-like in surgical pathology reports is premature. Tumor morphologic features associated with triple-negative status include Nottingham grade 3 with high mitotic rate, pushing border of invasion, geographic tumor necrosis, solid/sheet-like growth pattern, lymphocytic infiltrate, and large central acellular zone. Most breast cancers arising in patients who have a germ-line BRCA1 mutation show similar histologic features and a triple-negative phenotype. Not all TNBCs are associated with an unfavorable prognosis, drawing attention to the heterogeneity of this tumor group and the continued need to link tumor morphology and grade with triple-negative status. This article focuses on histopathology, molecular characterization, carcinogenesis, clinical behavior, and treatment of these

  6. Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

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    Jeffrey Carson

    2012-01-01

    Full Text Available We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

  7. Targeting EGFR in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Naoto T. Ueno, Dongwei Zhang

    2011-01-01

    Full Text Available Our preliminary data show that erlotinib inhibits Triple-negative breast cancer (TNBC in a xenograft model. However, inhibition of metastasis by erlotinib is accompanied by nonspecific effects because erlotinib can inhibit other kinases; thus, more direct targets that regulate TNBC metastasis need to be identified to improve its therapeutic efficacy.

  8. Triple Negative Breast Cancer and Metabolic Regulation

    Science.gov (United States)

    2015-08-01

    Lactate Dehydrogenase A is an isoform of lactate dehydrogenase, which catalyzes the conversion of pyruvate to lactate . LDHA is expressed in cancer ...AWARD NUMBER: W81XWH-13-1-0167 TITLE: Triple Negative Breast Cancer and Metabolic Regulation PRINCIPAL INVESTIGATOR: Amy S. Yee, Ph.D...Negative Breast Cancer and Metabolic Regulation 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0167 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Amy S

  9. Quantitative proteome profiling of lymph node-positive vs. -negative colorectal carcinomas pinpoints MX1 as a marker for lymph node metastasis.

    Science.gov (United States)

    Croner, Roland S; Stürzl, Michael; Rau, Tilman T; Metodieva, Gergana; Geppert, Carol I; Naschberger, Elisabeth; Lausen, Berthold; Metodiev, Metodi V

    2014-12-15

    We used high-resolution mass spectrometry to measure the abundance of more than 9,000 proteins in 19 individually dissected colorectal tumors representing lymph node metastatic (n = 10) and nonmetastatic (n = 9) phenotypes. Statistical analysis identified MX1 and several other proteins as overexpressed in lymph node-positive tumors. MX1, IGF1-R and IRF2BP1 showed significantly different expression in immunohistochemical validation (Wilcoxon test p = 0.007 for IGF1-R, p = 0.04 for IRF2BP1 and p = 0.02 for MX1 at the invasion front) in the validation cohort. Knockout of MX1 by siRNA in cell cultures and wound healing assays provided additional evidence for the involvement of this protein in tumor invasion. The collection of identified and quantified proteins to our knowledge is the largest tumor proteome dataset available at the present. The identified proteins can give insights into the mechanisms of lymphatic metastasis in colorectal carcinoma and may act as prognostic markers and therapeutic targets after further prospective validation.

  10. Axillary Irradiation as an Imperative Alternative to Axillary Dissection in Clinically Lymph Node-Negative but Sentinel Node-Positive Breast Cancer Patients?

    OpenAIRE

    Nitsche, Mirko; Hermann, Robert

    2011-01-01

    At the moment, positive sentinel lymph node dissection (SLND) of the axilla is followed by axillary lymph node dissection (ALND) as standard of care. Recent data proves that omitting ALND after positive SLND in clinically lymph node-negative early stage breast cancer patients is feasible with low recurrence rates. The well known effect of radiotherapy to destroy occult tumor cells highly contributes to these results as a large extent of level I and II lymph nodes are unavoidably included in s...

  11. De-escalating and escalating systemic therapy in triple negative breast cancer.

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    Carey, Lisa A

    2017-08-01

    Triple negative breast cancer has the highest relapse risk of all the clinical subsets, although the escalation of chemotherapy has benefited this subset substantially over recent years. Systemic options are limited to chemotherapy, which makes meaningful de-escalation or escalation of therapy more challenging but possible. Observational cohorts suggest a less than 10% risk of relapse and minimal if any benefit of chemotherapy in very small (<1 cm), node-negative triple negative disease. In higher risk, particularly node-positive disease, anthracycline/taxane-based regimens remain standard. Neoadjuvant chemotherapy clearly de-escalates surgery, although there are insufficient data to give less than standard chemotherapy on the basis of response to neoadjuvant therapy. Efforts to meaningfully escalate therapy in high-risk disease have included incorporating platinums into Neoadjuvant therapy, with clear benefit in pCR but uncertain impact on relapse and survival at this time. Residual disease after neoadjuvant chemotherapy carries a particularly poor prognosis; a recent randomized trial of 6 months' capecitabine in this setting suggested a survival advantage to this approach in higher risk residual disease. While not validated at this time, future directions are likely to include biologic prognostication with tumor and immune variables, as well as targeted non-cytotoxic approaches leveraging the molecular heterogeneity of triple negative disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Clinicopathological Features of Triple Negative Breast Carcinoma

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    Reddy, Gowry Maram; Pai, Radha R.

    2017-01-01

    Introduction Breast carcinoma is one of the most common malignancies affecting women in developing countries. Molecular studies of breast carcinoma have classified the tumour based on the immunohistochemical staining into 4 subtypes, such as Luminal A, Luminal B, HER2/neu Positive and Triple Negative Breast Carcinoma (TNBC). TNBCs are reported to have an aggressive behaviour and wide metastasis, leading to selective treatment outcomes. Aim The aim was to study the clinicopathological features such as age, site, tumour size, histopathological type, histologic grade, lymph node status, stage and treatment outcomes of triple negative breast carcinoma. Materials and Methods A retrospective study was conducted on 108 cases of breast carcinoma received during the period of 2 years. The tumour was classified based on immunohistochemical staining into four subtypes. The clinicopathological details, histomorphological and immunohistochemical features of TNBC were studied. Results Of the 108 patients, 34 patients were diagnosed as TNBC. The average age at presentation was 48 years. Most of the cases showed Nottingham Modification of Scarff Bloom-Richardson (NMBR) grade 3 (55.9%) and stage II (67.6%). Ly-mph node metastasis was seen in 50% of cases. Infiltrating ductal carcinoma (not otherwise specified) type (91.2%) was the most common histological type. Among the other subtypes, Luminal A carcinoma was the most common (36.1%), followed by TNBC (31.5%) and HER2/neu positive carcinomas (28.7%). Compared to the other types of tumours, TNBC showed the most frequent distant lymph node metastasis (50%) when compared to luminal A (38.5%), luminal B (25%), HER2/neu positive (48.4%). Unlike the other types of tumours, TNBC were mostly high-grade. Conclusion TNBC have an aggressive behaviour compared to other subtypes with higher NMBR grade, nuclear pleomorphism, high mitotic rate and lymph node metastasis. PMID:28273970

  13. Triple negative breast cancer: an Indian perspective

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    Akhtar M

    2015-08-01

    Full Text Available Murtaza Akhtar, Subhrajit Dasgupta, Murtuza Rangwala Department of Surgery, NKP Salve Institute of Medical Sciences and Research Centre, Nagpur, Maharashtra, India Introduction: Breast cancer is the most common female cancer in the world. Triple negative breast cancer (TNBC is a recently identified biological variant with aggressive tumor behavior and poor prognosis. Data of hormonal status from the Indian population is scarce due to financial constraints in performing immunohistochemistry evaluation. The present study aims to prospectively analyze receptor status of all breast cancer patients and identify TNBC and compare their clinical profile and short term survival with other non-TNBC group. Materials and methods: All cytologically and histopathologically confirmed cases of carcinoma breast were prospectively enrolled. In a longitudinal study at tertiary care hospital in central India based on the hormonal status, they were further divided into TNBC and other groups. Comparison of risk factors, clinical profile and short-term survival was carried out. Results: A total 85 patients were enrolled and of them 37 (43.7% were TNBC. On comparing risk factors ie, age, age at menarche, total reproductive age, age at first child birth, and menopausal status – no statistical significance was observed between the TNBC and non-TNBC groups. But on comparison of clinical profile TNBC tumors were significantly large with majority of patients presenting as locally advanced breast cancer (83%. No statistical difference was observed in axillary lymph node status between two groups. TNBC tumors were histologically more aggressive (grade 3 compared to other groups. No statistically significant difference was observed in short term overall survival but all three deaths were observed in the TNBC group only and two local recurrences after surgery were observed in the TNBC group. Conclusion: TNBC forms a large proportion of carcinoma breast patients in a central

  14. Targeting Prolyl Peptidases in Triple-Negative Breast Cancer

    Science.gov (United States)

    2017-02-01

    AWARD NUMBER: W81XWH-16-1-0025 TITLE: Targeting Prolyl Peptidases in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Carl G. Maki, PhD...SUBTITLE Targeting Prolyl Peptidases in Triple-Negative Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0025 5c. PROGRAM ELEMENT NUMBER 6...ABSTRACT Triple negative breast cancer (TNBC) is an aggressive sub-type with limited treatment options and poor prognosis. The most life-threatening

  15. Axillary Irradiation as an Imperative Alternative to Axillary Dissection in Clinically Lymph Node-Negative but Sentinel Node-Positive Breast Cancer Patients?

    Science.gov (United States)

    Nitsche, Mirko; Hermann, Robert

    2011-10-01

    At the moment, positive sentinel lymph node dissection (SLND) of the axilla is followed by axillary lymph node dissection (ALND) as standard of care. Recent data proves that omitting ALND after positive SLND in clinically lymph node-negative early stage breast cancer patients is feasible with low recurrence rates. The well known effect of radiotherapy to destroy occult tumor cells highly contributes to these results as a large extent of level I and II lymph nodes are unavoidably included in standard tangential radiation treatment fields. Reviewing the up to date published data on axillary lymph node treatment with radiotherapy, we hypothesize that full dosage coverage of level I and II of the axilla in early stage breast cancer will improve outcome and should be further evaluated.

  16. Triple negative breast carcinoma is a prognostic factor in Taiwanese women

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    Kuo Shou-Jen

    2009-06-01

    Full Text Available Abstract Background Currently, there is a debate as to whether triple negative breast carcinoma (TNBC has a worse prognosis than non-TNBC. Our aim was to determine whether TNBC is a prognostic factor for survival. Methods We identified 1,048 Taiwanese breast carcinoma patients, of whom 167 (15.9% had TNBC. Data used for analysis were derived from our cancer registry database for women with breast cancer who were diagnosed between 2002 January and 2006 December. Results In the Kaplan-Meier analysis, tumor subgroup (TNBC vs. non-TNBC was a prognosis factor related to 5-year overall survival. In the univariate analysis, tumor subgroup (TNBC vs. non-TNBC was a significant factor related to 5-year overall survival, in addition to age, tumor size, lymph node, metastasis, grade, stage, estrogen receptor status, progesterone receptor status, and HER2 overexpression status. In the multivariate analysis, tumor subgroup was not a significant factor related to 5-year disease-free survival (DFS. In node-positive patients, tumor subgroup was a significant factor related to 5-year overall survival, in addition to age, tumor size, metastasis, and grade. In node-negative patients, tumor subgroup was not a significant factor related to 5-year disease-free survival and 5-year overall survival. Conclusion Our results indicated that TNBC patients in Taiwan have worse 5-year overall survival than non-TNBC patients. Notably, in node-positive patients, TNBC played a prognostic role in 5-year overall survival.

  17. A Study of Neoadjuvant Paclitaxel in Combination With Bavituximab in Early- Stage Triple- Negative Breast Cancer

    Science.gov (United States)

    2017-03-08

    Breast Cancer; Triple Negative Breast Neoplasms; Triple-Negative Breast Neoplasm; Triple-Negative Breast Cancer; Triple Negative Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Neoplasms; ER-Negative PR-Negative HER2-Negative Breast Cancer

  18. A CLDN1-negative phenotype predicts poor prognosis in triple-negative breast cancer.

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    Fei Ma

    Full Text Available INTRODUCTION: Triple-negative breast cancer (TNBC is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs. MATERIALS AND METHODS: The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed. RESULTS: Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014. The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003. Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS in both lymph node positive (LN+ and negative (LN- cases (both P<0.001. Similarly it was also associated with shorter overall survival (OS(P = 0.003 in LN+ cases; P = 0.018 in LN- cases. In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008. Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002. However, neither CLDN4 nor CLDN7 expression was associated with survival. CONCLUSION: In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor

  19. Triple negative breast cancer: adjuvant chemotherapy effect on survival

    National Research Council Canada - National Science Library

    Steponaviciene, L; Lachej-Mikeroviene, N; Smailyte, G; Aleknavicius, E; Meskauskas, R; Didziapetriene, J

    2011-01-01

    Purpose: The purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival.Material/Methods...

  20. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2015-08-01

    respiration by 17β-estradiol through lactate dehydrogenase in MCF7 breast cancer cells. AACR Metabolism and Cancer , Baltimore, October 16-19, 2011. 20...1 AWARD NUMBER: W81XWH-14-1-0237 TITLE: Targeting Histone Abnormality in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Yi...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Histone Abnormality in Triple-Negative Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0237 5c

  1. Epigenetic Subtypes of Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-10-01

    1 AD______________ AWARD NUMBER: W81XWH-14-1-0213 TITLE: Epigenetic Subtypes of Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR...SUBTITLE Epigenetic Subtypes of Triple-Negative Breast Cancer 5a. CONTRACT NUMBER W81XWH-14-1-0213 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...generally dominant. Based on the analysis of a limited number of TNBC cell lines we found that the epigenetic profiles of TNBCs are highly heterogeneous

  2. A triple negative breast cancer: what it is not!

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    Katakkar SB

    2012-02-01

    Full Text Available Suresh B KatakkarRegional Medical Oncology Hematology Leader, Centre for the North, BC Cancer Agency, Prince George, British Columbia, CanadaAbstract: The triple negative cancer is an unusual, and at the same time, a unique entity where the discordance rate is almost 18%. That means 18% of Her2 negative results will transform into a Her2 positive status and will have the affinity to spread to the central nervous system (CNS. With the identification of CD44, CD24, and ALDH1, we may be able to determine which group of triple negative breast cancer patients will have CNS metastasis. This case illustrates the Her2 expressing cells have higher CNS affinity. As the original tumor was Her2 negative, if a genomic assay was then done on this patient, we would have identified the potential of CNS involvement. In conclusion, genomic assays should be routinely done on triple negative cancers.Keywords: triple negative, breast cancer, claudin high or low, genomic microassay

  3. Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

    Science.gov (United States)

    2017-03-15

    Breast Carcinoma Metastatic in the Bone; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  4. Ferritin heavy chain in triple negative breast cancer

    DEFF Research Database (Denmark)

    Liu, Ning Qing; De Marchi, Tommaso; Timmermans, Annemieke M

    2014-01-01

    Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes...

  5. Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer

    DEFF Research Database (Denmark)

    Szallasi, Zoltan Imre; Eklund, Aron Charles; Li, Qiyuan

    2010-01-01

    PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer...

  6. mTOR in breast cancer: differential expression in triple-negative and non-triple-negative tumors.

    LENUS (Irish Health Repository)

    Walsh, S

    2012-04-01

    Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptors (ER), progesterone receptors (PR) and overexpression of HER2. Targeted therapy is currently unavailable for this subgroup of breast cancer patients. mTOR controls cancer cell growth, survival and invasion and is thus a potential target for the treatment of patients with TNBC. Using immunohistochemistry, mTOR and p-mTOR were measured in 89 TNBCs and 99 non-TNBCs. While mTOR expression was confined to tumor cell cytoplasm, p-mTOR staining was located in the nucleus, perinuclear area and in the cytoplasm. Potentially important, was our finding that nuclear p-mTOR was found more frequently in triple-negative than non triple-negative cancers (p < 0.001). These results suggest that mTOR may play a more important role in the progression of TNBC compared to non-TNBC. Based on these findings, we conclude that mTOR may be a new target for the treatment of triple-negative breast cancer.

  7. The Proteomic Landscape of Triple-Negative Breast Cancer

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    Robert T. Lawrence

    2015-04-01

    Full Text Available Triple-negative breast cancer is a heterogeneous disease characterized by poor clinical outcomes and a shortage of targeted treatment options. To discover molecular features of triple-negative breast cancer, we performed quantitative proteomics analysis of twenty human-derived breast cell lines and four primary breast tumors to a depth of more than 12,000 distinct proteins. We used this data to identify breast cancer subtypes at the protein level and demonstrate the precise quantification of biomarkers, signaling proteins, and biological pathways by mass spectrometry. We integrated proteomics data with exome sequence resources to identify genomic aberrations that affect protein expression. We performed a high-throughput drug screen to identify protein markers of drug sensitivity and understand the mechanisms of drug resistance. The genome and proteome provide complementary information that, when combined, yield a powerful engine for therapeutic discovery. This resource is available to the cancer research community to catalyze further analysis and investigation.

  8. High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal B HER2 negative and node-positive breast cancer.

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    Criscitiello, Carmen; Disalvatore, Davide; De Laurentiis, Michele; Gelao, Lucia; Fumagalli, Luca; Locatelli, Marzia; Bagnardi, Vincenzo; Rotmensz, Nicole; Esposito, Angela; Minchella, Ida; De Placido, Sabino; Santangelo, Michele; Viale, Giuseppe; Goldhirsch, Aron; Curigliano, Giuseppe

    2014-02-01

    The indication of adjuvant chemotherapy for patients with highly proliferative estrogen receptor-positive breast cancer is controversial. We analyzed the predictive value of Ki67 for the efficacy of adjuvant chemotherapy in patients with estrogen receptor-positive, node-positive breast cancer. We identified 1241 patients with Luminal B early stage breast cancer with 1-3 axillary positive nodes who underwent surgery between 1995 and 2005 at the European Institute of Oncology and received adjuvant hormonotherapy and/or chemotherapy. Differences in the distribution of characteristics according to treatment were evaluated by the Chi-square test. To evaluate the effect of adding chemotherapy to hormonotherapy, the propensity score method was used to match patients' characteristics minimizing bias related to the non-random assignment of treatment. The probability of receiving chemotherapy was significantly associated with age, tumor grade, degree of hormone responsiveness, tumor size and peripheral vascular invasion. The propensity score distribution was statistically different between the two treatment groups (p value 0.663). The 5-year DFS percentages were 84.6% (95% CI, 81.0-87.6%) in the hormonotherapy group and 84.2% (95% CI, 81.3-86.7%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.388). However, when analyzing the 5-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis showed a beneficial effect of chemotherapy in patients with highly proliferative tumor (Ki-67 ≥ 32%). The interaction between Ki-67 and treatment was statistically significant (p = 0.027). Ki67 expression identifies a subset of patients with Luminal B and node-positive breast cancer who could benefit from addition of adjuvant chemotherapy to hormonotherapy. Dichotomy was observed for Ki67 at 32% level. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Clinical significance of morphologic characteristics in triple negative breast cancer.

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    Ryu, Dong Won; Jung, Min Jung; Choi, Woo Sik; Lee, Chung Han

    2011-05-01

    No clinically useful target molecule has been identified for triple-negative (TN) breast cancer, i.e., estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-2-negative phenotype, and its prognosis is poor. The aim of this study is to clarify the clinical and pathologic characteristics of triple negative breast cancer (TNBC). The study subjects, 87 women with TNBC, were a subset of patients operated at Kosin University Gospel Hospital from January 2000 to December 2005. We examined pathologic characteristics such as tumor necrosis, infiltrating border, lymphocytic infiltration, prominent nucleoli in TNBC. And we studied the correlation between TNBC and several factors related to pathologic morphology. Chi-squared tests were used for statistical analysis. Kaplan-Meier estimates are presented for the survival function, and differences in survival were analyzed using the log rank test. Tumor necrosis was found in 51 patients (58.3%) in TNBC. And infiltrating border was found in 71 patients (81.0%). Also continuous lymphocytic distribution and prominent nucleoli was found in 31 patients (35.7%), 52 patients (59.7%), respectively. No association was detected between pathologic characteristics and other biological markers. Patients with tumor necrosis positive for TNBC didn't show shorter disease-free survival (P = 0.4490) or overall survival (P = 0.979) than patients without tumor necrosis. These findings suggest that pathologic characteristics cannot be used to classify triple-negative breast cancer into only two subtypes with differing prognoses. But because our study is small size study, more abundant patients' dates will be needed to evaluate the morphologic characteristics' predictive role.

  10. Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers.

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    Pawel Domagala

    Full Text Available This study sought to assess the prevalence of common germline mutations in several genes engaged in the repair of DNA double-strand break by homologous recombination in patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers. Tumors deficient in this type of DNA damage repair are known to be especially sensitive to DNA cross-linking agents (e.g., platinum drugs and to poly(ADP-ribose polymerase (PARP inhibitors.Genetic testing was performed for 36 common germline mutations in genes engaged in the repair of DNA by homologous recombination, i.e., BRCA1, BRCA2, CHEK2, NBN, ATM, PALB2, BARD1, and RAD51D, in 202 consecutive patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers.Thirty five (22.2% of 158 patients in the triple-negative group carried mutations in genes involved in DNA repair by homologous recombination, while 10 (22.7% of the 44 patients in the hereditary non-triple-negative group carried such mutations. Mutations in BRCA1 were most frequent in patients with triple-negative breast cancer (18.4%, and mutations in CHEK2 were most frequent in patients with hereditary non-triple-negative breast cancers (15.9%. In addition, in the triple-negative group, mutations in CHEK2, NBN, and ATM (3.8% combined were found, while mutations in BRCA1, NBN, and PALB2 (6.8% combined were identified in the hereditary non-triple-negative group.Identifying mutations in genes engaged in DNA damage repair by homologous recombination other than BRCA1/2 can substantially increase the proportion of patients with triple-negative breast cancer and hereditary non-triple-negative breast cancer who may be eligible for therapy using PARP inhibitors and platinum drugs.

  11. Prognostic significance of Bcl-2 in invasive mammary carcinomas: a comparative clinicopathologic study between "triple-negative" and non-"triple-negative" tumors.

    Science.gov (United States)

    Tawfik, Kareem; Kimler, Bruce F; Davis, Marilyn K; Fan, Fang; Tawfik, Ossama

    2012-01-01

    Bcl-2 is a tumorigenic protein that is expressed in 25% to 50% of breast cancers. Although its expression has been widely accepted as a favorable prognostic marker, its protective mechanism of action remains unclear. "Triple-negative" tumors are an aggressive subgroup known to carry a poor prognosis. Studies documenting prognostic significance of Bcl-2 expression in triple-negative in comparison to non-triple-negative breast cancers are limited. Bcl-2 expression was correlated with tumor size, grade, histologic type, lymphovascular invasion, lymph node status, patients' overall survival, estrogen receptor, progesterone receptor, Her-2, p53, and epidermal growth factor receptor in 124 triple-negative and 458 non-triple-negative tumors. There were significant differences between triple-negative and non-triple-negative tumors in their relationship to Bcl-2 expression (81% versus 29%, respectively) and tumor aggression. As previously reported, in non-triple-negative tumors, Bcl-2 positivity correlated with less aggressive tumors (94% of grade I tumors were Bcl-2+ versus 62% of grade III tumors, P < .011) and overall survival (P = .008). However, the opposite was true in patients with triple-negative tumors, where Bcl-2 positivity was associated with poorer survival (P = .64). In triple-negative tumors, Bcl-2 positivity was not associated with any of the aforementioned parameters except for a lower incidence of lymph node metastasis. Moreover, by Cox regression analysis of all variables, in patients with triple-negative tumors, lymphovascular invasion (P = .009) and Bcl-2 expression (P = .028) were predictors of poor survival. In conclusion, there are major clinicopathologic differences between breast cancer phenotypes. Our results establish the value of using Bcl-2 in prognostic stratification of patients and its potential therapeutic implications in selecting patients for treatment.

  12. Management Options in Triple-Negative Breast Cancer

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    Minami, Christina A.; Chung, Debra U.; Chang, Helena R.

    2011-01-01

    Notorious for its poor prognosis and aggressive nature, triple-negative breast cancer (TNBC) is a heterogeneous disease entity. The nature of its biological specificity, which is similar to basal-like cancers, tumors arising in BRCA1 mutation carriers, and claudin-low cancers, is currently being explored in hopes of finding the targets for novel biologics and chemotherapeutic agents. In this review, we aim to give a broad overview of the disease’s nomenclature and epidemiology, as well as the basic mechanisms of emerging targeted therapies and their performance in clinical trials to date. PMID:21863131

  13. Current approaches in treatment of triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    Hanan Ahmed Wahba; Hend Ahmed El-Hadaad

    2015-01-01

    Triple-negative breast cancer (TNBC) is diagnosed more frequently in younger and premenopausal women and is highly prevalent in African American women. TNBC is a term derived from tumors that are characterized by the absence of ER, PgR, and HER2. So patients with TNBC do not beneift from hormonal or trastuzumab-based therapies. TNBCs are biologically aggressive, although some reports suggest that they respond to chemotherapy better than other types of breast cancer, prognosis remains poor. hTis is due to:shortened disease-free interval in the adjuvant and neoadjuvant setting and a more aggressive course in the metastatic setting.

  14. Triple Negative Breast Cancer Team Project — EDRN Public Portal

    Science.gov (United States)

    Triple negative breast cancers (TNBC), comprise 15-20% of breast cancers, and are associated with later stage at diagnosis, increased mortality, and occur more frequently in younger women where mammographic screening is less reliable. TNBCs are more likely to be diagnosed by physical exam than by mammographic screening. There is an unmet clinical need for biomarkers for the early detection of TNBC. Here, we are proposing the development of a plasma-based biomarker panel for the routine screening of women over the age of 40 for TNBC that can be used to identify women for further imaging.

  15. An overview of triple negative breast cancer for surgical oncologists.

    Science.gov (United States)

    Sharma, Shiva; Barry, Mitchel; Gallagher, David J; Kell, Malcolm; Sacchini, Virgilio

    2015-09-01

    Triple negative breast cancers (TNBCs) represent a distinct subgroup of breast cancers with an immunohistochemical phenotype that is negative for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The aim of this article is to provide a broad overview of recent developments in the diagnosis and management of TNBC for surgical oncologists. This overview discusses the subtypes of TNBC and the relationship between this type of breast cancer and the BRCA1 gene. In addition, the article explores recent advances in the treatment of TNBC from a surgical, radiation, and medical oncology point of view. Lastly, evolving therapeutic strategies that have potential to enhance outcomes for patients with TNBC are also discussed.

  16. Vascular characterisation of triple negative breast carcinomas using dynamic MRI

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    Li, Sonia P.; Beresford, Mark J.; Ah-See, Mei-Lin W.; Makris, Andreas [Mount Vernon Cancer Centre, Academic Oncology Unit, Northwood, Middlesex (United Kingdom); Padhani, Anwar R.; Taylor, N.J.; Stirling, J.J. [Mount Vernon Hospital, Paul Strickland Scanner Centre, Northwood, Middlesex (United Kingdom); D' Arcy, James A.; Collins, David J. [Royal Marsden NHS Foundation Trust and Institute of Cancer Research, CR UK and EPSRC Cancer Imaging Centre, Sutton, Surrey (United Kingdom)

    2011-07-15

    Triple-negative (ER-/PR-/HER2-) breast carcinomas (TNBC) are aggressive tumours with underexplored imaging features. This study investigates whether their vascular characteristics as assessed by dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI are distinct from the prognostically more favourable ER+/PR+/HER2- cancers. Patients with primary breast cancer underwent MRI before neoadjuvant chemotherapy and were identified as ER-/PR-/HER2- or ER+/PR+/HER2- from core biopsy specimens. MRI parameters reflecting tissue perfusion, permeability, and extracellular leakage space were measured. Values for inflow transfer constant (K{sup trans}), outflow rate constant (k{sub ep}), leakage space (v{sub e}), area under the gadolinium curve (IAUGC{sub 60}), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables. Thirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower v{sub e} (p = 0.001), shorter MTT (p = 0.007) and higher k{sub ep} values (p = 0.044) were observed in TNBC. v{sub e} was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). v{sub e} was the best predictor of triple negativity (ROC AUC 0.80). TNBC possess characteristic features on imaging, with lower extracellular space (higher cell density) and higher contrast agent wash-out rate (higher vascular permeability) suggesting a distinctive phenotype detectable by MRI. (orig.)

  17. Regulator of G protein signaling 20 correlates with clinicopathological features and prognosis in triple-negative breast cancer.

    Science.gov (United States)

    Li, Quan; Jin, Wenxu; Cai, Yefeng; Yang, Fang; Chen, Endong; Ye, Danrong; Wang, Qingxuan; Guan, Xiaoxiang

    2017-04-08

    Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Therefore, finding a novel molecular biomarker for TNBC to achieve target therapy and predict its prognosis is crucial in preventing inappropriate treatment. Regulator of G-protein signaling (RGS) families of protein can negatively regulate signaling of heterotrimeric G proteins and are known to be upregulated in various tumors. In this study, we demonstrated that RGS20 was more highly expressed in TNBC tumor tissue than in adjacent normal tissue by analyzing the cancer genome atlas (TCGA) database. However, RGS20 expression was low in all breast cancer and luminal breast cancer patients. Validated by the TCGA cohort, RGS20 was upregulated in lymph node-positive TNBC compared with that in lymph node-negative breast cancer. High expression of RGS20 had a risk of lymph node metastasis, ki-67 > 14%, poor N stage, and poor clinical stage in the immunohistochemistry of tissue microarrays. Moreover, K-M plot analysis showed that TNBC patients with high RGS20 expression had poor relapse-free survival. In summary, the findings revealed that RGS20 was a special TNBC oncogene that promoted tumor progression and influenced TNBC prognosis. This study is the first to show that RGS20 was a special oncogene, and its high expression was significantly associated with the progression and prognosis of TNBC. RGS20 may be a novel molecular biomarker for the targeted therapy and prognosis of TNBC.

  18. Distinct microbiological signatures associated with triple negative breast cancer.

    Science.gov (United States)

    Banerjee, Sagarika; Wei, Zhi; Tan, Fei; Peck, Kristen N; Shih, Natalie; Feldman, Michael; Rebbeck, Timothy R; Alwine, James C; Robertson, Erle S

    2015-10-15

    Infectious agents are the third highest human cancer risk factor and may have a greater role in the origin and/or progression of cancers, and related pathogenesis. Thus, knowing the specific viruses and microbial agents associated with a cancer type may provide insights into cause, diagnosis and treatment. We utilized a pan-pathogen array technology to identify the microbial signatures associated with triple negative breast cancer (TNBC). This technology detects low copy number and fragmented genomes extracted from formalin-fixed paraffin embedded archival tissues. The results, validated by PCR and sequencing, define a microbial signature present in TNBC tissue which was underrepresented in normal tissue. Hierarchical clustering analysis displayed two broad microbial signatures, one prevalent in bacteria and parasites and one prevalent in viruses. These signatures demonstrate a new paradigm in our understanding of the link between microorganisms and cancer, as causative or commensal in the tumor microenvironment and provide new diagnostic potential.

  19. Triple-negative breast cancer: treatment challenges and solutions

    Directory of Open Access Journals (Sweden)

    Collignon J

    2016-05-01

    Full Text Available Joëlle Collignon,1 Laurence Lousberg,1 Hélène Schroeder,1 Guy Jerusalem,1,21Medical Oncology Department, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium; 2University of Liege, Liege, Belgium Abstract: Triple-negative breast cancers (TNBCs are defined by the absence of estrogen and progesterone receptors and the absence of HER2 overexpression. These cancers represent a heterogeneous breast cancer subtype with a poor prognosis. Few systemic treatment options exist besides the use of chemotherapy (CT. The heterogeneity of the disease has limited the successful development of targeted therapy in unselected patient populations. Currently, there are no approved targeted therapies for TNBC. However, intense research is ongoing to identify specific targets and develop additional and better systemic treatment options. Standard adjuvant and neoadjuvant regimens include anthracyclines, cyclophosphamide, and taxanes. Platinum-based CT has been proposed as another CT option of interest in TNBC. We review the role of this therapy in general, and particularly in patients carrying BRCA germ-line mutations. Available data concerning the role of platinum-based CT in TNBC were acquired primarily in the neoadjuvant setting. The routine use of platinum-based CT is not yet recommended by available guidelines. Many studies have reported the molecular characterization of TNBCs. Several actionable targets have been identified. Novel therapeutic strategies are currently being tested in clinical trials based on promising results observed in preclinical studies. These targets include androgen receptor, EGFR, PARP, FGFR, and the angiogenic pathway. We review the recent data on experimental drugs in this field. We also discuss the recent data concerning immunologic checkpoint inhibitors. Keywords: triple-negative breast cancer, molecular subtype, platinum-based chemotherapy, targeted therapy, androgen receptor, BRCA1/2 mutation

  20. Triple-negative breast cancer: new perspectives for targeted therapies

    Directory of Open Access Journals (Sweden)

    Tomao F

    2015-01-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Eleonora Zaccarelli,2 Luigi Rossi,2 Davide Caruso,2 Marina Minozzi,2 Patrizia Vici,3 Luigi Frati,4 Silverio Tomao21Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, 3Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; 4Department of Molecular Medicine, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, ItalyAbstract: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.Keywords: basal-like breast cancer, estrogen–progesterone receptors, gene-expression microarray, human epidermal growth factor receptor 2, chemotherapy, target therapy

  1. Triple negative breast cancer: adjuvant chemotherapy effect on survival.

    Science.gov (United States)

    Steponaviciene, L; Lachej-Mikeroviene, N; Smailyte, G; Aleknavicius, E; Meskauskas, R; Didziapetriene, J

    2011-01-01

    The purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival. The study group consisted of 99 breast cancer patients with immunohistochemically confirmed triple negative breast cancer. The impact of various factors as well as the impact of different chemotherapy regimens on survival was evaluated. The overall survival of breast cancer patients was 97.0% (95% CI 90.9-99.0), 84.9% (95% CI 76.1-90.6) and 66.5% (95% CI 55.5-75.3) 10, 30 and 60 months after diagnosis, respectively. Univariate analysis demonstrated that the following were significant risk factors for breast cancer patients survival: patient's age, stage of disease, tumour size, lymph node status, type of surgery and chemotherapy. Better survival was related to younger patients' age, smaller tumour size, lower stage of disease, no lymph nodes involvement. Survival rates were higher among patients who received adjuvant chemotherapy and underwent quadrantectomy. In the multivariate statistical analysis the significant independent prognostic variables influencing survival were lymph node status and adjuvant chemotherapy. Survival rates of the patients, who received adjuvant anthracycline containing chemotherapy were higher, than those in non-anthracycline containing treatment group, but the difference was not statistically significant. Patients who had lymph node status N2-3 and those who did not receive adjuvant chemotherapy showed worse prognosis and survival than other patients. The impact of chemotherapy type (anthracycline containing or non-anthracycline containing) on patients survival was not statistically significant.

  2. Analysis of the Clinicopathologic Features and Prognosis in Triple-Negative Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Dehong Yang; Hong Liu; Jing Zhao

    2008-01-01

    OBJECTIVE To investigate the clinical and pathological features,as well as prognosis in triple-negative breast cancer patients.METHODS A total of 509 cases of operable breast cancer from January,2002 to June,2002 treated in the Cancer Hospital of Tianjin Medical University were analyzed.The Her-2,ER and PR status was determined using immunohistochemistry.Of the total cases,one group was identified as triple negative breast cancer,ie defined as ER,PR and Her-2 negative.The other group was nontriple-negative breast cancer.Clinicopathologic features of the groups were compared and 5-year disease-free survival (DFS)analyzed by the Kaplan-Meier method.RESULTS Of the total cases,21.4% (109/509) of cases were found to be triple- negative while 78.6% (400/509) were non-triplenegative.The triple negative group had higher incidence rates than the non-triple-negative group of the medullary type and Grade Ⅲ tumors (P < 0.05).There was no other difference in the clinicopathologic features between the 2 groups.From follow-up to June,2007,21.1% (23/109) of the triple-negative group and 12.7%(51/400) of the non-triple negative group had a local recurrence or distant metastasis,resulting in a significant difference (P < 0.05).In the triple-negative group and non-triple-negative group,5-year DFS were 78.9% and 87.3% respectively.There was a statistically significant difference between the 2 groups (P = 0.031).CONCLUSION Compared with non-triple-negative breast cancer,triple-negative breast cancer patients have an increased likehood of a local recurrence or distant metastasis and a poorer prognosis.

  3. Molecular characteristics and metastasis predictor genes of triple-negative breast cancer: a clinical study of triple-negative breast carcinomas.

    Directory of Open Access Journals (Sweden)

    Wen-Hung Kuo

    Full Text Available BACKGROUND: Triple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible. METHODOLOGY/PRINCIPAL FINDINGS: Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94% of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI 1.04-5.06, Cox P=0.04, outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-β signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer. CONCLUSIONS/SIGNIFICANCE: Gene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene

  4. Degree of tumor FDG uptake correlates with proliferation index in triple negative breast cancer.

    Science.gov (United States)

    Tchou, Julia; Sonnad, Seema S; Bergey, Meredith R; Basu, Sandip; Tomaszewski, John; Alavi, Abass; Schnall, Mitchell

    2010-12-01

    2-Deoxy-2-[F-18]fluoro-D-glucose (FDG) uptake may be a useful surrogate marker for proliferation index, but the correlation has not always been clear-cut. Previous research by our group suggests that FDG-positron emission tomography (PET) is sensitive in detecting triple negative breast cancer. We therefore performed a pilot study to test if FDG uptake correlated with proliferation index in women with triple negative cancer. To determine whether proliferation index correlates with metabolic uptake of FDG in women with triple negative breast cancer, we performed a retrospective analysis correlating %Ki67 nuclear stain with tumor maximum standardized uptake values (SUVmax) in a group of 41 women, 22 with triple negative and 19 with non-triple negative breast cancer. As expected, [18F]-PET imaging was significantly more sensitive in detecting triple negative breast cancer than non-triple negative breast cancer, 95.5% vs 68.4% (p = 0.036). In general, SUVmax and %Ki67 nuclear stain values rise as histologic grade worsens. Histologic grade of triple negative breast cancer was more often poorly differentiated than non-triple negative cancer (p = 0.001). SUVmax correlated with %Ki67 nuclear staining in our entire cohort (spearman correlation = 0.485, p = 0.002). Moreover, this significant correlation appeared to be driven primarily by a subset of women with triple negative cancer (spearman correlation = 0.497, p = 0.019). Degree of tumor FDG uptake correlated significantly with proliferation index in women with triple negative breast cancer suggesting a potential role of FDG-PET in treatment response monitoring for this group of women. Future studies are necessary to define the role of PET imaging as a non-invasive means to monitor breast cancer treatment response in the neoadjuvant setting.

  5. Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study

    NARCIS (Netherlands)

    Roozendaal, van Lori M.; Smit, Leonie H.M.; Duijsens, Gaston H.N.M.; Vries, de Bart; Siesling, Sabine; Lobbes, Marc B.I.; Boer, de Maaike; Wilt, de Johannes H.W.; Smidt, Marjolein L.

    2016-01-01

    Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancer

  6. New Therapeutic Strategies for Triple-Negative Breast Cancer.

    Science.gov (United States)

    Székely, Borbála; Silber, Andrea L M; Pusztai, Lajos

    2017-02-15

    Relatively few clinically important therapeutic advances have occurred in the treatment of triple-negative breast cancer (TNBC) since the introduction of taxanes as adjuvant therapy over 20 years ago. However, this is rapidly changing due to a variety of conceptually important clinical trials and emerging new options such as immune checkpoint inhibitors and antibody-drug conjugates. Evidence also increasingly supports that platinum drugs and inhibitors of poly (ADP-ribose) polymerase, or PARP, are particularly effective in the treatment of germline BRCA-mutant cancers, including TNBC. An important development in early-stage TNBC was the recognition that extensive residual cancer after neoadjuvant chemotherapy identifies patients who remain at high risk for recurrence. This has led to the design of two ongoing adjuvant trials (one testing pembrolizumab, the other investigating platinum drugs and capecitabine) that offer a "second chance" to improve the survival of patients with residual cancer after neoadjuvant chemotherapy. Genomic analysis of TNBC has revealed large-scale transcriptional, mutational, and copy number heterogeneity, without any frequently recurrent mutations, other than TP53. Consistent with this molecular heterogeneity, most targeted agents, so far, have demonstrated low overall activity in unselected TNBC, but important "basket" trials are ongoing.

  7. Basal-like and triple-negative breast cancers: searching for positives among many negatives.

    Science.gov (United States)

    Alluri, Prasanna; Newman, Lisa A

    2014-07-01

    Triple-negative breast cancers (TNBC) are defined by their failure to express the estrogen receptor, progesterone receptor, and HER2/neu protein markers. This basic feature is clinically relevant because it indicates that these cancers cannot be managed with endocrine or anti-HER2 systemic therapies. Furthermore, most TNBC cases are also characterized as being of the genetically defined basal subtype, which is an inherently and biologically more aggressive pattern of disease. The two terms, however, are not synonymous, and some TNBC cases are prognostically more favorable. TNBC differs from non-TNBC in risk-factor profile, pattern, and rate of metastatic spread.

  8. Differences in Multi-Modal Ultrasound Imaging between Triple Negative and Non-Triple Negative Breast Cancer.

    Science.gov (United States)

    Li, Ziyao; Tian, Jiawei; Wang, Xiaowei; Wang, Ying; Wang, Zhenzhen; Zhang, Lei; Jing, Hui; Wu, Tong

    2016-04-01

    The objective of this study was to identify multi-modal ultrasound imaging parameters that could potentially help to differentiate between triple negative breast cancer (TNBC) and non-TNBC. Conventional ultrasonography, ultrasound strain elastography and 3-D ultrasound (3-D-US) findings from 50 TNBC and 179 non-TNBC patients were retrospectively reviewed. Immunohistochemical examination was used as the reference gold standard for cancer subtyping. Different ultrasound modalities were initially analyzed to define TNBC-related features. Subsequently, logistic regression analysis was applied to TNBC-related features to establish models for predicting TNBC. TNBCs often presented as micro-lobulated, markedly hypo-echoic masses with an abrupt interface (p = 0.015, 0.0015 and 0.004, compared with non-TNBCs, respectively) on conventional ultrasound, and showed a diminished retraction pattern phenomenon in the coronal plane (p = 0.035) on 3-D-US. Our findings suggest that B-mode ultrasound and 3-D-US in multi-modality ultrasonography could be a useful non-invasive technique for differentiating TNBCs from non-TNBCs.

  9. Lymphatic and blood vessels in basal and triple-negative breast cancers: characteristics and prognostic significance.

    Science.gov (United States)

    Mohammed, Rabab A A; Ellis, Ian O; Mahmmod, Ali M; Hawkes, E Claire; Green, Andrew R; Rakha, Emad A; Martin, Stewart G

    2011-06-01

    Basal and triple-negative breast cancer phenotypes are characterised by unfavourable biological behaviour and outcome. Although certain studies have examined their pathological and molecular profile, the vascular characteristics of lymphatic and blood vessels have not been examined. Immunohistochemical staining with podoplanin, CD34 and CD31 was used to examine lymphatic and microvessel density, as well as vascular invasion in 197 basal-like and in 99 triple-negative breast tumours and compared against 200 non-basal and 334 non-triple-negative cases. All specimens were lymph node negative. Vascular invasion was identified as blood or lymphatic vascular invasion by the differential expression of markers. All measurements were correlated with clinicopathological features and prognosis. No significant difference was detected between the basal and triple-negative groups in terms of lymphatic or microvessel density or vascular invasion. However, both the basal and the triple-negative groups showed significantly higher microvessel density than did the non-basal and non-triple-negative groups (P=0.017 and Pcontrols. Interestingly, vascular invasion, almost entirely lymphatic invasion, was detected in 27% of the basal and in 26% of the triple-negative groups with no significant difference in comparison with control groups. In both basal and triple negatives, vascular invasion was associated with poorer survival by univariate and multivariate analyses. The 20-year overall survival rate in basal-like tumours was 55% in vascular invasion-positive cases compared with 73% in vascular invasion-negative tumours (P=0.012), and 46% in triple-negative vascular invasion-positive compared with 79% in vascular invasion-negative tumours (P=0.001). Basal-like vs non-basal-like and triple-negative vs non-triple-negative tumours have similar vascular characteristics in terms of lymphatic vessel density and vascular invasion but higher microvessel density, suggesting that such groups may

  10. A clinicopathologic study of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Vandana L Gaopande

    2015-01-01

    Full Text Available Background: Triple negative breast cancers (TNBC are defined by absence of estrogen and progesterone receptors (ER and PR and absence of overexpression of human epidermal growth factor receptor 2 (Her2. They are associated with poor prognosis. The purpose of this study is to study the clinicopathologic parameters of TNBC such as age, tumor size, stage, grade, and lymph node involvement and compare them with nonTNBC tumors. There are many studies which have shown that TNBC are similar to basal-like breast cancers (BBC. We have found the proportion of BBC in the TNBC group using surrogate immunohistochemical (IHC markers cytokeratin5 (CK5 and epidermal growth factor receptor (EGFR. Materials and Methods : This is a retrospective study of 102 cases of carcinoma breast. Clinical records of the cases were retrieved. Histopathology slides and the IHC slides (ER, PR, Her2 were reviewed. Thus, two groups of patients were made TNBC and nonTNBC. Using the software SPSS version 16 statistical significance of the difference between clinicopathologic variables of the two groups was calculated. TNBC group was later studied for the presence of basal markers CK5 and EGFR using tissue microarray. Results: Statistically significant difference was found between the two groups in the variables such as mean age at diagnosis, mean tumor size, tumor grade, and the presence of lymphovascular invasion. Conclusions: TNBC formed 23.5% of total cases. Overall, TNBC were high grade tumors with larger size at diagnosis, presenting in younger women and showing lymphovascular invasion in a higher number of cases. 87.5% of TNBC were BBC.

  11. Dipyridamole prevents triple-negative breast-cancer progression.

    Science.gov (United States)

    Spano, Daniela; Marshall, Jean-Claude; Marino, Natascia; De Martino, Daniela; Romano, Alessia; Scoppettuolo, Maria Nunzia; Bello, Anna Maria; Di Dato, Valeria; Navas, Luigi; De Vita, Gennaro; Medaglia, Chiara; Steeg, Patricia S; Zollo, Massimo

    2013-01-01

    Dipyridamole is a widely prescribed drug in ischemic disorders, and it is here investigated for potential clinical use as a new treatment for breast cancer. Xenograft mice bearing triple-negative breast cancer 4T1-Luc or MDA-MB-231T cells were generated. In these in vivo models, dipyridamole effects were investigated for primary tumor growth, metastasis formation, cell cycle, apoptosis, signaling pathways, immune cell infiltration, and serum inflammatory cytokines levels. Dipyridamole significantly reduced primary tumor growth and metastasis formation by intraperitoneal administration. Treatment with 15 mg/kg/day dipyridamole reduced mean primary tumor size by 67.5 % (p = 0.0433), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in primary tumors (p = 0.0182). Experimental metastasis assays show dipyridamole reduces metastasis formation by 47.5 % in the MDA-MB-231T xenograft model (p = 0.0122), and by 50.26 % in the 4T1-Luc xenograft model (p = 0.0292). In vivo dipyridamole decreased activated β-catenin by 38.64 % (p < 0.0001), phospho-ERK1/2 by 25.05 % (p = 0.0129), phospho-p65 by 67.82 % (p < 0.0001) and doubled the expression of IkBα (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. Moreover dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p < 0.005), and the inflammatory cytokines levels in the sera of the treated mice. We suggest that when used at appropriate doses and with the correct mode of administration, dipyridamole is a promising agent for breast-cancer treatment, thus also implying its potential use in other cancers that show those highly activated pathways.

  12. TMEPAI genome editing in triple negative breast cancer cells

    Directory of Open Access Journals (Sweden)

    Bantari W.K. Wardhani

    2017-05-01

    Full Text Available Background: Clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9 is a powerful genome editing technique. It consists of RNA-guided DNA endonuclease Cas9 and single guide RNA (gRNA. By combining their expressions, high efficiency cleavage of the target gene can be achieved, leading to the formation of DNA double-strand break (DSB at the genomic locus of interest which will be repaired via NHEJ (non-homologous end joining or HDR (homology-directed repair and mediate DNA alteration. We aimed to apply the CRISPR/Cas9 technique to knock-out the transmembrane prostate androgen-induced protein (TMEPAI gene in the triple negative breast cancer cell line.Methods: Designed gRNA which targets the TMEPAI gene was synthesized, annealed, and cloned into gRNA expression vector. It was co-transfected into the TNBC cell line using polyethylenimine (PEI together with Cas9-GFP and puromycin resistant gene vector. At 24-hours post-transfection, cells were selected by puromycin for 3 days before they were cloned. Selected knock-out clones were subsequently checked on their protein levels by western blotting.Results: CRISPR/Cas9, a genome engineering technique successfully knocked-out TMEPAI in the Hs578T TNBC cell line. Sequencing shows a frameshift mutation in TMEPAI. Western blot shows the absence of TMEPAI band on Hs578T KO cells.Conclusion: TMEPAI gene was deleted in the TNBC cell line using the genomic editing technique CRISPR/Cas9. The deletion was confirmed by genome and protein analysis.

  13. Epidermal Growth Factor Receptor Expression in Triple Negative and Nontriple Negative Breast Carcinomas.

    Science.gov (United States)

    Changavi, Arathi A; Shashikala, Arundhathi; Ramji, Ashwini S

    2015-01-01

    The panel of markers used for molecular classification include estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor (HER)-2/neu, p53, Bcl-2 and basal markers like cytokeratin 5/6 or epidermal growth factor receptor (EGFR). Among these, EGFR plays an important role and is associated with bad prognosis. To study EGFR expression in triple negative breast carcinoma (TNBC) and non-TNBCs (NTNBCs). Fifty cases of breast carcinomas were classified and graded according to World Health Organization and Nottingham modification of Scarff-Bloom-Richardson (SBR) system, respectively. The age of the patients ranged from 28 to 69 years. Histological features such as necrosis, pushing borders, lymphocytic infiltrate and periductal elastosis were noted. The panel of markers used in our study included ER, PR, HER-2/neu and EGFR. EGFR expression was assessed based on membrane staining. Chi-square test was applied for statistical analysis to compare EGFR expression with hormonal status and prognostic factors. P triple negative and strongly expressed EGFR. EGFR expression was inversely associated with ER status and showed strong association with necrosis and lymphocytic infiltrate, but not with pushing border and periductal elastosis. EGFR is an important marker to stratify patients with breast cancer according to molecular classification. Its expression correlated positively with young age, higher SBR grade, necrosis, lymphocytic infiltrate and inversely with hormonal receptor expression.

  14. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus

    DEFF Research Database (Denmark)

    Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M

    2012-01-01

    associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER......-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170...... and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence...

  15. Effect of body mass index on clinical and morphological characteristics of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    I. B. Schepotin

    2014-01-01

    Full Text Available Triple negative breast cancer phenotype characterized by a more aggressive than other molecular types of tumor. In addition to non-modifiable clinical and pathological factors of aggressiveness of triple negative breast cancer is caused by potentially modifiable lifestyle (obesity, alcohol consumption, hypodynamia etc.. In this study we investigated the relationship between body mass index at diagnosis, clinical and morphological outcome predictors, and the impact of obesity on overall and disease-free survival of patients with triple negative breast cancer.

  16. Transgelin: a potentially useful diagnostic marker differentially expressed in triple-negative and non-triple-negative breast cancers.

    Science.gov (United States)

    Rao, Deepthi; Kimler, Bruce F; Nothnick, Warren B; Davis, Marilyn K; Fan, Fang; Tawfik, Ossama

    2015-06-01

    Triple negative (TN) (estrogen receptor [ER], progesterone receptor [PR] and HER2-) are highly aggressive, rapidly growing, hormone-unresponsive tumors diagnosed at later stage that affect younger women with shorter overall survival. Most TN tumors are of the basal type. For the remainder, identification of target markers for effective treatment strategies remains a challenge. Transgelin (TGLN) is a 22-kd actin-binding protein of the calponin family. It is one of the earliest markers of smooth muscle differentiation. TGLN has been shown to have important biologic activities including regulating muscle fiber contractility, cell migration, and tumor suppression. We examined TGLN expression in the different molecular subtypes of breast cancer. TGLN expression was examined as a function of tumor size, grade, histologic type, lymph node status, patients' age and overall survival, ER, PR, HER2, and Ki-67 in 101 tumors that included 35 luminal A, 28 luminal B, 4 HER2, and 34 TN types. TGLN positivity (defined as 2+ or 3+) was associated with more aggressive tumors (10% of grade I/II tumors were TGLN+ versus 53% of grade III tumors; P < .001), high Ki-67 count, and low ER and PR expression (P < .001) but not with tumor size, age, or lymph node metastasis. TN (n = 34) tumors were 7.7 times more likely to be TGLN+ than non-TN (n = 67) tumors (77% versus 10%, respectively; P < .001). TGLN may be an excellent diagnostic marker of TN tumors and could be useful in stratification of patients. TGLN may also prove a potential target for future treatment strategies.

  17. Triple-negative breast cancer: epidemiological considerations and recommendations.

    Science.gov (United States)

    Boyle, P

    2012-08-01

    Breast cancer is a major problem for global public health. Breast Cancer is the most common incident form of cancer in women around the world. The incidence is increasing while mortality is declining in many high-income countries. The last decade has seen a revolution in the understanding of breast cancer, with new classifications proposed that have significant prognostic value and provide guides to treatment options. Breast cancers that demonstrate the absence of oestrogen receptor and progesterone receptor and no overexpression of human epidermal growth factor receptor 2 (HER2) are referred to as triple-negative breast cancer (TNBC). There is now evidence emerging from epidemiological studies regarding important characteristics of this group of tumours that carry a relatively poorer prognosis than the major breast cancer sub-types. From this review of available data and information, there are some consistent findings that emerge. Women with TNBC experience the peak risk of recurrence within 3 years of diagnosis, and the mortality rates appear to be increased for 5 years after diagnosis. TNBC represents 10%-20% of invasive breast cancers and has been associated with African-American race, deprivation status, younger age at diagnosis, more advanced disease stage, higher grade, high mitotic indices, family history of breast cancer and BRCA1 mutations. TNBC is regularly reported to be three times more common in women of African descent and in pre-menopausal women, and carries a poorer prognosis than other forms of breast cancer. Although prospects for prevention of non-hormone-dependent breast cancer are currently poor, it is still important to understand the aetiology of such tumours. There remains a great deal of work to be done to arrive at a comprehensive picture of the aetiology of breast cancer. Key recommendations are that there is a clear and urgent need to have more epidemiological studies of the breast cancer sub-types to integrate aetiological and

  18. Engineering Remotely Triggered Liposomes to Target Triple Negative Breast Cancer

    Science.gov (United States)

    Sneider, Alexandra; Jadia, Rahul; Piel, Brandon; VanDyke, Derek; Tsiros, Christopher; Rai, Prakash

    2017-01-01

    Triple Negative Breast Cancer (TNBC) continues to present a challenge in the clinic, as there is still no approved targeted therapy. TNBC is the worst sub-type of breast cancer in terms of prognosis and exhibits a deficiency in estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. One possible option for the treatment of TNBC is chemotherapy. The issue with many chemotherapy drugs is that their effectiveness is diminished due to poor water solubility, and the method of administration directly or with a co-solvent intravenously can lead to an increase in toxicity. The issues of drug solubility can be avoided by using liposomes as a drug delivery carrier. Liposomes are engineered, biological nanoconstructs that possess the ability to encapsulate both hydrophobic and hydrophilic drugs and have been clinically approved to treat cancer. Specific targeting of cancer cell receptors through the use of ligands conjugated to the surface of drug-loaded liposomes could lessen damage to normal, healthy tissue. This study focuses on polyethylene glycol (PEG)-coated, folate conjugated, benzoporphyrin derivative (BPD)-loaded liposomes for treatment via photodynamic therapy (PDT). The folate receptor is over expressed on TNBC cells so these liposomes are targeted for greater uptake into cancer cells. PDT involves remotely irradiating light at 690 nm to trigger BPD, a hydrophobic photosensitive drug, to form reactive oxygen species that cause tumor cell death. BPD also displays a fluorescence signal when excited by light making it possible to image the fluorescence prior to PDT and for theranostics. In this study, free BPD, non-targeted and folate-targeted PEGylated BPD-loaded liposomes were introduced to a metastatic breast cancer cell line (MDA-MB-231) in vitro. The liposomes were reproducibly synthesized and characterized for size, polydispersity index (PDI), zeta potential, stability, and BPD release kinetics. Folate competition tests, fluorescence

  19. BRCA1/2-negative hereditary triple-negative breast cancers exhibit BRCAness.

    Science.gov (United States)

    Domagala, Pawel; Hybiak, Jolanta; Cybulski, Cezary; Lubinski, Jan

    2017-04-01

    BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2-associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs.

  20. Identification of prognostic genes for recurrent risk prediction in triple negative breast cancer patients in Taiwan.

    Directory of Open Access Journals (Sweden)

    Lee H Chen

    Full Text Available Discrepancies in the prognosis of triple negative breast cancer exist between Caucasian and Asian populations. Yet, the gene signature of triple negative breast cancer specifically for Asians has not become available. Therefore, the purpose of this study is to construct a prediction model for recurrence of triple negative breast cancer in Taiwanese patients. Whole genome expression profiling of breast cancers from 185 patients in Taiwan from 1995 to 2008 was performed, and the results were compared to the previously published literature to detect differences between Asian and Western patients. Pathway analysis and Cox proportional hazard models were applied to construct a prediction model for the recurrence of triple negative breast cancer. Hierarchical cluster analysis showed that triple negative breast cancers from different races were in separate sub-clusters but grouped in a bigger cluster. Two pathways, cAMP-mediated signaling and ephrin receptor signaling, were significantly associated with the recurrence of triple negative breast cancer. After using stepwise model selection from the combination of the initial filtered genes, we developed a prediction model based on the genes SLC22A23, PRKAG3, DPEP3, MORC2, GRB7, and FAM43A. The model had 91.7% accuracy, 81.8% sensitivity, and 94.6% specificity under leave-one-out support vector regression. In this study, we identified pathways related to triple negative breast cancer and developed a model to predict its recurrence. These results could be used for assisting with clinical prognosis and warrant further investigation into the possibility of targeted therapy of triple negative breast cancer in Taiwanese patients.

  1. BRCA1 deficient Mouse Models to Study Pathogenesis and Therapy of Triple Negative Breast Cancer

    OpenAIRE

    Diaz-Cruz, Edgar S.; Cabrera, Marina C.; Nakles, Rebecca; Rutstein, Beth H.; Furth, Priscilla A

    2010-01-01

    Genetically engineered mice along with allograft and xenograft models can be used to effectively model triple negative breast cancer both for studies of pathophysiology as well as preclinical prevention and therapeutic drug studies. In this review eight distinct genetically engineered mouse models of BRCA1 deficiency are discussed in relationship to the generation of triple negative mammary cancer. Allograft models derived from some of these genetically engineered mice are considered and xeno...

  2. Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

    Science.gov (United States)

    2016-10-25

    Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer

  3. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer.

    Science.gov (United States)

    Huo, Dezheng; Ikpatt, Francis; Khramtsov, Andrey; Dangou, Jean-Marie; Nanda, Rita; Dignam, James; Zhang, Bifeng; Grushko, Tatyana; Zhang, Chunling; Oluwasola, Olayiwola; Malaka, David; Malami, Sani; Odetunde, Abayomi; Adeoye, Adewumi O; Iyare, Festus; Falusi, Adeyinka; Perou, Charles M; Olopade, Olufunmilayo I

    2009-09-20

    Compared with white women, black women experience a disproportionate burden of aggressive breast cancer for reasons that remain unknown and understudied. In the first study of its kind, we determined the distribution of molecular subtypes of invasive breast tumors in indigenous black women in West Africa. The study comprised 507 patients diagnosed with breast cancer between 1996 and 2007 at six geographic regions in Nigeria and Senegal. Formalin-fixed and paraffin-embedded sections were constructed into tissue microarrays and immunostained with 15 antibodies. Five molecular subtypes were determined, and hierarchical cluster analysis was conducted to explore subgroups for unclassified cases. The mean (+/- standard deviation) age of 378 patients in the first cohort was 44.8 +/- 11.8 years, with the majority of women presenting with large (4.4 +/- 2.0 cm) high-grade tumors (83%) in advanced stages (72% node positive). The proportions of estrogen receptor (ER) -positive, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2) -positive tumors were 24%, 20%, and 17%, respectively. Triple negativity for these markers was predominant, including basal-like (27%) and unclassified subtype (28%). Other subtypes were luminal A (27%), luminal B (2%), and HER2 positive/ER negative (15%). The findings were replicated in the second cohort of 129 patients. The unclassified cases could be grouped into a bad prognosis branch, with expression of vascular endothelial growth factor, B-cell lymphoma extra-large protein, and Cyclin E, and a good prognosis branch, with expression of B-cell lymphoma protein 2 and Cyclin D1. These findings underscore the urgent need for research into the etiology and treatment of the aggressive molecular subtypes that disproportionately affect young women in the African diaspora.

  4. Triple-negative breast cancer: correlation between imaging and pathological findings

    Energy Technology Data Exchange (ETDEWEB)

    Ko, Eun Sook; Lee, Byung Hee [Korea Cancer Centre Hospital, Department of Radiology, Seoul (Korea); Kim, Hyun-A; Noh, Woo-Chul [Korea Cancer Centre Hospital, Department of Surgery, Seoul (Korea); Kim, Min Suk [Korea Cancer Centre Hospital, Department of Pathology, Seoul (Korea); Lee, Sang-Ah [Kangwon National University, Department of Preventive Medicine, Kangwon-do (Korea)

    2010-05-15

    This study was designed to investigate the mammography and ultrasound findings of triple-negative breast cancer and to compare the results with characteristics of ER-positive/PR-negative/HER2-negative breast cancer and ER-negative/PR-negative/HER2-positive breast cancer. From January 2007 to October 2008, mammography and ultrasound findings of 245 patients with pathologically confirmed triple-negative (n = 87), ER-positive/PR-negative/HER2-negative (n = 93) or ER-negative/PR-negative/HER2-positive breast cancers (n = 65) were retrospectively reviewed. We also reviewed pathological reports for information on the histological type, histological grade and the status of the biological markers. Triple-negative breast cancers showed a high histological grade. On mammography, triple-negative breast cancers usually presented with a mass (43/87, 49%) or with focal asymmetry (19/87, 22%), and were less associated with calcifications. On ultrasound, the cancers were less frequently seen as non-mass lesions (12/87, 14%), more likely to have circumscribed margins (43/75, 57%), were markedly hypoechoic (36/75, 57%) and less likely to show posterior shadowing (4/75, 5%). Among the three types of breast cancers, ER-negative/PR-negative/HER2-positive breast cancers most commonly had associated calcifications (52/65, 79%) on mammography and were depicted as non-mass lesions (21/65, 32%) on ultrasound. Our results suggest that the imaging findings might be useful in diagnosing triple-negative breast cancer. (orig.)

  5. Triple-negative breast cancer: correlation between imaging and pathological findings.

    Science.gov (United States)

    Ko, Eun Sook; Lee, Byung Hee; Kim, Hyun-A; Noh, Woo-Chul; Kim, Min Suk; Lee, Sang-Ah

    2010-05-01

    This study was designed to investigate the mammography and ultrasound findings of triple-negative breast cancer and to compare the results with characteristics of ER-positive/PR-negative/HER2-negative breast cancer and ER-negative/PR-negative/HER2-positive breast cancer. From January 2007 to October 2008, mammography and ultrasound findings of 245 patients with pathologically confirmed triple-negative (n = 87), ER-positive/PR-negative/HER2-negative (n = 93) or ER-negative/PR-negative/HER2-positive breast cancers (n = 65) were retrospectively reviewed. We also reviewed pathological reports for information on the histological type, histological grade and the status of the biological markers. Triple-negative breast cancers showed a high histological grade. On mammography, triple-negative breast cancers usually presented with a mass (43/87, 49%) or with focal asymmetry (19/87, 22%), and were less associated with calcifications. On ultrasound, the cancers were less frequently seen as non-mass lesions (12/87, 14%), more likely to have circumscribed margins (43/75, 57%), were markedly hypoechoic (36/75, 57%) and less likely to show posterior shadowing (4/75, 5%). Among the three types of breast cancers, ER-negative/PR-negative/HER2-positive breast cancers most commonly had associated calcifications (52/65, 79%) on mammography and were depicted as non-mass lesions (21/65, 32%) on ultrasound. Our results suggest that the imaging findings might be useful in diagnosing triple-negative breast cancer.

  6. Targeted chemotherapy for triple-negative breast cancers via LHRH receptor.

    Science.gov (United States)

    Föst, Crispin; Duwe, Francesca; Hellriegel, Martin; Schweyer, Stefan; Emons, Günter; Gründker, Carsten

    2011-05-01

    Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to [D-Lys6]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors.Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.

  7. Identification of triple-negative and basal-like canine mammary carcinomas using four basal markers.

    Science.gov (United States)

    Kim, N H; Lim, H Y; Im, K S; Kim, J H; Sur, J-H

    2013-05-01

    Molecular-based classification of canine mammary carcinomas (CMCs) has been a recent research focus. In human breast cancer, triple-negative and basal-like phenotypes are distinct molecular subgroups that are known for their poor prognosis, but these tumours are not yet well defined in the dog. The aim of this study was to determine whether CMCs include triple-negative and basal-like phenotypes by immunohistochemical assessment of expression of the oestrogen receptor (OR), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and four basal markers, cytokeratin (CK) 14, CK5/6, p63 and the epidermal growth factor receptor (EGFR). In this study of 241 CMCs, 45 triple-negative tumours (OR(-), PR(-) and HER2(-)) were identified and this phenotype was associated with an unfavourable prognosis. In these tumours, the expression of CK14, CK5/6 and EGFR was related to clinicopathological parameters, while the expression of p63 was not relevant. The majority of the triple-negative tumours were of the basal-like phenotype, given that 75.6% of them expressed more than two basal markers. However, three of the basal markers were not uniformly expressed; therefore, the proportion of the basal-like phenotype was altered on the basis of the selection of the markers. Although both triple-negative and basal-like phenotypes are distinct entities in CMC, further study is needed to differentiate one from the other.

  8. ADAM-17: a novel therapeutic target for triple negative breast cancer.

    LENUS (Irish Health Repository)

    McGowan, P M

    2013-02-01

    Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR\\/HER family of receptors.

  9. Does a Negative Triple Test Reduce the Rate of Negative Appendectomy in Adults?

    Directory of Open Access Journals (Sweden)

    Mahmoud F. Sakr

    2012-08-01

    Results: Sixty-seven patients (65.9% were female and 35 (34.1% were male. Their ages ranged between 16 and 49 years (mean 27.5 years. Most patients (87.3% had their symptoms for 12-36 hours before hospital admission. The mean values for TLC, NP, and CRP were 7,573/ and micro;L, 54.53%, and 0.61 mg/L, respectively. Of the 102 patients with NTT, 101 (99% proved not to have appendiceal inflammation (NPV=99%. Only 39 patients were operated upon, of whom 38 (97.4% had a normal appendix, and the remaining 63 patients were either discharged (n=47 or referred to other specialties (n=16. There were significantly more women (76.3%, 29/38 with negative appendectomy than men (24.7%, 9/38 (X2= 21.1, p=0.0001. Gynecological causes were the most common (60.5%, 23/38 and in 11 cases, the exact etiology could not be identified. Conclusions: From the data presented, it may be concluded that TLC, NP and CRP blood levels (triple test should be measured upon hospital admission of adult patients with clinically suspected acute appendicitis. If used judiciously, they may spare the group of patients with an NTT an unnecessary surgical operation, hence markedly reducing the NAR with its potential risks. [Arch Clin Exp Surg 2012; 1(4.000: 229-236

  10. FPA-FTIR Microspectroscopy for Monitoring Chemotherapy Efficacy in Triple-Negative Breast Cancer

    Science.gov (United States)

    Zawlik, Izabela; Kaznowska, Ewa; Cebulski, Jozef; Kolodziej, Magdalena; Depciuch, Joanna; Vongsvivut, Jitraporn; Cholewa, Marian

    2016-11-01

    Triple-negative breast cancer is the most aggressive breast cancer subtype with limited treatment options and a poor prognosis. Approximately 70% of triple-negative breast cancer patients fail to achieve a pathologic complete response (pCR) after chemotherapy due to the lack of targeted therapies for this subtype. We report here the development of a focal-plane-array Fourier transform infrared (FPA-FTIR) microspectroscopic technique combined with principal component analysis (PCA) for monitoring chemotherapy effects in triple-negative breast cancer patients. The PCA results obtained using the FPA-FTIR spectral data collected from the same patients before and after the chemotherapy revealed discriminatory features that were consistent with the pathologic and clinical responses to chemotherapy, indicating the potential of the technique as a monitoring tool for observing chemotherapy efficacy.

  11. Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study.

    Science.gov (United States)

    van Roozendaal, Lori M; Smit, Leonie H M; Duijsens, Gaston H N M; de Vries, Bart; Siesling, Sabine; Lobbes, Marc B I; de Boer, Maaike; de Wilt, Johannes H W; Smidt, Marjolein L

    2016-04-01

    Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan-Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2-3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment.

  12. Molecular Basis of Triple Negative Breast Cancer and Implications for Therapy

    Directory of Open Access Journals (Sweden)

    Parvin F. Peddi

    2012-01-01

    Full Text Available Triple negative breast cancer is an aggressive form of breast cancer with limited treatment options and is without proven targeted therapy. Understanding the molecular basis of triple negative breast cancer is crucial for effective new drug development. Recent genomewide gene expression and DNA sequencing studies indicate that this cancer type is composed of a molecularly heterogeneous group of diseases that carry multiple somatic mutations and genomic structural changes. These findings have implications for therapeutic target identification and the design of future clinical trials for this aggressive group of breast cancer.

  13. Activation of mammalian target of rapamycin (mTOR) in triple negative feline mammary carcinomas

    OpenAIRE

    Maniscalco, Lorella; Millán, Yolanda; Iussich, Selina; Denina, Mauro; Sánchez-Céspedes, Raquel; Gattino, Francesca; Biolatti, Bartolomeo; SASAKI, Nobuo; Nakagawa, Takayuki; Di Renzo, Maria Flavia; de las Mulas, Juana Martín; De Maria, Raffaella

    2013-01-01

    Background Triple negative breast cancer (TNBC) in humans is defined by the absence of oestrogen receptor (ER), progesterone receptor (PR) and HER2 overexpression. Mammalian target of rapamycin (mTOR) is overexpressed in TNBC and it represents a potential target for the treatment of this aggressive tumour. Feline mammary carcinoma (FMC) is considered to be a model for hormone-independent human breast cancer. This study investigated mTOR and p-mTOR expression in FMC in relation to triple negat...

  14. Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Nicola Ferrari

    Full Text Available The RUNX1 transcription factor is widely recognised for its tumour suppressor effects in leukaemia. Recently a putative link to breast cancer has started to emerge, however the function of RUNX1 in breast cancer is still unknown. To investigate if RUNX1 expression was important to clinical outcome in primary breast tumours a tissue microarray (TMA containing biopsies from 483 patients with primary operable invasive ductal breast cancer was stained by immunohistochemistry. RUNX1 was associated with progesterone receptor (PR-positive tumours (P<0.05, more tumour CD4+(P<0.05 and CD8+(P<0.01 T-lymphocytic infiltrate, increased tumour CD138+plasma cell (P<0.01 and more CD68+macrophage infiltrate (P<0.001. RUNX1 expression did not influence outcome of oestrogen receptor (ER-positive or HER2-positive disease, however on univariate analysis a high RUNX1 protein was significantly associated with poorer cancer-specific survival in patients with ER-negative (P<0.05 and with triple negative (TN invasive breast cancer (P<0.05. Furthermore, multivariate Cox regression analysis of cancer-specific survival showed a trend towards significance in ER-negative patients (P<0.1 and was significant in triple negative patients (P<0.05. Of relevance, triple negative breast cancer currently lacks good biomarkers and patients with this subtype do not benefit from the option of targeted therapy unlike patients with ER-positive or HER2-positive disease. Using multivariate analysis RUNX1 was identified as an independent prognostic marker in the triple negative subgroup. Overall, our study identifies RUNX1 as a new prognostic indicator correlating with poor prognosis specifically in the triple negative subtype of human breast cancer.

  15. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2016-08-01

    visiting student of Tsinghua University High School Students 2013 Jennifer Han , UPCI Academy 2015 Jeewon Lee, UPCI Academy 2016 Kiera Regan, UPCI... Zimmer A, Schule R, Buettner R et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting...stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells. Cell Rep 2013; 5: 224–236. 21 Han X, Gui B, Xiong C, Zhao L, Liang J, Sun L et al

  16. Clinical correlates of 'BRCAness' in triple-negative breast cancer of patients receiving adjuvant chemotherapy

    NARCIS (Netherlands)

    Oonk, A.M.M.; Rijn, C. van; Smits, M.M.; Mulder, L.; Laddach, N.; Savola, S.P.; Wesseling, J.; Rodenhuis, S.; Imholz, A.L.; Lips, E.H.

    2012-01-01

    BACKGROUND: We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherap

  17. Prognostic role of adjuvant radiotherapy in triple-negative breast cancer : A historical cohort study

    NARCIS (Netherlands)

    Bhoo Pathy, Nirmala; Verkooijen, Helena M.; Wong, Fuh-Yong; Pignol, Jean-Philippe; Kwong, Ava; Tan, Ern-Yu; Taib, Nur Aishah; Nei, Wen-Long; Ho, Gwo-Fuang; Tan, Benita; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har; Dent, Rebecca

    2015-01-01

    The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N=1,138) were include

  18. The prognostic value of tumour-stroma ratio in triple-negative breast cancer

    NARCIS (Netherlands)

    Moorman, A.M.; Vink, R.; Heijmans, H.J.; Palen, van der J.A.M.; Kouwenhoven, E.A.

    2012-01-01

    Background Triple-negative cancer constitutes one of the most challenging groups of breast cancer given its aggressive clinical behaviour, poor outcome and lack of targeted therapy. Until now, profiling techniques have not been able to distinguish between patients with a good and poor outcome. Recen

  19. Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients

    NARCIS (Netherlands)

    Liu, N.Q.; Marchi, T. De; Timmermans, A.; Trapman-Jansen, A.M.; Foekens, R.; Look, M.P.; Smid, M.; Deurzen, C.H. van; Span, P.N.; Sweep, F.C.; Brask, J.B.; Timmermans-Wielenga, V.; Foekens, J.A.; Martens, J.W.M.; Umar, A.

    2016-01-01

    We have previously identified UMP-CMP kinase (CMPK1) as a prognostic marker for triple negative breast cancer (TNBC) by mass spectrometry (MS). In this study we evaluated CMPK1 association to prognosis in an independent set of samples by immunohistochemistry (IHC) and assessed biological pathways

  20. Prognostic role of adjuvant radiotherapy in triple-negative breast cancer : A historical cohort study

    NARCIS (Netherlands)

    Bhoo Pathy, Nirmala; Verkooijen, Helena M.; Wong, Fuh-Yong; Pignol, Jean-Philippe; Kwong, Ava; Tan, Ern-Yu; Taib, Nur Aishah; Nei, Wen-Long; Ho, Gwo-Fuang; Tan, Benita; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har; Dent, Rebecca

    2015-01-01

    The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N=1,138) were

  1. The Effect of Everolimus in an In Vitro Model of Triple Negative Breast Cancer and Osteoclasts

    Science.gov (United States)

    Mercatali, Laura; Spadazzi, Chiara; Miserocchi, Giacomo; Liverani, Chiara; De Vita, Alessandro; Bongiovanni, Alberto; Recine, Federica; Amadori, Dino; Ibrahim, Toni

    2016-01-01

    Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) on osteoclastogenesis induced by triple negative BC cells. To this aim, we developed an in vitro human model of osteoclastogenesis from peripheral blood monocytes co-cultured with the triple negative SCP2 and the hormonal receptor positive MCF7 cell lines. Osteoclastogenesis was evaluated by TRAP staining, evaluation of F actin rings and Calcitonin Receptor expression. Eve significantly reduced differentiation induced by cancer cells and resulted more effective when evaluated in combination with Denosumab and Zoledronic Acid (Zol). Combination with Zol showed a total abrogation of osteoclast differentiation induced by the triple negative cell line, not by MCF7. Finally, we observed that Eve was active in the inhibition of the crosstalk between cancer cells and osteoclasts reproduced by our model, highlighting a new therapeutic choice for the subsetting of triple negative BC patients. We observed a difference in the response to bone-targeted therapy with respect to BC subtypes. Our model may represent a valid platform for preclinical trials on bone-targeted drugs and for the study of the interplay of BC with bone stromal cells. PMID:27809291

  2. The Effect of Everolimus in an In Vitro Model of Triple Negative Breast Cancer and Osteoclasts.

    Science.gov (United States)

    Mercatali, Laura; Spadazzi, Chiara; Miserocchi, Giacomo; Liverani, Chiara; De Vita, Alessandro; Bongiovanni, Alberto; Recine, Federica; Amadori, Dino; Ibrahim, Toni

    2016-11-01

    Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) on osteoclastogenesis induced by triple negative BC cells. To this aim, we developed an in vitro human model of osteoclastogenesis from peripheral blood monocytes co-cultured with the triple negative SCP2 and the hormonal receptor positive MCF7 cell lines. Osteoclastogenesis was evaluated by TRAP staining, evaluation of F actin rings and Calcitonin Receptor expression. Eve significantly reduced differentiation induced by cancer cells and resulted more effective when evaluated in combination with Denosumab and Zoledronic Acid (Zol). Combination with Zol showed a total abrogation of osteoclast differentiation induced by the triple negative cell line, not by MCF7. Finally, we observed that Eve was active in the inhibition of the crosstalk between cancer cells and osteoclasts reproduced by our model, highlighting a new therapeutic choice for the subsetting of triple negative BC patients. We observed a difference in the response to bone-targeted therapy with respect to BC subtypes. Our model may represent a valid platform for preclinical trials on bone-targeted drugs and for the study of the interplay of BC with bone stromal cells.

  3. Clinical correlates of 'BRCAness' in triple-negative breast cancer of patients receiving adjuvant chemotherapy

    NARCIS (Netherlands)

    Oonk, A.M.M.; Rijn, C. van; Smits, M.M.; Mulder, L.; Laddach, N.; Savola, S.P.; Wesseling, J.; Rodenhuis, S.; Imholz, A.L.; Lips, E.H.

    2012-01-01

    BACKGROUND: We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose

  4. Configurational Information as Potentially Negative Entropy: The Triple Helix Model

    Directory of Open Access Journals (Sweden)

    Loet Leydesdorff

    2008-10-01

    Full Text Available Configurational information is generated when three or more sources of variance interact. The variations not only disturb each other relationally, but by selecting upon each other, they are also positioned in a configuration. A configuration can be stabilized and/or globalized. Different stabilizations can be considered as second-order variation, and globalization as a second-order selection. The positive manifestations and the negative selections operate upon one another by adding and reducing uncertainty, respectively. Reduction of uncertainty in a configuration can be measured in bits of information. The variables can also be considered as dimensions of the probabilistic entropy in the system(s under study. The configurational information then provides us with a measure of synergy within a complex system. For example, the knowledge base of an economy can be considered as such a synergy in the otherwise virtual (that is, fourth dimension of a regime

  5. Configurational Information as Potentially Negative Entropy: The Triple Helix Model

    Science.gov (United States)

    Leydesdorff, Loet

    2008-12-01

    Configurational information is generated when three or more sources of variance interact. The variations not only disturb each other relationally, but by selecting upon each other, they are also positioned in a configuration. A configuration can be stabilized and/or globalized. Different stabilizations can be considered as second-order variation, and globalization as a second-order selection. The positive manifestations and the negative selections operate upon one another by adding and reducing uncertainty, respectively. Reduction of uncertainty in a configuration can be measured in bits of information. The variables can also be considered as dimensions of the probabilistic entropy in the system(s) under study. The configurational information then provides us with a measure of synergy within a complex system. For example, the knowledge base of an economy can be considered as such a synergy in the otherwise virtual (that is, fourth) dimension of a regime

  6. Triple-negative breast cancer: are we making headway at least?

    Science.gov (United States)

    Arnedos, Monica; Bihan, Celine; Delaloge, Suzette; Andre, Fabrice

    2012-07-01

    The so-called triple-negative breast cancer, as defined by tumors that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression, has generated growing interest in recent years despite representing less than 20% of all breast cancers. These tumors constitute an important clinical challenge, as they do not respond to endocrine treatment and other targeted therapies. As a group they harbor an aggressive clinical phenotype with early development of visceral metastases and a poor long-term prognosis. While chemotherapy remains effective in triple-negative disease, research continues to further identify potential new targets based on phenotypical and molecular characteristics of these tumors. In this respect, the presence of a higher expression of different biomarkers including epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and Akt activation has led to a proliferation of clinical trials assessing the role of inhibitors to these pathways in triple-negative tumors. Moreover, the described overlap between triple-negative and basal-like tumors, and the similarities with tumors arising in the BRCA1 mutation carriers has offered potential therapeutic avenues for patients with these cancers including poly (ADP-ribose) polymerase inhibitors and a focus on a higher sensitivity to alkylating chemotherapy agents. Results from these trials have shown some benefit in small subgroups of patients, even in single-agent therapy, which reflects the heterogeneity of triple-negative breast cancer and highlights the need for a further subclassification of these types of tumors for better prognosis identification and treatment individualization.

  7. Triple negative breast carcinomas: similarities and differences with basal like carcinomas.

    Science.gov (United States)

    Lerma, Enrique; Barnadas, Agusti; Prat, Jaime

    2009-12-01

    The cDNA microarrays allows the classification of breast cancers into 6 groups: luminal A, luminal B, luminal C, normal breast-like, human epidermal growth factor receptor 2-positive, and basal-like. This latter is characterized by the expression of basal cytokeratins (CKs), and frequent negativity for hormone receptors and human epidermal growth factor receptor 2. There is a marked parallelism between triple negative breast carcinomas and basal-like carcinoma, but these are not equivalent terms. Estimated concordance is around 80%. CK5 seems to be the best marker for the identification of these tumors. Other good markers to identify these tumors are CK14, CK17, and epidermal growth factor receptor. A subset of triple negative breast carcinomas has myoepithelial differentiation, with positivities for smooth muscle actin, p63, S-100, and CD10 among others. Recent studies suggest that basal like carcinomas are originated from mammary stem cells.

  8. ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy

    Science.gov (United States)

    EL Baiomy, Mohamed Ali; El Kashef, Wagdi F

    2017-02-01

    Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxic chemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNA adducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatment options for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses or reduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expression would improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS, OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy. Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled. ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients received cisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34 patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expression was associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months; P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study further validated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancer patients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patients treated with platinum based chemotherapy.

  9. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    DeSai Damini

    2009-03-01

    Full Text Available Abstract Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2. The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE. All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%. Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

  10. GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.

    Science.gov (United States)

    Cimino-Mathews, Ashley; Subhawong, Andrea P; Illei, Peter B; Sharma, Rajni; Halushka, Marc K; Vang, Russell; Fetting, John H; Park, Ben Ho; Argani, Pedram

    2013-07-01

    GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all "luminal loss" metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

  11. In Vivo Uptake of Rare Earth Metals by Triple-Negative Breast Cancer Cells.

    Science.gov (United States)

    Roncati, Luca; Gatti, Antonietta Morena; Barbolini, Giuseppe; Piscioli, Francesco; Pusiol, Teresa; Maiorana, Antonio

    2017-02-09

    Rare earth metals (REM) are a group of 17 chemical elements in the periodic table, namely scandium (Sc), yttrium (Y) and the lanthanides. In relation to atomic volume and geological behavior, the lanthanides are further subdivided into light, medium and heavy REM. They find many applications in the technological field; however, their impact on the human health is still conflicting and, for many aspects, unknown. During a research program carried on 113 cases of female breast cancer, immunohistochemically categorized in Her2-positive (29 cases), Her2-negative (57 cases) and triple negative (27 cases), aimed to evaluate the role of environmental particulate in carcinogenesis by elemental microanalysis, for the first time in literature we have detected a REM uptake, in detail europium (Eu), dysprosium (Dy) and praseodymium (Pr), inside the neoplastic cells belonging to a single triple negative breast cancer. Curiously, the woman affected by this form of malignancy had worked in the ceramic industry, a well-known source of REM, during her life, and she was the one and only patient of our series to be dedicated to this activity. The medical repercussions of our findings are here discussed: in fact, a REM detection in only 1 of 113 examined cases seems to exclude active roles in breast carcinogenesis and discloses new possibilities for therapeutic developments in triple negative breast cancer.

  12. miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers.

    Science.gov (United States)

    Fkih M'hamed, Insaf; Privat, Maud; Trimeche, Mounir; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Kenani, Abderraouf

    2017-01-18

    MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR-153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR-146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM).

  13. 三阴乳腺癌的治疗%Therapy of triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    徐帅; 张喜平

    2012-01-01

    三阴乳腺癌具有自己独特的病理和分子生物学特性.目前对于三阴性乳腺癌的治疗指南并不完善,以化疗为主,而针对本类乳腺癌的靶向治疗正在深入研究中,将有助于提高疗效.%Triple negative breast cancer (TNBC) has its own exclusive pathological and molecular biological characteristic.At present,the treatment guidelines for triple negative breast cancer is not perfect,and the chemotherapy is the main method.A deeper insight into the targeted therapy of TNBC can improve the curative effect.

  14. Selective androgen receptor modulators (SARMs negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    Full Text Available The androgen receptor (AR is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC co-culture signaling studies were performed to understand the mechanisms of action.Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

  15. Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

    Science.gov (United States)

    Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

    2014-01-01

    The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

  16. Targeting Nuclear FGF Receptor to Improve Chemotherapy Response in Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-10-01

    in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma. Mol Cancer Res. 2013;11(12):1585–96. 12. Marek L, Ware KE, Fritzsche A...TK, Kleczko E, Singleton KR, Marek LA, Helfrich BA, et al. A mechanism of resistance to gefitinib mediated by cellular reprogramming and the...Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers after

  17. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Jinhua Xu

    Full Text Available Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs. Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.

  18. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.

    Science.gov (United States)

    Xu, Jinhua; Prosperi, Jenifer R; Choudhury, Noura; Olopade, Olufunmilayo I; Goss, Kathleen H

    2015-01-01

    Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.

  19. Five year retrospective survival analysis of triple negative breast cancer in North-West India

    Directory of Open Access Journals (Sweden)

    B Sharma

    2013-01-01

    Full Text Available Background: In our institute, about 10% of total cancer is female breast cancer. This analysis was performed to check triple negativity among these patients with their survival strength up to 5 years in relation to different age groups, stage and chemotherapy protocols. Materials and Methods: 208 immunohistochemistry proved triple negative breast cancer patients registered and treated until 2008 were retrospectively selected for the study. Overall survival up to 5 years was observed on the basis of stage, different age groups and chemotherapy regimens. All patients had undergone surgery, conventional external beam radiation therapy and adjuvant chemotherapy. The survival analyses were performed using the Kaplan-Meier method. Results: The majority of patients (41% were in the age group 21-30 years. Stage IV was seen in 18% of the patients at diagnosis and mainly in 21-40 years age group. Only 3% of females were >70 years age and were of Stage I and II. Overall 5 year survival in Stage I in Cyclophosphamide, Adriamycin/Epirubicin, 5-Flurouracil group was 37.5% as compared with Docetaxel/Paclitaxel, Epirubicin group 93% (P < 0.0001. Conclusion: Triple negativity in North-West India is about 11.8%. We observed it in younger patients mainly with highly aggressive behaviors. Taxane based chemotherapy gives better result as compared with anthracycline based regimens in all stages.

  20. Response of Triple Negative Breast Cancer to Neoadjuvant Chemotherapy: Correlation between Ki-67 Expression and Pathological Response.

    Science.gov (United States)

    Elnemr, Gamal M; El-Rashidy, Ahmed H; Osman, Ahmed H; Issa, Lotfi F; Abbas, Osama A; Al-Zahrani, Abdullah S; El-Seman, Sheriff M; Mohammed, Amrallah A; Hassan, Abdelghani A

    2016-01-01

    Triple-negative breast cancers constitute about 15% of all cases, but despite their higher response to neoadjuvant chemotherapy, the tumors are very aggressive and associated with a poor prognosis as well as a higher risk of early recurrence. This study was retrospectively performed on 101 patients with stage II and III invasive breast cancer who received 6-8 cycles of neo-adjuvant chemotherapy. Out of the total, 23 were in the triple negative breast cancer subgroup. Nuclear Ki-67 expression in both the large cohort group (n=101) and triple negative breast cancer subgroup (n=23) and its relation to the pathological response were evaluated. The purpose of the study was to identify the predictive value of nuclear protein Ki-67 expression among patients with invasive breast cancers, involving the triple negative breast cancer subgroup, treated with neoadjuvant chemotherapy in correlation to the rate of pathological complete response. The proliferation marker Ki-67 expression was highest in the triple negative breast cancer subgroup. No appreciable difference in the rate of Ki-67 expression in triple negative breast cancer subgroup using either a cutoff of 14% or 35%. Triple negative breast cancer subgroup showed lower rates of pathological complete response. Achievement of pathological complete response was significantly correlated with smaller tumor size and higher Ki-67 expression. The majority of triple negative breast cancer cases achieved pathological partial response. The study concluded that Ki-67 is a useful tool to predict chemosensitivity in the setting of neoadjuvant chemotherapy for invasive breast cancer but not for the triple negative breast cancer subgroup.

  1. Reduced risk of axillary lymphatic spread in triple-negative breast cancer

    DEFF Research Database (Denmark)

    Holm-Rasmussen, Emil Villiam; Jensen, Maj-Britt; Balslev, Eva

    2015-01-01

    involvement at diagnosis compared to a HER2-negative status (OR 1.37; 95 % CI 1.24-1.50; P negative patients (P triple-negative...... of tumor subtypes in ALN involvement. The risk of ALN metastases at the time of diagnosis was significantly reduced in HR-negative patients compared to HR-positive patients [adjusted odds ratio (OR) 0.69; 95 % CI 0.63-0.76; P = 0.0009]. A HER2-positive status was associated with an increased risk of ALN...... breast cancer (TNBC) patients showed a significantly reduced risk of ALN involvement at the time of diagnosis compared to patients with HR-positive/HER2-negative tumors (OR 0.55; 95 % CI 0.49-0.62; P

  2. Triple negative permeability band in plasmon-hybridized cut-wire-pair metamaterials

    Science.gov (United States)

    Thuy, V. T. T.; Viet, D. T.; Hieu, N. V.; Lee, Y. P.; Lam, V. D.; Tung, N. T.

    2010-11-01

    We expand the picture of plasmon hybridization in metamagnetic structure via numerically studying the electromagnetic coupling in the metallic cut-wire-pair super cells. It is shown that a triple negative permeability band can be achieved by systematically controlling the plasmon hybridization in such the structure. The corresponding transmission properties as well as the electromagnetic responses of the plasmon-hybridized structures were presented by using the finite integration technique simulations. Our results would reveal a promising design to obtain the multiple negative refractions based on the combination of hybridized cut-wire-pairs and continuous wires.

  3. Multi-epitope Folate Receptor Alpha Peptide Vaccine, Sargramostim, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer

    Science.gov (United States)

    2017-01-24

    Bilateral Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma; Unilateral Breast Carcinoma

  4. miR-103 regulates triple negative breast cancer cells migration and invasion through targeting olfactomedin 4.

    Science.gov (United States)

    Xiong, Bin; Lei, Xuefeng; Zhang, Lei; Fu, Jia

    2017-03-18

    Our previous study showed olfactomedin 4 (OLFM4) suppressed triple-negative breast cancer cells migration, invasion and metastasis-associated protein MMP 9 expression. OLFM4 was identified as a potential target of miR-103 according to microRNA target databases and published studies. The aim of this study is to validate the relationship between miR-103 and OLFM4, and explore the function and clinical significance of miR-103 in triple-negative breast cancer patients. In our results, miR-103 negatively regulated OLFM4 expression by directly targeting its 3'-UTR. OLFM4 was a functional target of miR-103 to regulate triple-negative breast cancer cells migration, invasion and MMP 9 expression. Moreover, miR-103 overexpression was observed in triple-negative breast cancer tissues and cell lines, and associated with lymph node metastasis, distant metastasis and clinical stage. Univariate and multivariate analyses suggested that miR-103 overexpression was a poor independent prognostic factor for triple-negative breast cancer patients. In conclusion, miR-103 acts as an oncogene miRNA to promote triple-negative breast cancer cells migration and invasion through targeting OLFM4.

  5. Hypermethylation of BRCA1 gene: implication for prognostic biomarker and therapeutic target in sporadic primary triple-negative breast cancer.

    Science.gov (United States)

    Zhu, X; Shan, L; Wang, F; Wang, J; Wang, F; Shen, G; Liu, X; Wang, B; Yuan, Y; Ying, J; Yang, H

    2015-04-01

    Paraffin sections from 239 cases of surgical resected mammary gland carcinomas were assessed to determine the role of BRCA1 gene methylation in sporadic triple-negative breast cancer and to evaluate the relationship between BRCA1 gene methylation and clinicopathologic features of triple-negative breast cancer in the National Cancer Center, China. Diagnostic tissues collected from patients received mastectomy in the National Cancer Center from January 1, 1999 to December 31, 2008 were reviewed. Tissue microarrays were constructed using 239 triple-negative breast cancer cases and stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor. Methylation status of the BRCA1 promoter was measured by methylation-specific PCR and analyzed against clinicopathologic characteristics, subtypes, and prognosis using standard statistical methods. Among the 239 triple-negative breast cancer cases, 137 (57.3 %) showed methylation of the BRCA1. According to the immunohistochemistry results, triple-negative breast cancer cases were classified into basal-like breast cancer (60.7 %) and non-basal-like breast cancer (39.3 %). The frequency of BRCA1 methylation was significantly higher in basal-like breast cancer subtype (71.7 %) than the non-basal subtype (35.1 %). Thus, BRCA1 methylation is statistically significantly correlated with basal-like breast cancer subtype (p triple-negative breast cancer. Here we demonstrated that epigenetic alteration of key tumor suppressor gene can be a promising biomarker for the prognosis of triple-negative breast cancer/basal-like breast cancer. Specifically our finding revealed that BRCA1 methylation is closely associated with a significant decrease in overall survival and disease-free survival, highlighting BRCA1 promoter methylation as promising and powerful biomarkers for effect and better prognosis of DNA damaging agents for triple-negative breast cancer

  6. Expression of dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype.

    Directory of Open Access Journals (Sweden)

    Wen-Huan Xu

    Full Text Available BACKGROUND AND AIM: We investigated the prognostic importance of dickkopf-1(DKK1 and beta-catenin expression in triple negative breast cancers. METHODS: The expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: The expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000. Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis. CONCLUSION: DKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer.

  7. Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

    2014-11-21

    Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

  8. Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer.

    LENUS (Irish Health Repository)

    Gonzalez-Angulo, Ana M

    2011-03-01

    To investigate the incidence of germline and somatic BRCA1\\/2 mutations in unselected patients with triple-negative breast cancer (TNBC) and determine the prognostic significance of carrying a mutation. Methods: DNA was obtained from 77 TNBC and normal tissues. BRCA1\\/2 exons\\/flanking regions were sequenced from tumor and patients classified as mutant or wild type (WT). Sequencing was repeated from normal tissue to identify germline and somatic mutations. Patient characteristics were compared with chi-square. Survival was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of mutation status with outcome.

  9. Targeting Nuclear FGF Receptor to Improve Chemotherapy Response in Triple-Negative Breast Cancer

    Science.gov (United States)

    2014-10-01

    FGFR3 activity, but not high FGFR1 or FGFR4 activity, in SUM159 triple-negative tumor cells. Based on these discoveries in grant year 1, we have...34 2000" 4000" 6000" 8000" 10000" 12000" 14000" 16000" 18000" 20000" FGFR1" FGFR3" FGFR4 " Nega0ve" !5000$ 0$ 5000$ 10000$ 15000$ 20000$ EG FR $/$ Er bB

  10. Concepts and targets in triple-negative breast cancer: recent results and clinical implications.

    Science.gov (United States)

    Saha, Poornima; Nanda, Rita

    2016-09-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC.

  11. Concepts and targets in triple-negative breast cancer: recent results and clinical implications

    Science.gov (United States)

    Saha, Poornima; Nanda, Rita

    2016-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC. PMID:27583027

  12. Modeling vitamin D actions in triple negative/basal-like breast cancer.

    Science.gov (United States)

    LaPorta, Erika; Welsh, JoEllen

    2014-10-01

    Breast cancer is a heterogeneous disease with six molecularly defined subtypes, the most aggressive of which are triple negative breast cancers that lack expression of estrogen receptor (ER) and progesterone receptor (PR) and do not exhibit amplification of the growth factor receptor HER2. Triple negative breast cancers often exhibit basal-like gene signatures and are enriched for CD44+ cancer stem cells. In this report we have characterized the molecular actions of the VDR in a model of triple negative breast cancer. Estrogen independent, invasive mammary tumor cell lines established from wild-type (WT) and VDR knockout (VDRKO) mice were used to demonstrate that VDR is necessary for 1,25-dihydroxyvitamin D3 (1,25D) mediated anti-cancer actions in vitro and to identify novel targets of this receptor. Western blotting confirmed differential VDR expression and demonstrated the lack of ER, PR and Her2 in these cell lines. Re-introduction of human VDR (hVDR) into VDRKO cells restored the anti-proliferative actions of 1,25D. Genomic profiling demonstrated that 1,25D failed to alter gene expression in KO240 cells whereas major changes were observed in WT145 cells and in KO clones stably expressing hVDR (KO(hVDR) cells). With a 2-fold cutoff, 117 transcripts in WT145 cells and 197 transcripts in the KO(hVDR) clones were significantly altered by 1,25D. Thirty-five genes were found to be commonly regulated by 1,25D in all VDR-positive cell lines. Of these, we identified a cohort of four genes (Plau, Hbegf, Postn, Has2) that are known to drive breast cancer invasion and metastasis whose expression was markedly down regulated by 1,25D. These data support a model whereby 1,25D coordinately suppresses multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells. Since studies have demonstrated a high prevalence of vitamin D deficiency in women with basal-like breast cancer, correction of vitamin D deficiency in these women represents a

  13. Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

    OpenAIRE

    Tao, Yajun; Mao, Jun; Zhang, Qingqing; Li, Lianhong

    2011-01-01

    The purpose of this study was to investigate the activation of Hedgehog (Hh) signaling molecules and its involvement in triple-negative breast cancer (TNBC). A total of 123 cases of paraffin blocks, including 83 cases of primary breast carcinoma, 30 cases of mammary hyperplasia and 10 cases of normal breast tissue, were immunohistochemically analyzed for Sonic Hedgehog (SHH), Patched-1 (PTCH1), Smoothened (SMO) and glioma-associated oncogene homoglog 1 (GLI1) expression. The expression of SMO...

  14. Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Ye J

    2016-08-01

    Full Text Available Jun Ye,1,2 Xuejun Xia,1,2 Wujun Dong,1,2 Huazhen Hao,1,2 Luhua Meng,1,2 Yanfang Yang,1,2 Renyun Wang,1,2 Yuanfeng Lyu,3 Yuling Liu1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 3School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: There is no effective clinical therapy for triple-negative breast cancers (TNBCs, which have high low-density lipoprotein (LDL requirements and express relatively high levels of LDL receptors (LDLRs on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231 and non-TNBC (MCF7 cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native

  15. Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer.

    Science.gov (United States)

    Recchia, Francesco; Candeloro, Giampiero; Cesta, Alisia; DI Staso, Mario; Bonfili, Pierluigi; Gravina, Giovanni Luca; DI Cesare, Ernesto; Necozione, Stefano; Rea, Silvio

    2014-05-01

    The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS.

  16. BRCA1-Associated Triple-Negative Breast Cancer and Potential Treatment for Ruthenium-Based Compounds.

    Science.gov (United States)

    Hongthong, Khwanjira; Ratanaphan, Adisorn

    2016-01-01

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). The clinicopathological characteristics of TNBC include a high grading, a high rate of cell proliferation and a greater degree of chromosomal rearrangement. Patients with triple-negative breast cancer are more likely to be drug resistant and more difficult to treat, and are also frequently BRCA1 mutants. Methylation of the BRCA1 promoter region is associated with a reduction of the BRCA1 mRNA level. TNBC patients with a methylated BRCA1 had a better disease-free survival compared with those with non-methylated BRCA1. From a therapeutic perspective, the expression level of BRCA1 has been a major determinant of the responses to different classes of chemotherapy. BRCA1-dysfunctional tumors are hypersensitive to DNA damaging chemotherapeutic agents like platinum drugs. Although platinum based drugs are currently widely used as conventional chemotherapeutic drugs in breast cancer chemotherapy, their use has several disadvantages. It is therefore of interest to seek out alternative therapeutic metal-based compounds that could overcome the limitations of these platinum based drugs. Ruthenium-based compounds could be the most promising alternative to the platinum drugs. This review highlights the use of BRCA1 as a predictive marker as well as for a potential drug target for anticancer ruthenium compounds.

  17. Targeting the androgen receptor in triple-negative breast cancer: current perspectives

    Directory of Open Access Journals (Sweden)

    Mina A

    2017-09-01

    Full Text Available Alain Mina,1 Rachel Yoder,2 Priyanka Sharma1 1Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Westwood, 2University of Kansas Cancer Center, Kansas City, KS, USA Abstract: Triple-negative breast cancer (TNBC is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition. Keywords: triple-negative breast cancer, androgen signaling, targeted therapy, biomarkers, prognosis 

  18. Robotic Mammosphere Assay for High-Throughput Screening in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Fitzpatrick, P A; Akrap, N; Söderberg, E M V; Harrison, H; Thomson, G J; Landberg, G

    2017-02-01

    In order to identify novel treatment principles specifically affecting cancer stem cells in triple-negative breast cancer, we have developed a high-throughput screening method based on the mammosphere and anoikis resistance assays allowing us to screen compounds using a functional readout. The assay was validated against manual protocols and through the use of positive controls, such as the response to hypoxia and treatment with the known cancer stem cell-targeting compound salinomycin. Manual and robotic procedures were compared and produced similar results in cell handling, cell cultures, and counting techniques, with no statistically significant difference produced from either method. The variance between samples processed manually versus robotically was no greater than 0.012, while Levene's test of significance was 0.2, indicating no significant difference between mammosphere data produced manually or robotically. Through the screening of 989 FDA-approved drugs and a follow-up screen assessing the antineoplastic subgroup, we have identified three therapeutic compounds with the ability to modulate the breast cancer stem cell fraction in the triple-negative breast cancer cell line MDA-MB-231, highlighting their potential usage as stem cell-specific adjuvant treatments.

  19. Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    R Joseph Bender

    Full Text Available Triple negative breast cancers (TNBC are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.

  20. Treatment outcome in patients with triple negative early stage breast cancers compared with other molecular subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ja Young; Chang, Sei Kyung; Lee, Bo Mi; Shin, Hyun Soo [Dept. of Radiation Oncology, CHA Bundang Medical Center, CHA University, Seongnam (Korea, Republic of); Park, Heily [Dept. of Radiation Oncology, Presbyterian Hospital, Jeonju (Korea, Republic of)

    2012-09-15

    To determine whether triple negative (TN) early stage breast cancers have poorer survival rates compared with other molecular types. Between August 2000 and July 2006, patients diagnosed with stage I, II early stage breast cancers, in whom all three markers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor [HER]-2) were available and treated with modified radical mastectomy or breast conserving surgery followed by radiotherapy, were retrospectively reviewed. Of 446 patients, 94 (21.1%) were classified as TN, 57 (12.8%) as HER-2 type, and 295 (66.1%) as luminal. TN was more frequently associated with young patients younger than 35 years old (p = 0.002), higher histologic grade (p < 0.0001), and nuclear (p < 0.0001). The median follow-up period was 78 months (range, 4 to 130 months). There were 9 local relapses (2.0%), 15 nodal (3.4%), 40 distant metastases (9.0%), and 33 deaths (7.4%) for all patients. The rates of 5-year OS, DFS, LFS, and DMFS for all patients were 95.5%, 89.9%, 95.4%, and 91.7%, respectively. There were no significant differences in OS, DFS, LFS, and DMFS between triple negative and other subtypes (p > 0.05). We found that patients with TN early stage breast cancers had no difference in survival rates compared with other molecular subtypes. Prospective study in homogeneous treatment group will need for a prognosis of TN early stage breast cancer.

  1. TNF-α Gene Knockout in Triple Negative Breast Cancer Cell Line Induces Apoptosis

    Directory of Open Access Journals (Sweden)

    Valentina Pileczki

    2012-12-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a pro-inflammatory cytokine involved in the promotion and progression of cancer, including triple negative breast cancer cells. Thus, there is significant interest in understanding the molecular signaling pathways that connect TNF-α with the survival of tumor cells. In our experiments, we used as an in vitro model for triple negative breast cancer the cell line Hs578T. The purpose of this study is to determine the gene expression profiling of apoptotic signaling networks after blocking TNF-α formation by using specially designed siRNA molecules to target TNF-α messenger RNA. Knockdown of TNF-α gene was associated with cell proliferation inhibition and apoptosis, as observed by monitoring the cell index using the xCELLigence RTCA System and flow cytometry. PCR array technology was used to examine the transcript levels of 84 genes involved in apoptosis. 15 genes were found to be relevant after comparing the treated group with the untreated one of which 3 were down-regulated and 12 up-regulated. The down-regulated genes are all involved in cell survival, whereas the up-regulated ones are involved in and interact with pro-apoptotic pathways. The results described here indicate that the direct target of TNF-α in the Hs578T breast cancer cell line increases the level of certain pro-apoptotic factors that modulate different cellular networks that direct the cells towards death.

  2. Kaiso depletion attenuates the growth and survival of triple negative breast cancer cells.

    Science.gov (United States)

    Bassey-Archibong, Blessing I; Rayner, Lyndsay G A; Hercules, Shawn M; Aarts, Craig W; Dvorkin-Gheva, Anna; Bramson, Jonathan L; Hassell, John A; Daniel, Juliet M

    2017-03-23

    Triple negative breast cancers (TNBC) are highly aggressive and lack specific targeted therapies. Recent studies have reported high expression of the transcription factor Kaiso in triple negative tumors, and this correlates with their increased aggressiveness. However, little is known about the clinical relevance of Kaiso in the growth and survival of TNBCs. Herein, we report that Kaiso depletion attenuates TNBC cell proliferation, and delays tumor onset in mice xenografted with the aggressive MDA-231 breast tumor cells. We further demonstrate that Kaiso depletion attenuates the survival of TNBC cells and increases their propensity for apoptotic-mediated cell death. Notably, Kaiso depletion downregulates BRCA1 expression in TNBC cells expressing mutant-p53 and we found that high Kaiso and BRCA1 expression correlates with a poor overall survival in breast cancer patients. Collectively, our findings reveal a role for Kaiso in the proliferation and survival of TNBC cells, and suggest a relevant role for Kaiso in the prognosis and treatment of TNBCs.

  3. HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Sandeep N Shah

    Full Text Available Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1 gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.

  4. [Non-metastatic triple-negative breast cancer in 2016: Definitions and management].

    Science.gov (United States)

    Portha, H; Jankowski, C; Cortet, M; Desmoulins, I; Martin, E; Lorgis, V; Arnould, L; Coutant, C

    2016-09-01

    Triple-negative breast cancer (TN), as defined by the triple negativity in immunohistochemistry: the absence of estrogen receptor, progesterone receptor and the absence of overexpression or amplification of HER2, corresponds to 15 % of invasive breast cancers. This is a very heterogeneous group of tumors both at the genomic and transcriptomic level and at morphological, clinical and prognostic level. Although there are some good prognosis forms, the majority of TN tumors is characterized by a poor prognosis with a greater frequency of visceral metastases and a maximum risk of relapse in the first two years after diagnosis. Systemic adjuvant treatment with chemotherapy is almost always indicated. The surgical treatment and radiotherapy treatment should be comparable to the other subtypes and obey the same rules of oncologic surgery. TN tumors are not associated with a higher risk of locoregional relapse after conservative treatment and adjuvant radiotherapy. Optimization of systemic therapies is currently and for the last decade a challenge. A number of targeted therapies and efficiency biomarkers identification of these targeted therapies is essential to allow significant progress in optimizing systemic therapy for these tumors.

  5. Cisplatin With or Without Veliparib in Treating Patients With Stage IV Triple-Negative and/or BRCA Mutation-Associated Breast Cancer

    Science.gov (United States)

    2017-03-14

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  6. Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097, Paclitaxel, and Carboplatin Before Surgery in Treating Patients With Stage II or Stage III Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-09-03

    Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

  7. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.

    Science.gov (United States)

    Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Geyer, Felipe C; De Filippo, Maria R; Eberle, Carey A; Akram, Muzaffar; Fusco, Nicola; Ichihara, Shu; Sakr, Rita A; Yatabe, Yasushi; Vincent-Salomon, Anne; Rakha, Emad A; Ellis, Ian O; Wen, Y Hannah; Weigelt, Britta; Schnitt, Stuart J; Reis-Filho, Jorge S

    2016-04-01

    Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute

  8. Neoadjuvant Therapy in Operable Breast Cancer: Application to Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Foluso O. Ademuyiwa

    2013-01-01

    Full Text Available Systemic treatment for triple negative breast cancer (TNBC: negative for the expression of estrogen receptor and progesterone receptor and HER2 amplification has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today’s standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed.

  9. "Targeting" triple-negative breast cancer: the lessons learned from BRCA1-associated breast cancers.

    Science.gov (United States)

    Nanda, Rita

    2011-04-01

    Breast cancer has long been recognized as a heterogeneous entity, with distinct subsets characterized by differences in tumor biology and response to therapy. With the advent of molecular profiling, we have gained a further appreciation of the heterogeneity of this complex disease. While the last decade has seen advances in the treatment of hormone receptor (HR) and human epidermal growth factor receptor 2/erb-B2 (HER2)-positive breast cancers, outcomes for women with estrogen receptor (ER)-, progesterone receptor (PR)-, and HER2-negative-or "triple-negative"-breast cancer (TNBC) remain poor. A better understanding of the shared biology of BRCA1-associated breast cancer and sporadic TNBC holds much promise for changing the outlook for women with this aggressive disease. This review focuses on our current understanding of the clinicopathological features of TNBC, therapeutic options and ongoing research efforts.

  10. Approach to the Triple Negative Breast Cancer in New Drugs Area.

    Science.gov (United States)

    Mirzania, Mehrzad

    2016-04-01

    Triple negative breast cancers (TNBCs) are associated with aggressive course, higher rates of visceral and central nervous system metastases and lower survival rate than hormone receptor positive. Once metastasis has occurred, a median survival was approximately one year. Currently, chemotherapy in TNBC is similar to other HER2- negative breast cancers but in the near future, it will revolutionize. TNBCs are quite heterogeneous based on biomarkers and genetic variations. The series of new drugs have been tried; in this article, platinum, anti-epigenetic drugs, PARP inhibitors, epidermal growth factor receptor inhibitor, Src family kinase inhibitor, anti androgen, glycoprotein Non-metastatic melanoma B (gpNMB) antibody, LHRH conjugated to cytotoxic drugs and inhibition of the PI3K/AKT/mTOR pathway will be explained. What is the optimal therapy for TNBC patients? It is still not clear but it seems that the road map according to biological and genetic markers is taking shape.

  11. Negative Expression of Melanoma Cell Adhesion Molecule (MCAM Correlated with Axillary Lymph Node Metastasis in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sartika Nurwenda

    2016-09-01

    Full Text Available Triple negative breast cancer (TNBC is breast cancer that demonstrate the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. TNBC has an aggressive behaviour, high frequency of metastasis to the axillary lymph nodes and recurrence, and poor prognosis. Metastasis to the axillary lymph nodes will affect the rate of survival and recurrence in TNBC. Melanoma cell adhession molecule (MCAM is a membrane glycoprotein of the immunoglobulin superfamily, which is involved in the cells binding, which later became known as the marker for the progression and metastasis of melanoma and carcinoma of the prostate. However, MCAM role in mammary carcinoma still controversial. The aim of this study was to assess correlation between MCAM expression with incidence of metastatic to axillary lymph nodes in TNBC. This research was conducted during January 1st 2010–April 31st 2015 at Pathology Anatomy, Faculty of Medicine, Universitas Padjadjaran. This study used a cross-sectional design, using lambda correlation test. MCAM immunohistochemical staining performed on 56 samples of paraffin blocks of TNBC group that did not metastasized and has metastasized to the axillary lymph nodes. A total of 22 of 28 (78.6% of TNBC metastatic to axillary lymph nodes have histoskor MCAM value <4 (negative, whereas 16 of 28 (57.1% of TNBC non-metastatic have histoskor value ≥ 4 (positive. Negative expression of MCAM correlated with TNBC that had metastasized to axillary lymph nodes, although not the only factor that influenced them.

  12. Triple-negative (ER, PgR, HER-2/neu breast cancer in Indian women

    Directory of Open Access Journals (Sweden)

    Vinayak W Patil

    2011-03-01

    Full Text Available Vinayak W Patil1, Rajeev Singhai1, Amit V Patil2, Prakash D Gurav21Department of Biochemistry, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India; 2Department of Surgery, Government Medical College, Miraj, IndiaAbstract: The aim of our study was to analyze triple-negative (TN breast cancer, which is defined as being negative for the estrogen receptor (ER, the progesterone receptor (PgR, and the human epidermal growth factor receptor 2 (HER-2/neu and which represents a subset of breast cancer with different biologic behavior. We investigated the clinicopathological characteristics and prognostic indicators of lymph node-negative TN breast cancer. Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India, from May 2007 to October 2010. Clinicopathological variables and clinical outcomes were evaluated. Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (<35 years, P = 0.003 and a higher histopathologic and nuclear grade (P < 0.001. It also correlated with a molecular profile associated with biological aggressiveness: negative for Bcl-2 expression (P < 0.001, positive for the epidermal growth factor receptor (P = 0.003, and a high level of p53 (P < 0.001 and Ki-67 expression (P < 0.00. The relapse rates during the follow-up period (median 56.8 months were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (P = 0.004. Relapse-free survival (RFS was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer: 3.5-year RFS rate 85.5% versus 94.2%, respectively; P = 0.001. On multivariate analysis, young age, close resection margin, and triple negativity were independent predictors of shorter RFS. TN breast cancer had a higher relapse rate and more aggressive clinicopathological

  13. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth

    Science.gov (United States)

    Rane, Chetan; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Crochiere, Marsha; Das-Gupta, Soumyasri; Minden, Audrey

    2017-01-01

    Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. PMID:28198380

  14. The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer.

    Science.gov (United States)

    Villarreal-Garza, C; Weitzel, J N; Llacuachaqui, M; Sifuentes, E; Magallanes-Hoyos, M C; Gallardo, L; Alvarez-Gómez, R M; Herzog, J; Castillo, D; Royer, R; Akbari, Mohammad; Lara-Medina, F; Herrera, L A; Mohar, A; Narod, S A

    2015-04-01

    Various guidelines recommend that women with triple-negative breast cancer should be tested for BRCA1 mutations, but the prevalence of mutations may vary with ethnic group and with geographic region, and the optimal cutoff age for testing has not been established. We estimated the frequencies of BRCA1 and BRCA2 (BRCA) mutations among 190 women with triple-negative breast cancer, unselected for family history, diagnosed at age 50 or less at a single hospital in Mexico City. Patients were screened for 115 recurrent BRCA mutations, which have been reported previously in women of Hispanic origin, including a common large rearrangement Mexican founder mutation (BRCA1 ex9-12del). A BRCA mutation was detected in 44 of 190 patients with triple-negative breast cancer (23 %). Forty-three mutations were found in BRCA1 and one mutation was found in BRCA2. Seven different mutations accounted for 39 patients (89 % of the total mutations). The Mexican founder mutation (BRCA1 ex9-12del) was found 18 times and accounted for 41 % of all mutations detected. There is a high prevalence of BRCA1 mutations among young triple-negative breast cancer patients in Mexico. Women with triple-negative breast cancer in Mexico should be screened for mutations in BRCA1.

  15. Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Rajeshwari Mehta

    Full Text Available BACKGROUND: Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines. METHODS/FINDINGS: In vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight, when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin. CONCLUSION/SIGNIFICANCE: These results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.

  16. Targeting Metabolic Remodeling in Triple Negative Breast Cancer in a Murine Model

    Science.gov (United States)

    García-Castillo, Verónica; López-Urrutia, Eduardo; Villanueva-Sánchez, Octavio; Ávila-Rodríguez, Miguel Á.; Zentella-Dehesa, Alejandro; Cortés-González, Carlo; López-Camarillo, César; Jacobo-Herrera, Nadia J; Pérez-Plasencia, Carlos

    2017-01-01

    Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis. Materials and Methods: Thirty-five female nude mice were transplanted subcutaneously with MDA-MB-231 triple negative human cancer cell line. Once tumors were visible, mice were treated with doxorubicin, metformin, oxamate or all possible pharmacologic combinations. Treatments were administered daily for 15 days and tumors were measured by calipers every day. MicroPET images were taken in three different occasions, basal state, in the middle of the treatment, and at the end of treatment. Western blot analyses, qRT-PCR, flow cytometry, and cytotoxicity assays were performed to elucidate the mechanism of cell death promoted by the drugs in vitro. Results: In this work we assessed the proof of concept of metabolic correction in solid tumors as an effective drug treatment; hence, mice bearing tumors treated with the DoxMetOx therapy showed a complete inhibition of the tumor mass growing in 15 days of treatment depicted by the micro PET images. In vitro studies displayed that the three drugs together act by inhibiting both, mTOR-phosphorylation and expression of LDH-A gene, promoting apoptosis via dependent on the caspase-3 pathway, accompanied by cleavage of PARP. Moreover, induction of autophagy process was observed by the accumulation of LC3-II, a primordial protein implicated in the conformation and elongation of the autophagolysosome. Conclusions: The lack of

  17. Treatment for triple-negative breast cancer%三阴乳腺癌治疗研究进展

    Institute of Scientific and Technical Information of China (English)

    Xuebing Shi; Lu Wang

    2012-01-01

    Triple-negative breast cancers (TNBCs) neither express estrogen receptor and progesterone receptor nor overexpress human epidermal growth factor receptor-2. Because of the special molecular features, triple-negative breast cancer is not either sensitive to endocrine therapy or targeted therapy of trastuzumab. There has not been standard treatment regimen for triple-negative breast cancer yet and chemotherapy has still been the chief therapy currently. However, with the great progress of oncology and molecular biology, the understanding of the natural history, pathophysiology and molecular features of this disease has been greatly improved, and a growing number of novel and effective therapies and discoveries of new biological targets for this phenotype of breast cancers have been reported, which provide new insights into therapeutic strategies for the women suffering from it.

  18. Immunohistochemical Expression of B Cell Lymphoma2 with Clinicopathological Correlation in Triple Negative Breast Cancers in Northern Pakistan.

    Science.gov (United States)

    Zubair, Muhammad; Hashmi, Shoaib Naiyar; Afzal, Saeed; Muhammad, Iqbal; Din, Hafeez Ud; Ahmed, Rabia

    2016-01-01

    Triple negative breast cancers (TNBCs) are high grade aggressive tumors generally with a poor prognosis, not responding to hormonal and anti Her2 Neu therapy. Expression of the antiapoptotic B cell lymphoma 2 gene (Bcl2) is associated with low grade, slowly proliferating hormone receptor positive tumors with improved survival. Anti Bcl2 agents can be used as alternative targeted therapy in triple negative cancers. The objective of this study was to determine the immunohistochemical expression of Bcl2 in triple negative breast cancers and any correlation with clinicopathological variables in Northern Pakistan. All 52 patients were females, aged between 28 and 80 years(average 48.0±12.1). 28 cases (53.8%) were positive for Bcl2, this being associated with low grade invasive ductal carcinomas, lymph node metastasis and lymphovascular invasion. Bcl2 may be an important prognostic factor and its expression might be used for targeted therapy using Anti Bcl2 drugs.

  19. Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy.

    Science.gov (United States)

    Feng, Tingting; Cao, Wei; Shen, Wanxiang; Zhang, Liang; Gu, Xinsheng; Guo, Yang; Tsai, Hsiang-I; Liu, Xuewen; Li, Jian; Zhang, Jingxuan; Li, Shan; Wu, Fuyun; Liu, Ying

    2017-01-03

    Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors.

  20. Triple Negative Breast Cancers Have a Reduced Expression of DNA Repair Genes

    Science.gov (United States)

    Andreis, Daniele; Bertoni, Ramona; Giardini, Roberto; Fox, Stephen B.; Broggini, Massimo; Bottini, Alberto; Zanoni, Vanessa; Bazzola, Letizia; Foroni, Chiara; Generali, Daniele; Damia, Giovanna

    2013-01-01

    DNA repair is a key determinant in the cellular response to therapy and tumor repair status could play an important role in tailoring patient therapy. Our goal was to evaluate the mRNA of 13 genes involved in different DNA repair pathways (base excision, nucleotide excision, homologous recombination, and Fanconi anemia) in paraffin embedded samples of triple negative breast cancer (TNBC) compared to luminal A breast cancer (LABC). Most of the genes involved in nucleotide excision repair and Fanconi Anemia pathways, and CHK1 gene were significantly less expressed in TNBC than in LABC. PARP1 levels were higher in TNBC than in LABC. In univariate analysis high level of FANCA correlated with an increased overall survival and event free survival in TNBC; however multivariate analyses using Cox regression did not confirm FANCA as independent prognostic factor. These data support the evidence that TNBCs compared to LABCs harbour DNA repair defects. PMID:23825533

  1. A biomimetic collagen derived peptide exhibits anti-angiogenic activity in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Elena V Rosca

    Full Text Available We investigated the application of a mimetic 20 amino acid peptide derived from type IV collagen for treatment of breast cancer. We showed that the peptide induced a decrease of proliferation, adhesion, and migration of endothelial and tumor cells in vitro. We also observed an inhibition of triple negative MDA-MB-231 xenograft growth by 75% relative to control when administered intraperitoneally for 27 days at 10 mg/kg. We monitored in vivo the changes in vascular properties throughout the treatment using MRI and found that the vascular volume and permeability surface area product decreased significantly. The treatment also resulted in an increase of caspase-3 activity and in a reduction of microvascular density. The multiple mode of action of this peptide, i.e., anti-angiogenic, and anti-tumorigenic, makes it a viable candidate as a therapeutic agent as a monotherapy or in combination with other compounds.

  2. Aurora A kinase activates YAP signaling in triple-negative breast cancer.

    Science.gov (United States)

    Chang, S-S; Yamaguchi, H; Xia, W; Lim, S-O; Khotskaya, Y; Wu, Y; Chang, W-C; Liu, Q; Hung, M-C

    2017-03-02

    The Yes-associated protein (YAP) is an effector that transduces the output of the Hippo pathway to transcriptional modulation. Considering the role of YAP in cancers, this protein has emerged as a key node in malignancy development. In this study, we determined that Aurora A kinase acts as a positive regulator for YAP-mediated transcriptional machinery. Specifically, YAP associates with Aurora A predominantly in the nucleus. Activation of Aurora A can impinge on YAP activity through direct phosphorylation. Moreover, aberrant expression of YAP and Aurora A signaling is highly correlated with triple-negative breast cancer (TNBC). We herein provide evidence to establish the functional relevance of this newly discovered regulatory axis in TNBC.

  3. Treatment of triple negative breast cancer%三阴乳腺癌的治疗

    Institute of Scientific and Technical Information of China (English)

    梁金屏; 张喜平

    2013-01-01

    Triple negative breast cancer (TNBC) is a special type of breast cancer.Its special clinical pathological characteristic and molecule expression type make the treatment of TNBC become an international problem.In recent years,a variety of attempts and explorations to the treatment of TNBC have made some initial results,which provides a direction for the treatment of TNBC and offers hope for the patients with TNBC.%三阴乳腺癌(TNBC)是乳腺癌中的一个特殊类型,其特殊的临床病理特征及分子表达类型使TNBC的治疗成为国际难题.近年来,研究者对TNBC的治疗进行的各种尝试及探索已初具成效,这为TNBC的治疗提供了方向,也为TNBC患者提供了希望.

  4. Adenosine Stimulate Proliferation and Migration in Triple Negative Breast Cancer Cells

    Science.gov (United States)

    Fernandez-Gallardo, Miriam; González-Ramírez, Ricardo; Sandoval, Alejandro; Monjaraz, Eduardo

    2016-01-01

    Emerging evidence suggests that the adenosine (Ado) receptors may play crucial roles in tumor progression. Here, we show that Ado increases proliferation and migration in a triple negative breast cancer model, the MDA-MB 231 cell line. The use of specific agonists and antagonists evidenced that these effects depend on the activation of the A2B receptor, which then triggers an intracellular response mediated by the adenylate cyclase/PKA/cAMP signaling pathway. Ado also increases the expression of NaV1.5 channels, a potential biomarker in breast cancer. Together, these data suggest important roles of the A2B receptors and NaV1.5 channels in the Ado-induced increase in proliferation and migration of the MDA-MB 231 cells. PMID:27911956

  5. Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer

    Science.gov (United States)

    Lawrence, Cortney L.; Baldwin, Albert S.

    2016-01-01

    Enhancer of zeste homology 2 (EZH2) is the methyltransferase component of the polycomb repressive complex (PRC2) which represses gene transcription via histone H3 trimethylation at lysine 23 (H3K27me3). EZH2 activity has been linked with oncogenesis where it is thought to block expression of certain tumor suppressors. Relative to a role in cancer, EZH2 functions to promote self-renewal and has been shown to be important for the tumor-initiating cell (TIC) phenotype in breast cancer. Recently a non-canonical role for EZH2 has been identified where it promotes transcriptional activation of certain genes. Here we show that EZH2, through a methyltransferase-independent mechanism, promotes the transcriptional activation of the non-canonical NF-κB subunit RelB to drive self-renewal and the TIC phenotype of triple-negative breast cancer cells. PMID:27764181

  6. Downregulation of androgen receptor is strongly associated with diabetes in triple negative breast cancer patients

    Science.gov (United States)

    Collina, Francesca; Cerrone, Margherita; Peluso, Valentina; Laurentiis, Michelino De; Caputo, Roberta; Cecio, Rossella De; Liguori, Giuseppina; Botti, Gerardo; Cantile, Monica; Bonito, Maurizio Di

    2016-01-01

    Developing of personalized therapies for Triple Negative Breast Cancer (TNBC) requires a more detailed knowledge of its biology and a correct stratification of molecular subtypes. Androgen Receptor (AR) is expressed in a large part of TNBCs but its prognostic role in this Breast Cancer (BC) subtype is highly debated. In this study, we analyzed AR expression in a series of 238 TNBCs and correlated its expression with clinical-pathological features, survival, and metabolic profile. We showed a consistent association between AR expression and a better prognosis of TNBC patients, while its downregulation appeared strongly associated with diabetic disease. Since a recent prospective study reported a lower BC risk in diabetic women treated with drugs able to reduce circulating levels of glucose compared with non-diabetic woman, and in vitro studies showed that AR level are regulated directly by hyperglycemia, we speculate on the perspective of new integrated therapies for TNBC. PMID:27648143

  7. Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy

    Science.gov (United States)

    Su, Yu-Cheng; Burnouf, Pierre-Alain; Chuang, Kuo-Hsiang; Chen, Bing-Mae; Cheng, Tian-Lu; Roffler, Steve R.

    2017-06-01

    Triple-negative breast cancer (TNBC) lacks effective treatment options due to the absence of traditional therapeutic targets. The epidermal growth factor receptor (EGFR) has emerged as a promising target for TNBC therapy because it is overexpressed in about 50% of TNBC patients. Here we describe a PEG engager that simultaneously binds polyethylene glycol and EGFR to deliver PEGylated nanomedicines to EGFR+ TNBC. The PEG engager displays conditional internalization by remaining on the surface of TNBC cells until contact with PEGylated nanocarriers triggers rapid engulfment of nanocargos. PEG engager enhances the anti-proliferative activity of PEG-liposomal doxorubicin to EGFR+ TNBC cells by up to 100-fold with potency dependent on EGFR expression levels. The PEG engager significantly increases retention of fluorescent PEG probes and enhances the antitumour activity of PEGylated liposomal doxorubicin in human TNBC xenografts. PEG engagers with specificity for EGFR are promising for improved treatment of EGFR+ TNBC patients.

  8. Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology.

    Science.gov (United States)

    Weisman, Paul S; Ng, Charlotte K Y; Brogi, Edi; Eisenberg, Rachel E; Won, Helen H; Piscuoglio, Salvatore; De Filippo, Maria R; Ioris, Rafael; Akram, Muzaffar; Norton, Larry; Weigelt, Britta; Berger, Michael F; Reis-Filho, Jorge S; Wen, Hannah Y

    2016-05-01

    Triple negative breast cancer represents a heterogeneous group of breast carcinomas, both at the histologic and genetic level. Although recent molecular studies have comprehensively characterized the genetic landscape of these tumors, few have integrated a detailed histologic examination into the analysis. In this study, we defined the genetic alterations in 39 triple negative breast cancers using a high-depth targeted massively parallel sequencing assay and correlated the findings with a detailed morphologic analysis. We obtained representative frozen tissue of primary triple negative breast cancers from patients treated at our institution between 2002 and 2010. We characterized tumors according to their histologic subtype and morphologic features. DNA was extracted from paired frozen primary tumor and normal tissue samples and was subjected to a targeted massively parallel sequencing platform comprising 229 cancer-associated genes common across all experiments. The average number of non-synonymous mutations was 3 (range 0-10) per case. The most frequent somatic alterations were mutations in TP53 (74%) and PIK3CA (10%) and MYC amplifications (26%). Triple negative breast cancers with apocrine differentiation less frequently harbored TP53 mutations (25%) and MYC gains (0%), and displayed a high mutation frequency in PIK3CA and other PI3K signaling pathway-related genes (75%). Using a targeted massively parallel sequencing platform, we identified the key somatic genetic alterations previously reported in triple negative breast cancers. Furthermore, our findings show that triple negative breast cancers with apocrine differentiation constitute a distinct subset, characterized by a high frequency of PI3K pathway alterations similar to luminal subtypes of breast cancer.

  9. p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors.

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    Chiche, A; Moumen, M; Romagnoli, M; Petit, V; Lasla, H; Jézéquel, P; de la Grange, P; Jonkers, J; Deugnier, M-A; Glukhova, M A; Faraldo, M M

    2016-10-24

    Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/β-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/β-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5ΔNβcat mice displaying a constitutive activation of Wnt/β-catenin signaling in basal cells. K5ΔNβcat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5ΔNβcat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53-deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and β-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies.Oncogene advance online publication, 24 October 2016; doi:10.1038/onc.2016.396.

  10. Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Clark O

    2014-01-01

    Full Text Available Otávio Clark,1 Tobias Engel Ayer Botrel,1 Luciano Paladini,1 Mariana Bhering Andrade Ferreira21Evidências Consulting, Campinas, Brazil; 2Roche do Brasil, São Paulo, BrazilObjective: To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT in patients with metastatic triple-negative breast cancer (TNBC.Methods: Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS. We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR or risk ratio, with their corresponding 95% confidence intervals (95% CIs.Results: The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib. PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51–0.75; P<0.00001. Also, PFS was higher in one study that tested Bev plus CT combination in previously treated patients (HR 0.49, 95% CI 0.33–0.74; P=0.0006. Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49–0.98; P=0.04. Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62–0.90; P=0.002.Conclusion: Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC.Keywords: triple-negative, chemotherapy, breast cancer, systematic review

  11. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

    Directory of Open Access Journals (Sweden)

    Robert Lindner

    Full Text Available Triple negative breast cancer (TNBC is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA. It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1 and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA

  12. A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells

    Science.gov (United States)

    Robles-Escajeda, Elisa; Das, Umashankar; Ortega, Nora M.; Parra, Karla; Francia, Giulio; Dimmock, Jonathan R.; Varela-Ramirez, Armando; Aguilera, Renato J.

    2016-01-01

    Purpose According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance. Methods The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their antineoplastic potencies in a variety of human breast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported. Results We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells. Conclusion Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231 breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug. PMID:26920032

  13. Triple negative status and BRCA mutations in contralateral breast cancer: a population-based study.

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    Pellegrino, Benedetta; Bella, Mariangela; Michiara, Maria; Zanelli, Paola; Naldi, Nadia; Porzio, Rosa; Bortesi, Beatrice; Boggiani, Daniela; Zanoni, Daniele; Camisa, Roberta; Neri, Tauro Maria; Pinto, Carmine; Musolino, Antonino

    2016-05-06

    BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life-time risk of developing contralateral breast cancer (CBC). We performed a population-based study with the aim of estimating the proportion of CBC associated with BRCA1/BRCA2 mutations, and the contribution of germline mutations to both molecular and clinical features of these tumors. Fifty-five women with invasive CBC consecutively seen at the at the Genetic Oncology Service of the University Hospital of Parma from 2000 to 2011 were subjected to BRCA1/2 testing. Fifty-five case-matched, unilateral breast cancer (UBC)  patients (pts), which tested negative for BRCA1/2 mutations, were selected as control group. BRCA mutations were detected in 13 (24%) of 55 CBC pts. Women with BRCA1 mutations, and to a lesser extent BRCA2 mutations, were significantly more likely to present with high histologic grade, negative hormone receptor status and high proliferation rate in both first and second primary breast cancers than BRCA-negative, CBC tumors. A diagnosis of triple-negative breast cancer (TNBC) was significantly more frequent in women with BRCA mutations in comparison with BRCA-negative, UBC controls. There were no survival differences between BRCA-positive and non-BRCA tumors. Results of the present study indicate that both first primary and second primary breast cancers in BRCA carriers are qualitatively distinct from BRCA negative CBC, and from sporadic UBC controls. These findings highlight relevant clinical considerations about the potential value of BRCA testing in women with CBC as well as therapeutic, preventive, and surveillance implications for patients carrying a mutation.

  14. T-cadherin is associated with prognosis in triple-negative breast cancer.

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    Kong, De-Di; Wang, Mei-Hong; Yang, Jie; Li, Liang; Wang, Wei; Wang, Shi-Bing; Zhou, Yan-Zhen

    2017-09-01

    The purpose of the present study was to assess the prognostic impact of T-cadherin expression in patients with triple-negative breast cancer (TNBC). On the basis of the results of immunohistochemical analysis, 106 patients with operable TNBC were divided into two groups, the T-cadherin-positive group and T-cadherin-negative group. Fisher's exact and χ(2) tests were employed to analyze clinical data, which included the association between T-cadherin expression and clinicopathological features and prognosis. The log-rank test was used to examine the impact of T-cadherin expression on the 5-year disease-free survival (DFS) and the 5-year overall survival (OS) of these patients. Kaplan-Meier and Cox regression analyses were introduced to analyze DFS and OS. Compared with the T-cadherin-positive group (58.3, 52.8 and 47.2, respectively; P=0.018, P=0.017, and P=0.047), tumor size >2 cm, grade II and III (Elston-Ellis modification of Bloom-Richardson grading system), and positive lymph node status were significantly more common in the T-cadherin-negative group compared with the T-cadherin-positive group (80.0 vs. 58.3%, 75.7 vs. 52.8% and 67.1 vs. 47.2%, respectively) (P=0.018, P=0.017, and P=0.047). Compared with the T-cadherin-positive group, 5-year DFS and OS levels were significantly lower in the T-cadherin-negative group (Z=6.233, P=0.013; Z=5.366, P=0.021). Multivariate analysis revealed that negative T-cadherin expression was an independent prognostic factor for DFS (P=0.009) and OS (P=0.048). The results of the present study indicated that negative T-cadherin expression indicated a worse prognosis for patients with TNBC.

  15. Integration of Genomic, Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer

    Science.gov (United States)

    2014-09-01

    Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer PRINCIPAL INVESTIGATOR: Jennifer A. Pietenpol, Ph.D...Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer 5a. CONTRACT NUMBER...states resulting from alterations in the p53 signaling pathway in triple negative breast cancer (TNBC). Development of therapies for TNBC is a

  16. A Transposon-based Analysis Reveals RASA1 Is Involved in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Suárez-Cabrera, Cristian; Quintana, Rita M; Bravo, Ana; Casanova, M Llanos; Page, Angustias; Alameda, Josefa P; Paramio, Jesús M; Maroto, Alicia; Salamanca, Javier; Dupuy, Adam J; Ramírez, Angel; Navarro, Manuel

    2017-03-15

    RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53(+/-) background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. Cancer Res; 77(6); 1357-68. ©2017 AACR.

  17. A three-long noncoding RNA signature as a diagnostic biomarker for differentiating between triple-negative and non-triple-negative breast cancers

    Science.gov (United States)

    Liu, Man; Xing, Lu-Qi; Liu, Yi-Jing

    2017-01-01

    Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive cancer with unfavorable outcome and it is useful to explore noninvasive biomarkers for its early diagnosis. Here, we identified differentially expressed long noncoding RNAs (lncRNAs) in blood samples of patients with TNBC to assess their diagnostic value. Methods: Differential expression of lncRNAs in plasma of patients with TNBC (n = 25) and non-TNBC (NTNBC; n = 35) and in healthy controls was compared by microarray analysis and validated by real-time PCR. lncRNA expression between plasma and BC tissues was compared using Pearson correlation test. Logit model was used to obtain a new lncRNA-based score. Receiver operating characteristic analysis was performed to assess the diagnostic value of the selected lncRNAs. Results: Microarray data showed that 41 lncRNAs were aberrantly expressed. Among these, antisense noncoding RNA in the INK4 locus (ANRIL), hypoxia inducible factor 1alpha antisense RNA-2 (HIF1A-AS2), and urothelial carcinoma-associated 1 (UCA1) were markedly upregulated in plasma of patients with TNBC compared with patients with NTNBC (P < 0.01). HIF1A-AS2 expression was positively associated with its tissue levels (r = 0.670, P < 0.01). AUC (95% CI) of ANRIL, HIF1A-AS2, and UCA1 was 0.785 (0.660–0.881), 0.739 (0.610–0.844), and 0.817 (0.696–0.905), respectively. TNBCSigLnc-3, a new score obtained using the logit model, showed excellent diagnostic performance, with AUC of 0.934 (0.839–0.982), sensitivity of 76.0%, and specificity of 97.1%. Conclusion: ANRIL, HIF1A-AS2, and UCA1 expression was significantly increased in plasma of patients with TNBC, suggesting their use as TNBC-specific diagnostic biomarkers. PMID:28248879

  18. Phenotypic characterization of circulating tumor cells in triple negative breast cancer patients

    Science.gov (United States)

    Agelaki, Sofia; Dragolia, Melina; Markonanolaki, Harris; Alkahtani, Saad; Stournaras, Christos; Georgoulias, Vassilis; Kallergi, Galatea

    2017-01-01

    Introduction Patients with triple negative breast cancer (TNBC), are considered as a poor prognosis group for whom no targeted therapies are currently available. The aim of the present study was to phenotypically characterize their CTCs in order to explore potential therapeutic targets. Methods PBMC's cytospins were prepared from 45 early (before and after adjuvant chemotherapy), 10 metastatic TNBC and 21 hormone receptor (HR) -positive patients. The expression of Cytokeratins (CK), ER, PR, EGFR and HER2 on CTCs was assessed using immunofluoresence staining and ARIOL analysis. Results In early stage TNBC, ER, PR, HER2 and EGFR expressing-CTCs were detected in 24.4%, 24.4%, 20% and 40% of patients before the initiation of adjuvant chemotherapy, and in 17.8%, 13.3% 6.7% and 51.1% respectively after the completion of adjuvant treatment. Triple staining experiments revealed distinct subpopulations of CTC expressed HR, and ErbB family receptors. In patients with metastatic disease, the frequency of HER2+ CTCs was significantly increased compared to adjuvant setting (60% vs 20%, p=0.014). The presence of CK+PR− CTCs, before adjuvant treatment was associated with reduced OS (p=0.032) and DFI (p=0.04). Furthermore, the frequency of ER-, PR- and HER2+ CTCs was higher in HR(+) than in TNBC tumors (57.1%, p=0.006; 52.4%, p=0.021 and 52.38%, p=0.009, respectively). Conclusions The CTCs in patients with early TNBC are phenotypically heterogeneous based on the expression of HR, EGFR and HER2 both before and after the completion of adjuvant chemotherapy whereas the presence of HER2+ CTCs prevails during disease evolution. These findings could be of clinical relevance in terms of CTC targeting. PMID:28029660

  19. Family history of breast cancer in first-degree relatives and triple-negative breast cancer risk.

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    Phipps, Amanda I; Buist, Diana S M; Malone, Kathleen E; Barlow, William E; Porter, Peggy L; Kerlikowske, Karla; Li, Christopher I

    2011-04-01

    Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER-/PR-/HER2+, N = 308) breast cancer among women aged 40-84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43-2.09, HR = 1.62, 95% CI: 1.54-1.70, and HR = 1.56, 95% CI: 1.15-2.13, for triple-negative, ER+, and ER-/PR-/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR(triple-negative) = 2.66, 95% CI: 1.66-4.27, HR(ER+) = 2.05, 95% CI: 1.79-2.36, HR(ER)-(/PR)-(/HER2+) = 2.25, 95% CI: 0.99-5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER-/PR-/HER2+ breast cancer.

  20. Expression and Clinical Significance of Androgen Receptor in Triple-Negative Breast Cancer

    Science.gov (United States)

    Asano, Yuka; Kashiwagi, Shinichiro; Goto, Wataru; Tanaka, Sayaka; Morisaki, Tamami; Takashima, Tsutomu; Noda, Satoru; Onoda, Naoyoshi; Ohsawa, Masahiko; Hirakawa, Kosei; Ohira, Masaichi

    2017-01-01

    Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR and its relationship with clinicopathologic features in TNBC. Methods: This study investigated 1036 cases of sporadic invasive breast carcinoma. Immunohistochemical assays were performed to determine the expression of AR in 190 TNBC samples. The relationships between AR expression and clinicopathologic data and prognosis were analyzed. Results: In 190 TNBC cases, the prognosis of AR-positive patients was significantly better (p = 0.019, log-rank) than AR-negative patients, and in multivariate analysis, AR expression was an independent indicator of good prognosis (p = 0.039, hazard ratio = 0.36). In patients with disease relapse, AR positivity was significantly correlated with better prognosis (p = 0.034, log-rank). Conclusions: AR expression may be useful as a subclassification marker for prognosis in TNBC. PMID:28067809

  1. FOXP3 Transcription Factor: A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Leandra Fiori Lopes

    2014-01-01

    Full Text Available Triple negative breast cancer (TNBC is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2. FOXP3 (forkhead transcription factor 3 is a marker of regulatory T cells (Tregs, whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548 and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction. Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06 in relation to TNBC susceptibility. Most of the patients (83% showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P=0.026. In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples.

  2. The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer.

    Science.gov (United States)

    Luo, Jiayan; Jin, Juan; Yang, Fang; Sun, Zijia; Zhang, Wenwen; Shi, Yaqin; Xu, Jing; Guan, Xiaoxiang

    2016-01-01

    Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression and thus cannot benefit from conventional hormonal or anti-HER2 targeted therapies. Anti-androgen therapy has shown a certain effect on androgen receptor (AR) positive TNBC. The emerging researches have proved that poly (ADP-ribose) polymerase (PARP) inhibitor is effective in BRCA1-deficient breast cancers. We demonstrated that combination of AR antagonist (bicalutamide) and PARP inhibitor (ABT-888) could inhibit cell viability and induce cell apoptosis significantly whatever in vitro or in vivo setting in AR-positive TNBC. Previous studies have proved that both BRCA1 and PARP1 have close connections with AR in prostate cancer. We explored the correlation among AR, PARP1 and BRCA1 in TNBC for the first time. After BRCA1 overexpression, the expression of AR and PARP1 were decreased in mRNA and protein levels. Additionally, AR positively regulated PARP1 while PARP1 also up-regulated AR expression in vitro. We also confirmed BRCA1 expression was negatively correlated with AR and PARP1 in TNBC patients using a tissue microarray with TNBC patient samples. These results suggest that the combination of bicalutamide and PARP inhibitor may be a potential strategy for TNBC patients and merits further evaluation.

  3. Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value.

    Science.gov (United States)

    Stirzaker, Clare; Zotenko, Elena; Song, Jenny Z; Qu, Wenjia; Nair, Shalima S; Locke, Warwick J; Stone, Andrew; Armstong, Nicola J; Robinson, Mark D; Dobrovic, Alexander; Avery-Kiejda, Kelly A; Peters, Kate M; French, Juliet D; Stein, Sandra; Korbie, Darren J; Trau, Matt; Forbes, John F; Scott, Rodney J; Brown, Melissa A; Francis, Glenn D; Clark, Susan J

    2015-02-02

    Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

  4. The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer

    Science.gov (United States)

    Luo, Jiayan; Jin, Juan; Yang, Fang; Sun, Zijia; Zhang, Wenwen; Shi, Yaqin; Xu, Jing; Guan, Xiaoxiang

    2016-01-01

    Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression and thus cannot benefit from conventional hormonal or anti-HER2 targeted therapies. Anti-androgen therapy has shown a certain effect on androgen receptor (AR) positive TNBC. The emerging researches have proved that poly (ADP-ribose) polymerase (PARP) inhibitor is effective in BRCA1-deficient breast cancers. We demonstrated that combination of AR antagonist (bicalutamide) and PARP inhibitor (ABT-888) could inhibit cell viability and induce cell apoptosis significantly whatever in vitro or in vivo setting in AR-positive TNBC. Previous studies have proved that both BRCA1 and PARP1 have close connections with AR in prostate cancer. We explored the correlation among AR, PARP1 and BRCA1 in TNBC for the first time. After BRCA1 overexpression, the expression of AR and PARP1 were decreased in mRNA and protein levels. Additionally, AR positively regulated PARP1 while PARP1 also up-regulated AR expression in vitro. We also confirmed BRCA1 expression was negatively correlated with AR and PARP1 in TNBC patients using a tissue microarray with TNBC patient samples. These results suggest that the combination of bicalutamide and PARP inhibitor may be a potential strategy for TNBC patients and merits further evaluation. PMID:27994514

  5. Triple negative breast cancer: 5 years follow-up%三阴性乳腺癌5年随访

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou

    2011-01-01

    Objective: The aim of the study was to investigate the long-term therapeutic effects of triple negative breast cancers (TNBCs) and find a standardized treatment. Methods: The clinical data and survival status of 69 patients with TNBC were collected, who were treated from 2003 to 2007 at Chongqing Cancer Institute, China. Results: Median observation for 61 months showed the local recurrence rate was 13.0% (9/69), the overall survival (OS) rate was 76.8% (53/69) and the disease free survival (DFS) rate was 59.4% (41/69). Log-rank univariate survival analysis showed the OS and DFS rates of TNBCs with axillary lymph node metastasis were 38.1% and 23.8%, respectively, and the OS and DFS rates of triple negative breast cancer with axillary lymph node non-metastasis were 93.8% and 75.0%, respectively. There were significant differences comparing with two groups. Indictor analysis of age, menstruation status, tumor size, TNM stage, histological type,neoadjuvant chemotherapy and p53 did not show any prognostic influence. Conclusion: The axillary nodes metastasis is associated with DFS and OS in triple negative breast cancers. Cisplatin-based chemotherapy may be good choice for triple negative breast cancers with metastasis or local recurrence, who received Anthracyciine and Taxane-based chemotherapy.Targeted therapies strategies such as EGFR-targeted therapy may be necessary.

  6. Poor prognosis of constitutive gamma-H2AX expressing triple-negative breast cancers is associated with telomere length

    NARCIS (Netherlands)

    Nagelkerke, A.P.; Kuijk, S.J. van; Martens, J.W.; Sweep, F.C.; Hoogerbrugge, N.; Bussink, J.; Span, P.N.

    2015-01-01

    AIM: Here, we set out to establish whether endogenous gamma-H2AX is a biomarker in triple-negative breast cancer. METHODS: We explored the association of gamma-H2AX with mutation status and sensitivity to 139 different anticancer drugs in up to 41 breast cancer cell lines. Further, we correlated gam

  7. A comparative study of Ki-67 antigen expression between luminal A and triple-negative subtypes of breast cancer.

    Science.gov (United States)

    Borges, Umbelina Soares; Costa-Silva, Danylo Rafhael; da Silva-Sampaio, João Paulo; Escórcio-Dourado, Carla Solange; Conde, Airton Mendes; Campelo, Viriato; Gebrim, Luiz Henrique; da Silva, Benedito Borges; Lopes-Costa, Pedro Vitor

    2017-09-01

    Tumor biomarkers such as hormone receptors, HER-2 and Ki-67 are used routinely in clinical practice for classification of molecular subtypes of breast cancer. Cell proliferation evaluated by Ki-67 antigen expression is important to determine tumor aggressiveness. However, there is a paucity of studies comparing Ki-67 expression in an expressive number of cells among molecular subtypes of breast cancer, particularly among less and more aggressive tumors, such as luminal A and triple-negative, which have led us to the present study. The current study included invasive ductal carcinoma samples of 59 patients, which were divided into two groups: luminal A (n = 29) and triple-negative (n = 30). For immunohistochemical reaction, the samples were incubated with monoclonal anti-Ki-67 antibody (clone MIB1) and cells expressing Ki-67 protein were identified by dark brown staining of the nuclei, counting at least 600 cells per slide. The mean percentages of stained nuclei were analyzed by Student's t test (p < 0.05). The mean percentage of nuclei stained with anti-ki-67 was 10.14 and 77.22 in luminal A and triple-negative breast cancers, respectively (p < 0.0001). Our study showed a high cell proliferation of triple-negative breast cancer in comparison with luminal A, justifying its aggressiveness and poor clinical outcome.

  8. Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis.

    Science.gov (United States)

    Dong, Tieying; Liu, Zhaoliang; Xuan, Qijia; Wang, Zhuozhong; Ma, Wenjie; Zhang, Qingyuan

    2017-07-20

    There are limited therapeutic methods for triple negative breast cancer in the clinic, which is easy to progress into the brain to form metastatic lesions and evolve into the terminal stage. Because both the primary cancer and the brain metastasis have high glycolysis, we hypothesize that lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, may be a predictor, as well as a treatment target, for breast cancer brain metastasis. Therefore, the expression of LDH-A was detected on 119 triple negative breast cancer tissues with immunohistochemistry, and the serum LDH levels were also measured. Our results showed that the LDH-A expression inside the tumor was significantly higher than the matched normal tissues. Tumor LDH-A expression, serum LDH status, and the slope of serum LDH status were closely associated with triple negative breast cancer brain metastasis and brain metastasis free survival. This study indicates that tumor LDH and serum LDH status are two predictors for triple negative breast cancer brain metastasis.

  9. Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.

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    Tiejun Zhao

    Full Text Available Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1 as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.

  10. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

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    Rowe, Danica L.; Tuba Ozbay; Ruth M. O’Regan; Rita Nahta

    2009-01-01

    In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple nega...

  11. Correlation of clinicopathologic parameters and immunohistochemical features of triple-negative invasive lobular carcinoma.

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    Harbhajanka, Aparna; Lamzabi, Ihab; Singh, Rohit I; Ghai, Ritu; Reddy, Vijaya B; Bitterman, Pincas; Gattuso, Paolo

    2014-07-01

    Invasive lobular carcinoma (ILC) is a subtype of invasive breast carcinoma. With the advent of gene profiling, breast cancer has been classified into luminal A, luminal B, HER2-overexpressing, and triple-negative carcinoma (TNC). Several studies have described TNC (ER, PR, HER2) as a surrogate for basal-like breast carcinoma. However, there is sparse literature on triple-negative lobular carcinoma (TNLC), as most of them show hormone receptor expression. The aim of this study was to investigate the correlation of clinicopathologic parameters of TNLC that has been demonstrated in invasive ductal carcinoma. Clinicopathologic parameters and immunohistochemical stains for ER, PR, E-cadherin, HER2, MIB1, and fluorescent in situ hybridization for HER2 of 255 ILC cases were retrieved. In addition, immunohistochemical analysis was performed for p53, c-kit, vimentin, p16, cyclinD1, and BCL2 on 78 cases where 12 were TNC cases and 66 were non-TNC cases. Of the 255 ILC cases, 218 (85.5%) were classic and 37 (14.5%) were pleomorphic. Seventy-seven (30.1%) cases showed axillary lymph node metastasis. There were 14 of the 255 TNC cases (5.49%) that showed higher incidence in the elderly patients. Six of the 37 (16.21%) cases were pleomorphic and 8 of the 218 (3.7%) cases were classic. Positivity for vimentin was seen in 8 of the 12 cases (67.7%), CK 5 in 3 of the 12 (25%) cases, p16 in 11 of the 12 (91.6%) cases, p53 in 8 of the 12 (66.7%) cases, c-kit in 6 of the 12 (50%) cases, and cyclinD1 in 6 of the 12 cases (50%) indicating basal-like phenotype in 3 cases and nonbasal-like phenotype in 9 cases. There was no statistical significance in lymph node metastasis, tumor recurrence, and distant metastasis between TNC and non-TNC. TNLC showed distinct clinicopathologic features such as more frequently seen in the elderly, pleomorphic, larger tumor size, increased expression of vimentin, CK 5, p16, p53, and c-kit. Not all cases showed basal-like phenotype. TNLC is less frequently

  12. The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

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    Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H., E-mail: rmach@mail.med.upenn.edu

    2015-11-27

    Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

  13. MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer.

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    Mao Ouyang

    Full Text Available OBJECTIVE: Triple-negative breast cancer (TNBC patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs that correlate with TNBC chemoresistance. METHODS: In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity. RESULTS: We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21-3p, miR-181a-5p, miR-181b-5p, and miR-183-5p and 6 down-regulated miRNAs (miR-10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p. Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer-associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up-regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs. CONCLUSION: The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients.

  14. Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer.

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    O'Flanagan, Ciara H; Rossi, Emily L; McDonell, Shannon B; Chen, Xuewen; Tsai, Yi-Hsuan; Parker, Joel S; Usary, Jerry; Perou, Charles M; Hursting, Stephen D

    2017-01-01

    The vast majority of cancer-related deaths are due to metastatic disease, whereby primary tumor cells disseminate and colonize distal sites within the body. Triple negative breast cancer typically displays aberrant Wnt signaling, lacks effective targeted therapies, and compared with other breast cancer subtypes, is more likely to recur and metastasize. We developed a Wnt-driven lung metastasis model of triple negative breast cancer (metM-Wnt(lung)) through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wnt(lung) cells displayed characteristics of epithelial-to-mesenchymal transition (e.g., increased invasiveness) with some re-epithealization (e.g., increased adhesion, tight colony formation, increased E-cadherin expression, and decreased Vimentin and Fibronectin expression). When orthotopically transplanted into syngeneic mice, metM-Wnt(lung) cells readily formed tumors and metastasized in vivo, and tumor growth and metastasis were enhanced in obese mice compared with non-obese mice. Gene expression analysis revealed several genes and pathways altered in metM-Wnt(lung) cells compared with M-Wnt cells, including multiple genes associated with epithelial-to-mesenchymal transition, energy metabolism and inflammation. Moreover, obesity caused significant transcriptomic changes, especially in metabolic pathways. Metabolic flux analyses showed greater metabolic plasticity, with heightened mitochondrial and glycolytic energetics in metM-Wnt(lung) cells relative to M-Wnt cells. Similar metabolic profiles were found in a second triple negative breast cancer progression series, M6 and M6C cells. These findings suggest that metabolic reprogramming is a feature of metastatic potential in triple negative breast cancer. Thus, targeting metastases-associated metabolic perturbations may represent a novel strategy for reducing the burden of metastatic triple negative breast cancer, particularly in obese women.

  15. BRCA mutations cause reduction in miR-200c expression in triple negative breast cancer.

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    Erturk, Elif; Cecener, Gulsah; Tezcan, Gulcin; Egeli, Unal; Tunca, Berrin; Gokgoz, Sehsuvar; Tolunay, Sahsine; Tasdelen, Ismet

    2015-02-10

    Triple negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer (BC). Over the recent years, miRNA expression studies have been providing certain detailed overview that aberrant expression of miRNAs is associated with TNBC. Although TNBC tumors are strongly connected with loss of function of BRCA genes, there is no knowledge about the effect of BRCA mutation status on miRNA expressions in TNBC cases. The aims of this study were to evaluate the expression profile of miRNAs that plays role in TNBC progression and the role of BRCA mutations in their regulation. The expression level of BC associated 13 miRNAs was analyzed in 7 BRCA mutations positive, 6 BRCA mutations negative TNBC cases and 20 non-tumoral tissues using RT-PCR. According to RT2 Profiler PCR Array Data Analysis, let-7a expression was 4.67 fold reduced in TNBCs as compared to normal tissues (P=0.031). In addition, miR-200c expression was 5.75 fold reduced in BRCA mutation positive TNBC tumors (P=0.005). Analysis revealed a negative correlation between miR-200c and VEGFA expressions (r=-468). Thus, miR-200c may be involved in invasion and metastasis in TNBC cases with BRCA mutation. In this study we provide the knowledge on the first report of association between microRNA-200c and BRCA mutations in TNBC. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for TNBC treatment and new directions for the development of anticancer drugs.

  16. KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple-Negative Breast Cancer

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    Stina M. Singel

    2014-03-01

    Full Text Available Despite evidence that kinesin family member 14 (KIF14 can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor–negative/progesterone receptor–negative/human epidermal growth factor receptor 2-negative, “triple-negative” breast cancers (TNBC. To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.

  17. Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance.

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    Yu, Tianjian; Di, Genhong

    2017-06-01

    Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re-programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings.

  18. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer.

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    Bhola, Neil E; Balko, Justin M; Dugger, Teresa C; Kuba, María Gabriela; Sánchez, Violeta; Sanders, Melinda; Stanford, Jamie; Cook, Rebecca S; Arteaga, Carlos L

    2013-03-01

    After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy. Biopsies after chemotherapy displayed increased RNA transcripts of genes associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse xenografts, the chemotherapeutic drug paclitaxel increased autocrine TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated by mammosphere formation and CSC markers. The TGF-β type I receptor kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8 transcription and CSC expansion. Moreover, treatment of TNBC xenografts with LY2157299 prevented reestablishment of tumors after paclitaxel treatment. These data suggest that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8-dependent expansion of CSCs and that TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. These findings support testing a combination of TGF-β inhibitors and anticancer chemotherapy in patients with TNBC.

  19. Hydrophobic Fractionation Enhances Novel Protein Detection by Mass Spectrometry in Triple Negative Breast Cancer

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    Lu, Ming; Whitelegge, Julian P.; Whelan, Stephen A.; He, Jianbo; Saxton, Romaine E.; Faull, Kym F.; Chang, Helena R.

    2010-01-01

    It is widely believed that discovery of specific, sensitive and reliable tumor biomarkers can improve the treatment of cancer. The goal of this study was to develop a novel fractionation protocol targeting hydrophobic proteins as possible cancer cell membrane biomarkers. Hydrophobic proteins of breast cancer tissues and cell lines were enriched by polymeric reverse phase columns. The retained proteins were eluted and digested for peptide identification by nano-liquid chromatography with tandem mass spectrometry using a hybrid linear ion-trap Orbitrap. Hundreds of proteins were identified from each of these three specimens: tumors, normal breast tissue, and breast cancer cell lines. Many of the identified proteins defined key cellular functions. Protein profiles of cancer and normal tissues from the same patient were systematically examined and compared. Stem cell markers were overexpressed in triple negative breast cancer (TNBC) compared with non-TNBC samples. Because breast cancer stem cells are known to be resistant to radiation and chemotherapy, and can be the source of metastasis frequently seen in patients with TNBC, our study may provide evidence of molecules promoting the aggressiveness of TNBC. The initial results obtained using a combination of hydrophobic fractionation and nano-LC mass spectrometry analysis of these proteins appear promising in the discovery of potential cancer biomarkers. When sufficiently refined, this approach may prove useful for early detection and better treatment of breast cancer. PMID:20596302

  20. The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer

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    Andras G. Lacko

    2013-06-01

    Full Text Available Triple Negative Breast Cancer, TNBC, a highly aggressive and metastatic type of breast cancer, is characterized by loss of expression of the estrogen receptor (ER, progesterone receptor (PR, and a lack of overexpression of the human epidermal growth factor receptor 2 (HER2. It is a heterogeneous group of tumors with diverse histology, molecular uniqueness and response to treatment. Unfortunately, TNBC patients do not benefit from current anti-HER2 or hormone positive targeted breast cancer treatments; consequently, these patients rely primarily on chemotherapy. However, the 5-year survival rate for woman with metastatic TNBC is less than 30%. As a result of ineffective treatments, TNBC tumors often progress to metastatic lesions in the brain and lung. Brain metastases of invasive breast cancer are associated with 1 and 2 year survival rate of 20% and <2% respectively. Because the only current systemic treatment for TNBC is chemotherapy, alternative targeted therapies are urgently needed to improve the prognosis for TNBC patients. This review is focused on opportunities for developing new approaches for filling the current void in an effective treatment for TNBC patients.

  1. Impact of Triple-Negative Phenotype on Prognosis of Patients With Breast Cancer Brain Metastases

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    Xu Zhiyuan [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States); Schlesinger, David [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Toulmin, Sushila [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States); Rich, Tyvin [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Sheehan, Jason, E-mail: jps2f@virginia.edu [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States)

    2012-11-01

    Purpose: To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). Methods and Materials: A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. Results: The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. Conclusion: The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor.

  2. Novel therapeutic strategies for patients with triple-negative breast cancer

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    Zhang J

    2016-10-01

    Full Text Available Jun-Fei Zhang,1 Jia Liu,1,2 Yu Wang,1,2 Bin Zhang1,2 1Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China; 2Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China Abstract: Triple-negative breast cancer (TNBC represents a very heterogeneous group of breast diseases. Currently, the backbone of therapy for TNBC is mainly chemotherapy as there are no effective specific targeted agents approved to treat TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. Therefore, new targeted strategies are, accordingly, urgently needed. This article discusses the recent developments in targeted agents explored for TNBC, aiming to offer novel therapeutic strategies that can potentially assist in designing personalized therapeutics in the future as well as provide the basis for further research in an attempt to target TNBC. Keywords: therapeutic strategies, TNBC, targeted agents

  3. KEY PLAYERS IN CHOLINE METABOLIC REPROGRAMMING IN TRIPLE NEGATIVE BREAST CANCER

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    Egidio Iorio

    2016-09-01

    Full Text Available Triple negative breast cancer (TNBC, defined by lack of estrogen and progesterone receptors in the absence of protein overexpression/gene amplification of human epidermal growth factor receptor 2 (HER2, is still a clinical challenge despite progress in breast cancer (BC care. 1H magnetic resonance spectroscopy (MRS allows identification and non-invasive monitoring of TNBC metabolic aberrations and elucidation of some key mechanisms underlying tumor progression. Thus, it has the potential to improve in vivo diagnosis and follow-up, and identify new targets for treatment. Several studies have shown an altered phosphatidylcholine (PtdCho metabolism in TNBCs, both in patients and in experimental models. Up-regulation of choline kinase-alpha, an enzyme of the Kennedy pathway that phosphorylates free choline (Cho to phosphocholine (PCho, is a major contributor to the increased PCho content detected in TNBCs. Phospholipase-mediated PtdCho headgroup hydrolysis also contributes to the build-up of a PCho pool in TNBC cells. The oncogene-driven PtdCho cycle appears to be fine tuned in TNBC cells in at least three ways: by modulating the choline import, by regulating the activity or expression of specific metabolic enzymes, and by contributing to the rewiring of the entire metabolic network. Thus, only by thoroughly dissecting these mechanisms, it will be possible to effectively translate this basic knowledge into further development and implementation of Cho-based imaging techniques and novel classes of therapeutics.

  4. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer

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    Cheang Maggie CU

    2007-07-01

    Full Text Available Abstract Background Basal-like breast cancer has been extensively characterized on the basis of gene expression profiles, but it is becoming increasingly common for these tumors to be defined on the basis of immunohistochemical (IHC staining patterns, particularly in retrospective studies where material for expression profiling may not be available. The IHC pattern that best defines basal-like tumors is under investigation and various combinations of ER, PR, HER2-, CK5/6+ and EGFR+ have been tested. Methods Using datasets from two different hospitals we describe how using different combinations of immunohistochemical patterns has different effects on estimating prognosis at different time intervals after diagnosis. As our baseline, we used two IHC patterns ER-/PR-/HER2-("triple negative phenotype", TNP and ER-/HER2-/CK5/6+ and/or EGFR+ ("core basal phenotype", CBP. Results There was no overall difference in survival between the two hospital-based series, but there was a difference between the TNP and non-TNP groups which was most marked at 3 years (76.8% vs 93.5%, p Conclusion Our findings suggests that CK5/6 and/or EGFR expressing tumor types have a persistently poorer prognosis over the longer term, an observation that may have important therapeutic implications as drugs that target the EGFR are currently being evaluated in breast cancer.

  5. Evaluation of growth inhibitory response of Resveratrol and Salinomycin combinations against triple negative breast cancer cells.

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    Rai, Girish; Suman, Shankar; Mishra, Sanjay; Shukla, Yogeshwer

    2017-03-11

    Resveratrol (RSVL) a dietary phytochemical showed to enhance the efficacy of chemotherapeutic drugs. Recently, Salinomycin (SAL) has gained importance as cancer therapeutic value for breast cancer (BC), however, its superfluxious toxicity delimits the utility. Taking the advantage of RSVL, the therapeutic efficacy of RSVL and SAL combination was studied in vitro and in vivo system. Firstly, the synergistic combination dose of RSVL and SAL was calculated and further, the efficacy was examined by wound healing, and Western blots analysis. Further, in vivo study was performed to confirm the effect of colony formation and apoptosis detection by flow cytometry based assays. Further, the molecular mode of action was determined at both transcript and translational level by quantitative Real Time PCR combination in Ehrlich ascitic carcinoma model.The combination of IC20 (R20) of RSVL and IC10 (S10) dose of SAL showed best synergism (CI<1) with ∼5 fold dose advantage of SAL. Gene expression results at mRNA and protein level revealed that the unique combination of RSVL and SAL significantly inhibited epithelial mesenchymal transition (Fibronectin, Vimentin, N-Cadherin, and Slug); chronic inflammation (Cox2, NF-kB, p53), autophagy (Beclin and LC3) and apoptotic (Bax, Bcl-2) markers. Further, i n vivo study showed that low dose of SAL in combination with RSVL increased life span of Ehrlich ascitic mice. Overall, our study revealed that RSVL synergistically potentiated the anticancer potential of SAL against triple negative BC.

  6. Metabolic response to everolimus in patient-derived triple negative breast cancer xenografts.

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    Euceda, Leslie R; Hill, Deborah K; Stokke, Endre; Hatem, Rana; Botty, Rania El; Bièche, Ivan; Marangoni, Elisabetta; Bathen, Tone F; Moestue, Siver A

    2017-03-14

    Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p=0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to non-responders. Additionally, the metabolic information predicted p53 mutation status, which may provide complimentary insight into the interplay between PI3K signaling and other drivers of disease progression.

  7. P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients

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    Pan, Yunbao; Yuan, Yufen; Liu, Guoshi; Wei, Yongchang

    2017-01-01

    Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer lack of effective target therapy. This study was to investigate the prognostic role of p53 and Ki-67 in 156 cases of TNBC patients. Logistic regression analysis was used to examine the association between clinical parameters and recurrence. Univariate and multivariate analyses were used to examine the association between clinical characteristics and disease-free survival (DFS) or overall survival (OS). Survival analyses using the Kaplan-Meier method were performed to examine the association between p53/Ki-67 and DFS and OS. Our data showed that p53 was positive in 71.3% and the Ki-67 high index was in 82.8% of TNBC. Elevated p53 and Ki-67 were associated with histological grade. The tumor size, lymph node involvement, and p53 expression are associated with risk of recurrence. Tumor size, lymph node involvement, family history, Ki-67 and p53 are independent variables associated with either DFS or OS. TNBC patients with positive p53 or Ki-67 high index or family history of cancer have a significant association with worse prognosis. This study suggests that p53, Ki-67 and family history are useful prognostic markers in TNBC. PMID:28235003

  8. Cyclooxygenase-2 regulates TGFβ-induced cancer stemness in triple-negative breast cancer

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    Tian, Jun; Hachim, Mahmood Y.; Hachim, Ibrahim Y.; Dai, Meiou; Lo, Chieh; Raffa, Fatmah Al; Ali, Suhad; Lebrun, Jean Jacques

    2017-01-01

    Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, display poor prognosis and exhibit resistance to conventional therapies, partly due to an enrichment in breast cancer stem cells (BCSCs). Here, we investigated the role of the cyclooxygenase-2 (COX-2), a downstream target of TGFβ, in regulating BCSCs in TNBC. Bioinformatics analysis revealed that COX-2 is highly expressed in TNBC and that its expression correlated with poor survival outcome in basal subtype of breast cancer. We also found TGFβ-mediated COX-2 expression to be Smad3-dependent and to be required for BCSC self-renewal and expansion in TNBCs. Knocking down COX-2 expression strikingly blocked TGFβ-induced tumorsphere formation and TGFβ-induced enrichment of the two stem-like cell populations, CD24lowCD44high and ALDH+ BCSCs. Blocking COX-2 activity, using a pharmacological inhibitor also prevented TGFβ-induced BCSC self-renewal. Moreover, we found COX-2 to be required for TGFβ-induced expression of mesenchymal and basal breast cancer markers. In particular, we found that TGFβ-induced expression of fibronectin plays a central role in TGFβ-mediated breast cancer stemness. Together, our results describe a novel role for COX-2 in mediating the TGFβ effects on BCSC properties and imply that targeting the COX-2 pathway may prove useful for the treatment of TNBC by eliminating BCSCs. PMID:28054666

  9. Irreversible electroporation inhibits pro-cancer inflammatory signaling in triple negative breast cancer cells.

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    Goswami, Ishan; Coutermarsh-Ott, Sheryl; Morrison, Ryan G; Allen, Irving C; Davalos, Rafael V; Verbridge, Scott S; Bickford, Lissett R

    2017-02-01

    Low-level electric fields have been demonstrated to induce spatial re-distribution of cell membrane receptors when applied for minutes or hours. However, there is limited literature on the influence on cell signaling with short transient high-amplitude pulses typically used in irreversible electroporation (IRE) for cancer treatment. Moreover, literature on signaling pertaining to immune cell trafficking after IRE is conflicting. We hypothesized that pulse parameters (field strength and exposure time) influence cell signaling and subsequently impact immune-cell trafficking. This hypothesis was tested in-vitro on triple negative breast cancer cells treated with IRE, where the effects of pulse parameters on key cell signaling factors were investigated. Importantly, real time PCR mRNA measurements and ELISA protein analyses revealed that thymic stromal lymphopoietin (TSLP) signaling was down regulated by electric field strengths above a critical threshold, irrespective of exposure times spanning those typically used clinically. Comparison with other treatments (thermal shock, chemical poration, kinase inhibitors) revealed that IRE has a unique effect on TSLP. Because TSLP signaling has been demonstrated to drive pro-cancerous immune cell phenotypes in breast and pancreatic cancers, our finding motivates further investigation into the potential use of IRE for induction of an anti-tumor immune response in vivo.

  10. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-03-06

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

  11. Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles.

    Science.gov (United States)

    Parvani, Jenny G; Jackson, Mark W

    2017-04-01

    Over the past decade, RNA interference (RNAi) has been ubiquitously utilized to study biological function in vitro; however, limitations were associated with its utility in vivo More recently, small interfering RNA (siRNA) nanoparticles with improved biocompatibility have gained prevalence as a potential therapeutic option for the treatment of various diseases. The adaptability of siRNA nanoparticles enables the delivery of virtually any siRNA, which is especially advantageous for therapeutic applications in heterogeneous diseases that lack unifying molecular features, such as triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast cancer that is stratified by the lack of estrogen receptor/progesterone receptor expression and HER2 amplification. There are currently no FDA-approved targeted therapies for the treatment of TNBCs, making cytotoxic chemotherapy the only treatment option available to these patients. In this review, we outline the current status of siRNA nanoparticles in clinical trials for cancer treatment and discuss the promising preclinical approaches that have utilized siRNA nanoparticles for TNBC treatment. Next, we address TNBC subtype-specific therapeutic interventions and highlight where and how siRNA nanoparticles fit into these strategies. Lastly, we point out ongoing challenges in the field of siRNA nanoparticle research that, if addressed, would significantly improve the efficacy of siRNA nanoparticles as a therapeutic option for cancer treatment.

  12. 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells.

    Science.gov (United States)

    Kim, Sun Young; Lee, Ik-Soo; Moon, Aree

    2013-05-25

    Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231 cells with IC50 values of 18.1, 4.6, and 6.7 μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231 cells. Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC.

  13. Combined Phosphoproteomics and Bioinformatics Strategy in Deciphering Drug Resistant Related Pathways in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Xinyu Deng

    2014-01-01

    Full Text Available Because of the absence of a clear therapeutic target for triple negative breast cancer (TNBC, conventional chemotherapy is the only available systemic treatment option for these patients. Despite chemotherapy treatment, TNBC patients still have worse prognosis when compared with other breast cancer patients. The study is to investigate unique phosphorylated proteins expressed in chemoresistant TNBC cell lines. In the current study, twelve TNBC cell lines were subjected to drug sensitivity assays against chemotherapy drugs docetaxel, doxorubicin, gemcitabine, and cisplatin. Based on their half maximal inhibitory concentrations, four resistant and two sensitive cell lines were selected for further analysis. The phosphopeptides from these cells were enriched with TiO2 beads and fractionated using strong cation exchange. 1,645 phosphoprotein groups and 9,585 unique phosphopeptides were identified by a high throughput LC-MS/MS system LTQ-Orbitrap. The phosphopeptides were further filtered with Ascore system and 1,340 phosphoprotein groups, 2,760 unique phosphopeptides, and 4,549 unique phosphosites were identified. Our study suggested that differentially phosphorylated Cdk5, PML, AP-1, and HSF-1 might work together to promote vimentin induced epithelial to mesenchymal transition (EMT in the drug resistant cells. EGFR and HGF were also shown to be involved in this process.

  14. Neoadjuvant strategies for triple negative breast cancer: 'state-of-the-art' and future perspectives.

    Science.gov (United States)

    Carbognin, Luisa; Furlanetto, Jenny; Vicentini, Cecilia; Nortilli, Rolando; Pilotto, Sara; Brunelli, Matteo; Pellini, Francesca; Pollini, Giovanni Paolo; Bria, Emilio; Tortora, Giampaolo

    2015-01-01

    Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.

  15. Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mancini, Patrizia, E-mail: patrizia.mancini@uniroma1.it [Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Angeloni, Antonio [Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Risi, Emanuela [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Orsi, Errico [Department of Surgical Science, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Mezi, Silvia [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy)

    2014-10-24

    Triple negative breast cancer (TNBC) is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF), poly (ADP-ribose) polymerase (PARP), HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

  16. Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

    Directory of Open Access Journals (Sweden)

    Patrizia Mancini

    2014-10-01

    Full Text Available Triple negative breast cancer (TNBC is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF, poly (ADP-ribose polymerase (PARP, HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

  17. Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

    Science.gov (United States)

    Tabassum, Doris P.; Roberts, Justin M.; Janiszewska, Michalina; Huh, Sung Jin; Liang, Yi; Ryan, Jeremy; Doherty, Ernest; Mohammed, Hisham; Guo, Hao; Stover, Daniel G.; Ekram, Muhammad B.; Brown, Jonathan; D'Santos, Clive; Krop, Ian E.; Dillon, Deborah; McKeown, Michael; Ott, Christopher; Qi, Jun; Ni, Min; Rao, Prakash K.; Duarte, Melissa; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Anders, Lars; Young, Richard A.; Winer, Eric; Letai, Antony; Barry, William T.; Carroll, Jason S.; Long, Henry; Brown, Myles; Liu, X. Shirley; Meyer, Clifford A.; Bradner, James E.; Polyak, Kornelia

    2015-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy1-3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer4-6, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs7-9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance. PMID:26735014

  18. Synergistic Effect of SH003 and Doxorubicin in Triple-negative Breast Cancer.

    Science.gov (United States)

    Woo, Sang-Mi; Kim, Ah Jeong; Choi, Youn Kyung; Shin, Young Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

    2016-11-01

    Triple-negative breast cancer (TNBC) is highly aggressive, resulting in poor prognosis. Chemotherapy of TNBC relies on anti-cancer agents with strong cytotoxicity, but it causes several side effects with recurrence. While combinational approaches of chemotherapeutics have been highlighted as a new treatment strategy for TNBC to reduce side effects, combinations of anti-cancer agents with herbal medicines have not been reported. We recently reported that newly modified traditional Chinese medicine named SH003 inhibited TNBC growth. Considering a combinational strategy for TNBC treatment, we further studied synergistic effects of SH003 with various anti-cancer drugs in TNBC treatment. Here, we demonstrate that SH003 shows a synergistic effect with doxorubicin on TNBC treatment. Our in vitro cell viability assays revealed that SH003 and doxorubicin showed a synergistic effect in the well-defined TNBC cell line, MDA-MB-231. Moreover, we found that the combinational treatment caused Caspase-dependent apoptotic cell death. Our in vivo mouse xenograft tumor growth assays confirmed that combinational treatment of SH003 with doxorubicin repressed MDA-MB-231 tumor growth with no weight loss. Therefore, we conclude that the combinational treatment of SH003 with doxorubicin shows the synergism in TNBC treatment, and suggest that SH003 can be used together with conventional anti-cancer drugs in chemotherapeutic approaches. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Mesenchymal Stem Cell-Induced Doxorubicin Resistance in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Dar-Ren Chen

    2014-01-01

    Full Text Available Triple negative breast cancer (TNBC is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs, tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM, noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

  20. Mesenchymal stem cell-induced doxorubicin resistance in triple negative breast cancer.

    Science.gov (United States)

    Chen, Dar-Ren; Lu, Dah-Yuu; Lin, Hui-Yi; Yeh, Wei-Lan

    2014-01-01

    Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

  1. MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells.

    Science.gov (United States)

    Kim, Sangmin; Lee, Jeongmin; Jeon, Myeongjin; Lee, Jeong Eon; Nam, Seok Jin

    2016-04-01

    Interleukin-8 (IL-8) serves as a prognostic marker for breast cancer, and its expression level correlates with metastatic breast cancer and poor prognosis. Here, we investigated the levels of IL-8 expression in a variety of breast cancer cells and the regulatory mechanism of IL-8 in triple-negative breast cancer (TNBC) cells. Our results showed that IL-8 expression correlated positively with overall survival in basal-type breast cancer patients. The levels of IL-8 mRNA expression and protein secretion were significantly increased in TNBC cells compared with non-TNBC cells. In addition, the invasiveness of the TNBC cells was dramatically increased by IL-8 treatment and then augmented invasion-related proteins such as matrix metalloproteinase (MMP)-2 or MMP-9. We observed that elevated IL-8 mRNA expression and protein secretion were suppressed by a specific MEK1/2 inhibitor, UO126. In contrast, the overexpression of constitutively active MEK significantly increased the level of IL-8 mRNA expression in BT474 non-TNBC cells. Finally, we investigated the effect of UO126 on the tumorigenecity of TNBC cells. Our results showed that anchorage-independent growth, cell invasion, and cell migration were also decreased by UO126 in TNBC cells. As such, we demonstrated that IL-8 expression is regulated through MEK/ERK-dependent pathways in TNBC cells. A diversity of MEK blockers, including UO126, may be promising for treating TNBC patients.

  2. Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

    Directory of Open Access Journals (Sweden)

    Andrew A. Davis

    2012-01-01

    Full Text Available Triple-negative breast cancers (TNBCs are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angiogenesis. Insulin, insulin-like growth factor I (IGF-I, and epidermal growth factor receptor (EGFR may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC.

  3. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer

    Science.gov (United States)

    Blau, C. Anthony; Ramirez, Arturo B.; Blau, Sibel; Pritchard, Colin C.; Dorschner, Michael O.; Schmechel, Stephen C.; Martins, Timothy J.; Mahen, Elisabeth M.; Burton, Kimberly A.; Komashko, Vitalina M.; Radenbaugh, Amie J.; Dougherty, Katy; Thomas, Anju; Miller, Christopher P.; Annis, James; Fromm, Jonathan R.; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A.; Linenberger, Michael L.; Becker, Pamela S.; Senecal, Francis M.; Mecham, Brigham H.; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L.; Stilwell, Jackie L.; Kaldjian, Eric P.; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient’s evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID:26733551

  4. Relation between radiographic BI-RADS scores and triple negativity in patients with ductal carcinomas.

    Science.gov (United States)

    Oktay, Murat; Oktay, Nilay Aydın; Besir, Fahri Halit; Buyukkaya, Ramazan; Erdem, Havva; Onal, Binnur; Ozaydın, Ismet; Yazıcı, Burhan

    2014-01-01

    The aim of this study was to investigate association of radiographic (BI-RADS 4 and 5) results and prognostic factors of invasive ductal carcinomas with their histopathological subtypes. A total of 103 patients histopathologically diagnosed with invasive ductal carcinoma of breast with in last five years period were enrolled. Of them, 69 patients who had radiological reports in were included from registry of Radiology Department; Duzce University Training and Research Hospital archives. BI-RADS scores (4 and 5) of radiological reports and subtypes of ductal carcinoma were compared. Of 69 cases, 12 of 22 cases with BIRADS 4 score were Triple negative (TN) while 5 of 47 cases with BIRADS 5 score were TN (p = 0.001). The patients with TN tumors were found to have lower average age, higher grade, higher Ki67 proliferative index and fewer lymph node metastasis than those with non-TN ductal carcinomas (p = 0.048; 0.019; 0.02; 0.048 respectively). Patients who had radiological BIRADS 4 score were significantly more frequent TN type carcinoma than BI-RADS 5. It is important to pay attention to this issue when clinicians evaluate patients with BI-RADS 4 score breast lesions.

  5. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Francesca Collina

    2015-01-01

    Full Text Available Triple-negative breast cancer (TNBC has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.

  6. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

    Science.gov (United States)

    Blau, C Anthony; Ramirez, Arturo B; Blau, Sibel; Pritchard, Colin C; Dorschner, Michael O; Schmechel, Stephen C; Martins, Timothy J; Mahen, Elisabeth M; Burton, Kimberly A; Komashko, Vitalina M; Radenbaugh, Amie J; Dougherty, Katy; Thomas, Anju; Miller, Christopher P; Annis, James; Fromm, Jonathan R; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A; Linenberger, Michael L; Becker, Pamela S; Senecal, Francis M; Mecham, Brigham H; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L; Stilwell, Jackie L; Kaldjian, Eric P; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.

  7. Highly adaptable triple-negative breast cancer cells as a functional model for testing anticancer agents.

    Directory of Open Access Journals (Sweden)

    Balraj Singh

    Full Text Available A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We describe a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have previously shown that metabolically adaptable cancer cells efficiently metastasize to multiple organs in nude mice. Here we show that the cancer cells modeled in our system feature an embryo-like gene expression and amplification of the fat mass and obesity associated gene FTO. We also provide evidence of upregulation of ZEB1 and downregulation of GRHL2 indicating increased epithelial to mesenchymal transition in metabolically adaptable cancer cells. Our results obtained with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance.

  8. The clonal and mutational evolution spectrum of primary triple negative breast cancers

    Science.gov (United States)

    Shah, Sohrab P.; Roth, Andrew; Goya, Rodrigo; Oloumi, Arusha; Ha, Gavin; Zhao, Yongjun; Turashvili, Gulisa; Ding, Jiarui; Tse, Kane; Haffari, Gholamreza; Bashashati, Ali; Prentice, Leah M.; Khattra, Jaswinder; Burleigh, Angela; Yap, Damian; Bernard, Virginie; McPherson, Andrew; Shumansky, Karey; Crisan, Anamaria; Giuliany, Ryan; Heravi-Moussavi, Alireza; Rosner, Jamie; Lai, Daniel; Birol, Inanc; Varhol, Richard; Tam, Angela; Dhalla, Noreen; Zeng, Thomas; Ma, Kevin; Chan, Simon; Griffith, Malachi; Moradian, Annie; Grace Cheng, S.-W.; Morin, Gregg B.; Watson, Peter; Gelmon, Karen; Chia, Stephen; Chin, Suet-Feung; Curtis, Christina; Rueda, Oscar; Pharoah, Paul D; Damaraju, Sambasivarao; Mackey, John; Hoon, Kelly; Harkins, Timothy; Tadigotla, Vasisht; Sigaroudinia, Mahvash; Gascard, Philippe; Tlsty, Thea; Costello, Joseph F; Meyer, Irmtraud M; Eaves, Connie J; Wasserman, Wyeth W; Jones, Steven; Huntsman, David; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel

    2013-01-01

    Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers1 and are a tumour type defined by exclusion, for which comprehensive landscapes of somatic mutation have not been determined. Here we show in 104 early TNBC cases, that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some exhibiting only a handful of somatic aberrations in a few pathways, whereas others contain hundreds of somatic events and multiple pathways implicated. Integration with matched whole transcriptome sequence data revealed that only ~36% of mutations are expressed. By examining single nucleotide variant (SNV) allelic abundance derived from deep re-sequencing (median >20,000 fold) measurements in 2414 somatic mutations, we determine for the first time in an epithelial tumour, the relative abundance of clonal genotypes among cases in the population. We show that TNBC vary widely and continuously in their clonal frequencies at the time of diagnosis, with basal subtype TNBC2,3 exhibiting more variation than non-basal TNBC. Although p53 and PIK3CA/PTEN somatic mutations appear clonally dominant compared with other pathways, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal and cell shape/motility proteins occurred at lower clonal frequencies, suggesting they occurred later during tumour progression. Taken together our results show that future attempts to dissect the biology and therapeutic responses of TNBC will require the determination of individual tumour clonal genotypes. PMID:22495314

  9. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

    Science.gov (United States)

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-01-01

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. PMID:28262781

  10. MiR-940 Inhibited Cell Growth and Migration in Triple-Negative Breast Cancer

    Science.gov (United States)

    Hou, Lingmi; Chen, Maoshan; Yang, Hongwei; Xing, Tianyong; Li, Jingdong; Li, Guangwu; Zhang, Lina; Deng, Shishan; Hu, Jiani; Zhao, Xiaobo; Jiang, Jun

    2016-01-01

    Background Breast cancer is the main type of cancer in women, and triple-negative breast cancer (TNBC) is a unique subtype of breast cancer. The expression of miR-940 has been shown to play an important role in various cancers; however, the role of miR-940 in TNBC remains unknown. Material/Methods The expression of miR-940 in TNBC tissues or cells were tested by qRT-PCR; the expression of miR-940 in cells were overexpressed by miR-940 mimics, and suppressed by anti-miR-940. Bioinformatics algorithms from TargetScanHuman were used to predict the target genes of miR-940. The interaction between miR-940 and ZNF24 was confirmed by dual luciferase assays. The protein level was assayed by Western blot. Results TNBC tissues and cells showed lower miR-940 levels. Conclusions MiR-940 inhibited cellular proliferation and migration in TNBC. PMID:27731867

  11. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting.

    Science.gov (United States)

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials.

  12. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

    Science.gov (United States)

    Bhola, Neil E.; Balko, Justin M.; Dugger, Teresa C.; Kuba, María Gabriela; Sánchez, Violeta; Sanders, Melinda; Stanford, Jamie; Cook, Rebecca S.; Arteaga, Carlos L.

    2013-01-01

    After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy. Biopsies after chemotherapy displayed increased RNA transcripts of genes associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse xenografts, the chemotherapeutic drug paclitaxel increased autocrine TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated by mammosphere formation and CSC markers. The TGF-β type I receptor kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8 transcription and CSC expansion. Moreover, treatment of TNBC xenografts with LY2157299 prevented reestablishment of tumors after paclitaxel treatment. These data suggest that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8–dependent expansion of CSCs and that TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. These findings support testing a combination of TGF-β inhibitors and anticancer chemotherapy in patients with TNBC. PMID:23391723

  13. [A Multivariate Analysis of the Efficacy of Adjuvant Chemotherapy in Triple-Negative Breast Cancer].

    Science.gov (United States)

    Nio, Yoshinori; Imai, Shiro; Uesugi, Kayo; Tamaoki, Mikako; Tamaoki, Masashi; Maruyama, Riruke

    2016-10-01

    Triple-negative breast cancers(TNBCs)are associated with early recurrence after surgery and unfavorable prognoses. To date, no effective therapies for TNBCs have been established. The present study was designed to evaluate the efficacy of adjuvant chemotherapy(ACT)for 111 TNBCs using a retrospective multivariate analysis(MVA). The intravenous(iv)ACTs included docetaxel, epirubicin, gemcitabine, and vinorelbine. The oral ACTs included UFT, doxifluridine, and cyclophosphamide. The 10-year disease-free survival(DFS)and overall survival(OS)rates were 77.5% and 86.0%, respectively. Recurrences were observed in 17 patients, and the first recurrence was most frequently located in the lung. MVA revealed that pT was a significant independent variable for poor DFS and OS. UFT was the only significant independent variable for improved DFS. The survival analysis also demonstrated that UFT alone may be an effective option for Stage I TNBCs. Furthermore, it suggested that the addition of further iv ACTs to UFT could improve the outcome in patients with Stage II-III TNBCs.

  14. Inhibition of triple-negative breast cancer models by combinations of antibodies to EGFR

    Science.gov (United States)

    Ferraro, Daniela A.; Gaborit, Nadège; Maron, Ruth; Cohen-Dvashi, Hadas; Porat, Ziv; Pareja, Fresia; Lavi, Sara; Lindzen, Moshit; Ben-Chetrit, Nir; Sela, Michael; Yarden, Yosef

    2013-01-01

    Breast tumors lacking expression of human epidermal growth factor receptor 2 (HER2) and the estrogen and the progesterone receptors (triple negative; TNBC) are more aggressive than other disease subtypes, and no molecular targeted agents are currently available for their treatment. Because TNBC commonly displays EGF receptor (EGFR) expression, and combinations of monoclonal antibodies to EGFR effectively inhibit other tumor models, we addressed the relevance of this strategy to treatment of TNBC. Unlike a combination of the clinically approved monoclonal antibodies, cetuximab and panitumumab, which displaced each other and displayed no cooperative effects, several other combinations resulted in enhanced inhibition of TNBC’s cell growth both in vitro and in animals. The ability of certain antibody mixtures to remove EGFR from the cell surface and to promote its intracellular degradation correlated with the inhibitory potential. However, unlike EGF-induced sorting of EGFR to lysosomal degradation, the antibody-induced pathway displayed independence from the intrinsic kinase activity and dimer formation ability of EGFR, and it largely avoided the recycling route. In conclusion, although TNBC clinical trials testing EGFR inhibitors reported lack of benefit, our results offer an alternative strategy that combines noncompetitive antibodies to achieve robust degradation of EGFR and tumor inhibition. PMID:23319610

  15. Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

    Science.gov (United States)

    Shen, Wanxiang; Zhang, Liang; Gu, Xinsheng; Guo, Yang; Tsai, Hsiang-i; Liu, Xuewen; Li, Jian; Zhang, Jingxuan; Li, Shan; Wu, Fuyun; Liu, Ying

    2017-01-01

    Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors. PMID:27861147

  16. Piperine inhibits the growth and motility of triple-negative breast cancer cells.

    Science.gov (United States)

    Greenshields, Anna L; Doucette, Carolyn D; Sutton, Kimberly M; Madera, Laurence; Annan, Henry; Yaffe, Paul B; Knickle, Allison F; Dong, Zhongmin; Hoskin, David W

    2015-02-01

    Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.

  17. Amygdalin Regulates Apoptosis and Adhesion in Hs578T Triple-Negative Breast Cancer Cells.

    Science.gov (United States)

    Lee, Hye Min; Moon, Aree

    2016-01-01

    Amygdalin, D-mandelonitrile-β-D-glucoside-6-β-glucoside, belongs to aromatic cyanogenic glycoside group derived from rosaceous plant seed. Mounting evidence has supported the anti-cancer effects of amygdalin. However, whether amygdalin indeed acts as an anti-tumor agent against breast cancer cells is not clear. The present study aimed to investigate the effect of amygdalin on the proliferation of human breast cancer cells. Here, we show that amygdalin exerted cytotoxic activities on estrogen receptors (ER)-positive MCF7 cells, and MDA-MB-231 and Hs578T triple-negative breast cancer (TNBC) cells. Amygdalin induced apoptosis of Hs578T TNBC cells. Amygdalin downregulated B-cell lymphoma 2 (Bcl-2), upregulated Bcl-2-associated X protein (Bax), activated of caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Amygdalin activated a pro-apoptotic signaling molecule p38 mitogen-activated protein kinases (p38 MAPK) in Hs578T cells. Treatment of amygdalin significantly inhibited the adhesion of Hs578T cells, in which integrin α5 may be involved. Taken together, this study demonstrates that amygdalin induces apoptosis and inhibits adhesion of breast cancer cells. The results suggest a potential application of amygdalin as a chemopreventive agent to prevent or alleviate progression of breast cancer, especially TNBC.

  18. Nuclear Kaiso expression is associated with high grade and triple-negative invasive breast cancer.

    Directory of Open Access Journals (Sweden)

    Jeroen F Vermeulen

    Full Text Available Kaiso is a BTB/POZ transcription factor that is ubiquitously expressed in multiple cell types and functions as a transcriptional repressor and activator. Little is known about Kaiso expression and localization in breast cancer. Here, we have related pathological features and molecular subtypes to Kaiso expression in 477 cases of human invasive breast cancer. Nuclear Kaiso was predominantly found in invasive ductal carcinoma (IDC (p = 0.007, while cytoplasmic Kaiso expression was linked to invasive lobular carcinoma (ILC (p = 0.006. Although cytoplasmic Kaiso did not correlate to clinicopathological features, we found a significant correlation between nuclear Kaiso, high histological grade (p = 0.023, ERα negativity (p = 0.001, and the HER2-driven and basal/triple-negative breast cancers (p = 0.018. Interestingly, nuclear Kaiso was also abundant in BRCA1-associated breast cancer (p<0.001 and invasive breast cancer overexpressing EGFR (p = 0.019. We observed a correlation between nuclear Kaiso and membrane-localized E-cadherin and p120-catenin (p120 (p<0.01. In contrast, cytoplasmic p120 strongly correlated with loss of E-cadherin and low nuclear Kaiso (p = 0.005. We could confirm these findings in human ILC cells and cell lines derived from conditional mouse models of ILC. Moreover, we present functional data that substantiate a mechanism whereby E-cadherin controls p120-mediated relief of Kaiso-dependent gene repression. In conclusion, our data indicate that nuclear Kaiso is common in clinically aggressive ductal breast cancer, while cytoplasmic Kaiso and a p120-mediated relief of Kaiso-dependent transcriptional repression characterize ILC.

  19. Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

    Directory of Open Access Journals (Sweden)

    Mirco Pistelli

    2014-06-01

    Full Text Available Background: Triple-negative breast cancers (TNBC are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001 and a lympho-vascular invasion (p = 0.01, but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72 or overall survival (p = 0.93. Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

  20. Do signal transduction cascades influence survival in triple-negative breast cancer? A preliminary study

    Science.gov (United States)

    Mumm, Jan-Niclas; Kölbl, Alexandra C; Jeschke, Udo; Andergassen, Ulrich

    2016-01-01

    Background Triple-negative breast cancer (TNBC) is a rather aggressive form of breast cancer, comprised by early metastasis formation and reduced overall survival of the affected patients. Steroid hormone receptors and the human epidermal growth factor receptor 2 are not overexpressed, limiting therapeutic options. Therefore, new treatment options have to be investigated. The aim of our preliminary study was to detect coherences between some molecules of intracellular signal transduction pathways and survival of patients with TNBC, in order to obtain some hints for new therapeutical solutions. Methods Thirty-one paraffin-embedded tumor tissue samples, which were determined to be negative for steroid hormone receptors as well as human epidermal growth factor receptor 2, were immunohistochemically stained for a number of signal transduction molecules from several signaling pathways. β-Catenin, HIF1α, MCL, Notch1, LRP6, XBP1, and FOXP3 were stained with specific antibodies, and their staining was correlated with patient survival by Kaplan–Meier analyses. Results Only two of the investigated molecules have shown correlation with overall survival. Cytoplasmic staining of HIF1α and centro-tumoral lymphocyte FOXP3 staining showed statistically significant correlations with survival. Conclusion The coherence of signal transduction molecules with survival of patients with TNBC is still controversially discussed in the literature. Our study comprises one more mosaic stone in the elucidation of these intracellular processes and their influences on patient outcome. Lots of research still has to be done in this field, but it would be worthwhile as it may offer new therapeutic targets for a group of patients with breast cancer, which is still hard to treat. PMID:27307757

  1. Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

    Energy Technology Data Exchange (ETDEWEB)

    Pistelli, Mirco, E-mail: mirco.pistelli@alice.it; Caramanti, Miriam [Clinica di Oncologia Medica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy); Biscotti, Tommasina; Santinelli, Alfredo [Anatomia Patologica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy); Pagliacci, Alessandra; De Lisa, Mariagrazia; Ballatore, Zelmira; Ridolfi, Francesca; Maccaroni, Elena; Bracci, Raffaella; Berardi, Rossana; Battelli, Nicola; Cascinu, Stefano [Clinica di Oncologia Medica, AO Ospedali Riuniti-Ancona, Università Politecnica delle Marche, Ancona 60020 (Italy)

    2014-06-27

    Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

  2. Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression.

    Science.gov (United States)

    Parvani, Jenny G; Davuluri, Gangarao; Wendt, Michael K; Espinosa, Christine; Tian, Maozhen; Danielpour, David; Sossey-Alaoui, Khalid; Schiemann, William P

    2015-03-01

    Transforming growth factor-β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain-containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α-negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.

  3. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer.

    Science.gov (United States)

    Skor, Maxwell N; Wonder, Erin L; Kocherginsky, Masha; Goyal, Anju; Hall, Ben A; Cai, Yi; Conzen, Suzanne D

    2013-11-15

    Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy. TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel. We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo. These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy

  4. Clinical correlates of 'BRCAness' in triple-negative breast cancer of patients receiving adjuvant chemotherapy.

    Science.gov (United States)

    Oonk, A M M; van Rijn, C; Smits, M M; Mulder, L; Laddach, N; Savola, S P; Wesseling, J; Rodenhuis, S; Imholz, A L T; Lips, E H

    2012-09-01

    We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients. DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups. Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival. BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.

  5. NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer.

    Science.gov (United States)

    Ademuyiwa, Foluso O; Bshara, Wiam; Attwood, Kristopher; Morrison, Carl; Edge, Stephen B; Karpf, Adam R; James, Smith A; Ambrosone, Christine B; O'Connor, Tracey L; Levine, Ellis G; Miliotto, Anthony; Ritter, Erika; Ritter, Gerd; Gnjatic, Sacha; Odunsi, Kunle

    2012-01-01

    NY-ESO-1 cancer testis (CT) antigen is an attractive candidate for immunotherapy as a result of its high immunogenicity. The aim of this study was to explore the potential for NY-ESO-1 antigen directed immunotherapy in triple negative breast cancer (TNBC) by determining the frequency of expression by immunohistochemistry (IHC) and the degree of inherent immunogenicity to NY-ESO-1. 168 TNBC and 47 ER+/HER2- primary breast cancer specimens were used to determine NY-ESO-1 frequency by IHC. As previous studies have shown that patients with a robust innate humoral immune response to CT antigens are more likely to develop CD8 T-cell responses to NY-ESO-1 peptides, we evaluated the degree to which patients with NY-ESO-1 expression had inherent immunogenicity by measuring antibodies. The relationship between NY-ESO-1 expression and CD8+ T lymphocytes was also examined. The frequency of NY-ESO-1 expression in the TNBC cohort was 16% versus 2% in ER+/HER2- patients. A higher NY-ESO-1 score was associated with a younger age at diagnosis in the TNBC patients with NY-ESO-1 expression (p = 0.026). No differences in OS (p = 0.278) or PFS (p = 0.238) by NY-ESO-1 expression status were detected. Antibody responses to NY-ESO-1 were found in 73% of TNBC patients whose tumors were NY-ESO-1 positive. NY-ESO-1 positive patients had higher CD8 counts than negative patients (p = 0.018). NY-ESO-1 is expressed in a substantial subset of TNBC patients and leads to a high humoral immune response in a large proportion of these individuals. Given these observations, patients with TNBC may benefit from targeted therapies directed against NY-ESO-1.

  6. Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

    Science.gov (United States)

    Pistelli, Mirco; Caramanti, Miriam; Biscotti, Tommasina; Santinelli, Alfredo; Pagliacci, Alessandra; De Lisa, Mariagrazia; Ballatore, Zelmira; Ridolfi, Francesca; Maccaroni, Elena; Bracci, Raffaella; Berardi, Rossana; Battelli, Nicola; Cascinu, Stefano

    2014-01-01

    Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target. PMID:24978437

  7. Deptor Enhances Triple-Negative Breast Cancer Metastasis and Chemoresistance through Coupling to Survivin Expression

    Directory of Open Access Journals (Sweden)

    Jenny G. Parvani

    2015-03-01

    Full Text Available Transforming growth factor–β (TGF-β functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs. Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR inhibitor, Dep domain–containing mTOR-interacting protein (Deptor, in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1 inversely correlated with the metastatic ability of human (MCF10A and mouse (4T1 TNBC progression series and 2 robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α–negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1 organoid growth in vitro, 2 pulmonary outgrowth in mice, and 3 resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.

  8. Analysis on Node Position of Imperfect Resonators for Cylindrical Shell Gyroscopes

    Science.gov (United States)

    Wang, Zidan; Wu, Yulie; Xi, Xiang; Zhang, Yongmeng; Wu, Xuezhong

    2016-01-01

    For cylindrical shell gyroscopes, node position of their operating eigenmodes has an important influence on the gyroscopes’ performance. It is considered that the nodes are equally separated from each other by 90° when the resonator vibrates in the standing wave eigenmode. However, we found that, due to manufacturing errors and trimming, the nodes may not be equally distributed. This paper mainly analyzes the influences of unbalanced masses on the cylindrical resonators’ node position, by using FEM simulation and experimental measurement. PMID:27483284

  9. Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.

    Science.gov (United States)

    Fostira, Florentia; Tsitlaidou, Marianthi; Papadimitriou, Christos; Pertesi, Maroulio; Timotheadou, Eleni; Stavropoulou, Alexandra V; Glentis, Stavros; Bournakis, Evangelos; Bobos, Mattheos; Pectasides, Dimitrios; Papakostas, Pavlos; Pentheroudakis, George; Gogas, Helen; Skarlos, Pantelis; Samantas, Epaminontas; Bafaloukos, Dimitrios; Kosmidis, Paris A; Koutras, Angelos; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Fountzilas, George

    2012-07-01

    In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations. Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8%. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77% of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16%). Median age of onset for mutation carriers was 39 years. Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36%) had a BRCA1 mutation, while 27% of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48% (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer. It is noteworthy, however, that of the 65 carriers, 15 (23%) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98%). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.

  10. Additional value of (18)F-FDG PET/CT response evaluation in axillary nodes during neoadjuvant therapy for triple-negative and HER2-positive breast cancer.

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    van Ramshorst, Mette S; Teixeira, Suzana C; Koolen, Bas B; Pengel, Kenneth E; Gilhuijs, Kenneth G; Wesseling, Jelle; Rodenhuis, Sjoerd; Valdés Olmos, Renato A; Rutgers, Emiel J; Vogel, Wouter V; Sonke, Gabe S; Vrancken Peeters, Marie-Jeanne T

    2017-05-25

    (18)F-FDG PET/CT can monitor metabolic activity in early breast cancer during neoadjuvant systemic therapy (NST), but it is unknown if the metabolic breast and axillary response differ. We evaluated the correlation between metabolic breast and axillary response at various time points during NST. Furthermore, we analysed if the combined metabolic response improves pathologic complete response (pCR) prediction compared to using the metabolic breast response alone. (18)F-FDG PET/CT was performed at baseline (PET1), 2-3 weeks (PET2), and 6-8 weeks (PET3) of NST in patients with triple-negative (TN) and HER2-positive node-positive breast cancer. SUVmax and ∆SUVmax were determined separately for breast and axilla. Spearman's correlation coefficients (r) between both localisations were calculated. The accuracy of pCR total (ypT0/is,ypN0) prediction using the metabolic response in breast, axilla or both was examined using logistic regression analysis. Hundred-five patients were included: 45 TN and 60 HER2-positive tumours. The metabolic response in breast and axilla correlated moderately in TN tumours (r = 0.57) using ∆SUVmax between PET1-PET3 and poorly in HER2-positive tumours (r = 0.49) using SUVmax at PET2. In TN tumours, metabolic breast response predicted pCR well without improvement after adding axillary response (c-index 0.82 versus 0.85, p = 0.63). In HER2-positive tumours, metabolic breast response predicted pCR poorly with improvement after adding axillary response (c-index 0.64 versus 0.72, p = 0.06). (18)F-FDG PET/CT response during NST differs between breast and axilla. In TN tumours, pCR total prediction can be made independent of metabolic axillary response. In HER2-positive tumours, axillary response may improve pCR total prediction. These findings may help guide PET/CT-response-based changes during NST. NTR NTR1797 . Registered 29 May 2009, retrospectively registered.

  11. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

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    Jones, Robert A.; Robinson, Tyler J.; Liu, Jeff C.; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E.D.; Pellecchia, Giovanna; Fell, Victoria L.; Bae, SooIn; Muthuswamy, Lakshmi; Egan, Sean E.; Jiang, Zhe; Leone, Gustavo; Bader, Gary D.; Schimmer, Aaron

    2016-01-01

    Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC. PMID:27571409

  12. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer

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    Takai, Ken; Le, Annie; Weaver, Valerie M.; Werb, Zena

    2016-01-01

    Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-β (TGF-β) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-β antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-β signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-β activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-β signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction. PMID:27756881

  13. Silibinin inhibits triple negative breast cancer cell motility by suppressing TGF-β2 expression.

    Science.gov (United States)

    Kim, Sangmin; Han, Jeonghun; Jeon, Myeongjin; You, Daeun; Lee, Jeongmin; Kim, Hee Jung; Bae, Sarang; Nam, Seok Jin; Lee, Jeong Eon

    2016-08-01

    Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that regulates many biological events including cell motility and angiogenesis. Here, we investigated the role of elevated TGF-β2 level in triple negative breast cancer (TNBC) cells and the inhibitory effect of silibinin on TGF-β2 action in TNBC cells. Breast cancer patients with high TGF-β2 expression have a poor prognosis. The levels of TGF-β2 expression increased significantly in TNBC cells compared with those in non-TNBC cells. In addition, cell motility-related genes such as fibronectin (FN) and matrix metalloproteinase-2 (MMP-2) expression also increased in TNBC cells. Basal FN, MMP-2, and MMP-9 expression levels decreased in response to LY2109761, a dual TGF-β receptor I/II inhibitor, in TNBC cells. TNBC cell migration also decreased in response to LY2109761. Furthermore, we observed that TGF-β2 augmented the FN, MMP-2, and MMP-9 expression levels in a time- and dose-dependent manner. In contrast, TGF-β2-induced FN, MMP-2, and MMP-9 expression levels decreased significantly in response to LY2109761. Interestingly, we found that silibinin decreased TGF-β2 mRNA expression level but not that of TGF-β1 in TNBC cells. Cell migration as well as basal FN and MMP-2 expression levels decreased in response to silibinin. Furthermore, silibinin significantly decreased TGF-β2-induced FN, MMP-2, and MMP-9 expression levels and suppressed the lung metastasis of TNBC cells. Taken together, these results suggest that silibinin suppresses metastatic potential of TNBC cells by inhibiting TGF-β2 expression in TNBC cells. Thus, silibinin may be a promising therapeutic drug to treat TNBC.

  14. Overweight as a Prognostic Factor for Triple-Negative Breast Cancers in Chinese Women.

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    Shuang Hao

    Full Text Available Obesity is associated with poorer outcomes in patients with hormone receptor-positive breast cancers, but this association is not well established for women with triple-negative breast cancers (TNBC. Here, we investigated the prognostic effects of body mass index (BMI on clinical outcomes in patients with TNBC.We identified 1106 patients with TNBC who met the inclusion criteria and were treated between January 2002 and June 2012. Clinical and biological features were collected to evaluate the relation between BMI and breast cancer-specific survival (BCSS and overall survival (OS after controlling for other clinically significant variables.Of 1106 patients, 656 (59.3% were normal weight (BMI ≤24 and 450 patients (40.7% were overweight(BMI>24. Median follow-up time was 44.8 months. Breast cancer specific death was observed in 140 patients. After adjusting for clinicopathologic risk factors, overweight was associated with OS (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.04-2.06, P =0.028 but not BCSS (HR: 1.34, 95% CI: 0.90-2.01, P =0.15in all the patients with TNBC. When stratified with menopausal status, overweight was associated with BCSS and OS (HR: 2.27, 95% CI: 1.11-4.63, P = 0.024 and HR: 2.16, 95% CI: 1.21-3.87, P = 0.010, respectively in premenopausal women. BMI was not associated with BCSS or OS in postmenopausal women.Overweight is an independent prognostic factor of OS in all women with TNBC, and menopause status may be a mitigating factor. Among premenopausal women, overweight women are at a greater risk of poor prognosis than normal weight women. If validated, these findings should be considered in developing preventive programs.

  15. Opportunities for improving triple-negative breast cancer outcomes: results of a population-based study.

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    Rapiti, Elisabetta; Pinaud, Kim; Chappuis, Pierre O; Viassolo, Valeria; Ayme, Aurélie; Neyroud-Caspar, Isabelle; Usel, Massimo; Bouchardy, Christine

    2017-03-01

    Triple-negative breast cancer (TNBC) is associated with a poor prognosis. Surgery, radiotherapy, chemotherapy, and referral for genetic counseling are the standard of care. We assessed TNBC prevalence, management, and outcome using data from the population-based Geneva cancer registry. 2591 women had a first invasive stage I-III breast cancer diagnosed between 2003 and 2011. We compared TNBC to other breast cancers (OBC) by χ(2) -test and logistic regression. Kaplan-Meier survival curves, up to 31-12-2014, were compared using log-rank test. TNBC risk of mortality overall (OS) and for breast cancer (BCSS) was evaluated through Cox models. Linkage with the Oncogenetics and Cancer Prevention Unit (OCPU) database of the Geneva University Hospitals provided genetic counseling information. TNBC patients (n = 192, 7.4%) were younger, more often born in Africa or Central-South America than OBC, had larger and more advanced tumors. 18% of TNBC patients did not receive chemotherapy. Thirty-one (17%) TNBC women consulted the OCPU, 39% among those aged <40 years. Ten-year survival was lower in TNBC than OBC (72% vs. 82% for BCSS; P < 0.001; 80% vs. 91% for OS; P < 0.001). The mortality risks remained significant after adjustment for other prognostic variables. The strongest determinants of mortality were age, place of birth, and lymph node status. A substantial proportion of TNBC patients in Geneva did not receive optimal care. Over 60% of eligible women did not receive genetic counseling and 18% did not receive chemotherapy. To improve TNBC prognosis, comprehensive care as recommended by standard guidelines should be offered to all patients.

  16. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells

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    Cook, Matthew T; Liang, Yayun; Besch-Williford, Cynthia; Hyder, Salman M

    2017-01-01

    Most breast cancer-related deaths from triple-negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic non-targeted treatment strategies. Women with TNBC frequently develop metastatic lesions originating from drug-resistant residual cells and have poor prognosis. For this reason, novel therapeutic strategies that are safer and more effective are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer. With this in mind, we conducted in vivo and in vitro studies to determine whether LU might suppress metastasis of TNBC. In an in vivo mouse metastasis model, LU suppressed metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. In in vitro assays, LU inhibited cell migration and viability of MDA-MB-435 and MDA-MB-231 (4175) LM2 cells. Further, LU induced apoptosis in MDA-MB-231 (4175) LM2 cells. Relatively low levels (10 µM) of LU significantly inhibited vascular endothelial growth factor (VEGF) secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor. In addition, migration of MDA-MB-231 (4175) LM2 cells was inhibited upon exposure to an antibody against the VEGF receptor, KDR, but not by exposure to a VEGF165 antibody. Collectively, these data suggest that the anti-metastatic properties of LU may, in part, be due to its ability to block VEGF production and KDR-mediated activity, thereby inhibiting tumor cell migration. These studies suggest that LU deserves further investigation as a potential treatment option for women with TNBC. PMID:28096694

  17. Efficacy of carboplatin-based preoperative chemotherapy for triple-negative breast cancer

    Science.gov (United States)

    Wang, Li-Yang; Xie, Hua; Zhou, Hang; Yao, Wen-Xiu; Zhao, Xin; Wang, Yi

    2017-01-01

    Objectives: To evaluate the efficacy and safety of carboplatin-based preoperative chemotherapy in triple-negative breast cancer patients (TNBC). Methods: PubMed, EMBASE, the Web of Science, the Cochrane Library, major clinical trial registries, and abstract collections from major international meetings were systematically searched for relevant randomized controlled trials. Endpoints included rates of pathologic complete response (pCR), overall response (ORR), breast-conserving surgery (BCS) and toxicity. Pooled relative risk (RR) was calculated for each endpoint using a fixed- or random-effect model depending on the heterogeneity among included studies. Results: A total of 5 randomized controlled trials involving 1007 patients were included in the meta-analysis. Carboplatin-based chemotherapy was associated with a pooled pCR rate of 53.3%, which was significantly higher than the rate associated with non-carboplatin therapy (37.8%, RR: 1.41, 95% confidence interval [CI]: 1.23 to 1.62, p<0.00001). Compared with non-carboplatin therapy (48.1%), carboplatin-based chemotherapy increased BCS rate (59.7%, RR: 1.24, 95% CI: 1.06 to 1.46, p=0.007). Carboplatin-based chemotherapy was associated with similar ORR as non-carboplatin therapy. Carboplatin-based chemotherapy was associated with higher incidence of grade 3 or 4 anemia, neutropenia, febrile neutropenia, and thrombocytopenia than non-carboplatin therapy, while the 2 regimens were associated with similar incidence of fatigue, leucopenia, and nausea/vomiting. Conclusion: The available evidence suggests that carboplatin-based preoperative chemotherapy is associated with significantly better pCR and BCS rates than non-carboplatin-based therapy in TNBC patients. PMID:28042625

  18. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

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    Kun-Chun Chiang

    2016-04-01

    Full Text Available Regarding breast cancer treatment, triple negative breast cancer (TNBC is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl-1α,25(OH2D3, the newly-synthesized 1α,25(OH2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9 activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.

  19. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

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    Paolo Cossu-Rocca

    Full Text Available Triple Negative Breast Cancer (TNBC accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

  20. Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures.

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    Thomas Karn

    Full Text Available BACKGROUND: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes. METHODOLOGY/PRINCIPAL FINDINGS: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases. CONCLUSIONS/SIGNIFICANCE: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets and a smaller (n = 26 probesets prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71-9.48; P = 0.001 and 4.08 (95% CI 1.79-9.28; P = 0.001, respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588 to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.

  1. Profiling EGFR in Triple Negative Breast Tumor Using Affibody PET Imaging

    Institute of Scientific and Technical Information of China (English)

    Yingding Xu; Gang Ren; Shibo Qi; Zhen Cheng

    2016-01-01

    Objective Triple negative breast cancer(TNBC) represents a group of refractory breast cancers with aggressive clinical manifestations as well as poor prognoses.Human epidermal growth factor receptor(EGFR) expression is strongly associated with TNBC progression and it may serve as a therapeutic target for TNBC.We aimed to evaluate EGFR affibody-based PET imaging to profile EGFR expression in small animal models.Methods 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(DOTA) conjugated Ac-Cys-ZEGFR:1907 was chemically synthesized using solid phase peptide synthesizer and then radiolabeled with 64Cu.The in vitro cell uptake study was performed using SUM159 and MCF7 cells.The biodistribution and small animal PET imaging using 64Cu-DOTA-ZEGFR:1907 were further carried out with nude mice bearing subcutaneous MDA-MB-231 and SUM159 tumors.Results DOTA-Ac-Cys-ZEGFR:1907 was successfully synthesized and radiolabeled with 64Cu.Biodistribution study showed that tumor uptake value of 64Cu-DOTA-Ac-Cys-ZEGFR:1907 remained at(4.07±0.93)%ID/g at 24 h in nude mice(n=4) bearing SUM159 xenografts.Furthermore,small animal PET imaging study clearly showed that 64Cu-DOTA-Ac-Cys-ZEGFR:1907 specifically delineated the EGFR positive TNBC tumors at 4 h or later.Conclusion The study demonstrates that 64Cu-DOTA-Ac-Cys-ZEGFR:1907 is a promising molecular probe for PET imaging of EGFR positive TNBC.EGFR based small protein scaffold holds great promise as a novel platform that can be used for EGFR profiling of TNBC.

  2. E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple negative breast cancer.

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    Liao, Liqiu; Song, Mei; Li, Xin; Tang, Lili; Zhang, Tuo; Zhang, Lixing; Pan, Yihang; Chouchane, Lotfi; Ma, Xiaojing

    2017-03-22

    Patients with triple negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. Here we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinoma model of TNBC dramatically abrogated tumor growth and metastasis in vivo, which could be reversed completely via reconstitution with wild type UBR5 but not a catalytically inactive mutant. Loss of UBR5 caused an impairment in angiogenesis within the tumor, associated with increased apoptosis, necrosis, and growth arrest. Absence of UBR5 in the tumor triggered aberrant epithelial to mesenchymal transition (EMT), principally via abrogated expression of E-cadherin, which resulted in severely reduced tumor metastasis to secondary organs. Use of NOD/SCID mice revealed that tumor-derived UBR5 facilitated tumor growth in a manner completely dependent upon immune cells in the microenvironment, whereas it promoted metastasis in a tumor cell-autonomous fashion. Our findings unveil UBR5 as a novel and critical regulator of tumor growth, metastasis, and immune response, and highlight the potential for UBR5 as an effective therapeutic target for the treatment of highly aggressive breast and ovarian cancers that fail conventional therapy.

  3. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

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    Chen, Xi; Iliopoulos, Dimitrios; Zhang, Qing; Tang, Qianzi; Greenblatt, Matthew B; Hatziapostolou, Maria; Lim, Elgene; Tam, Wai Leong; Ni, Min; Chen, Yiwen; Mai, Junhua; Shen, Haifa; Hu, Dorothy Z; Adoro, Stanley; Hu, Bella; Song, Minkyung; Tan, Chen; Landis, Melissa D; Ferrari, Mauro; Shin, Sandra J; Brown, Myles; Chang, Jenny C; Liu, X Shirley; Glimcher, Laurie H

    2014-04-01

    Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.

  4. Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study.

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    Recchia, Francesco; Candeloro, Giampiero; Desideri, Giovambattista; Necozione, Stefano; Recchia, Cornelia O C; Cirulli, Vincenzo; Rea, Silvio

    2012-08-01

    Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile.

  5. Histological analysis of gamma delta T lymphocytes infiltrating human triple-negative breast carcinomas

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    Jose Villacorta Hidalgo

    2014-12-01

    Full Text Available Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic and prognostic factors. Triple-negative breast cancers (TNBCs lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs are somewhat less frequent. Infiltrating T cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of γδ T cells within CD3+ tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs and 12 MBCs, using immunohistochemistry for the quantity and patterns of γδ T-cell infitrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of γδ T cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating γδ T cells were higher in MBCs than in IDCs. γδ T cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most γδ T cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient’s prognosis in MBCs is better than that in IDCs. Further studies to characterize these γδ T cells at the molecular and functional level are in progress.

  6. Current advances in biomarkers for targeted therapy in triple-negative breast cancer

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    Fleisher B

    2016-10-01

    Full Text Available Brett Fleisher,1 Charlotte Clarke,2 Sihem Ait-Oudhia1 1Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, 2Department of Translational Research, UT MD Anderson Cancer Center, Houston, TX, USA Abstract: Triple-negative breast cancer (TNBC is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-­8; cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the glucocorticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC. Keywords: anti-cancer directed pharmacotherapy, difficult

  7. Integrated analysis of differentially expressed genes and pathways in triple-negative breast cancer

    Science.gov (United States)

    Peng, Cancan; Ma, Wenli; Xia, Wei; Zheng, Wenling

    2017-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by an aggressive phenotype and reduced survival. The aim of the present study was to investigate the molecular mechanisms involved in the carcinogenesis of TNBC and to identify novel target molecules for therapy. The differentially expressed genes (DEGs) in TNBC and normal adjacent tissue were assessed by analyzing the GSE41970 microarray data using Qlucore Omics Explorer, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes. Pathway enrichment analyses for DEGs were performed using the Database for Annotation, Visualization and Integrated Discovery online resource. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes, and subnetworks were analyzed by ClusterONE. The PPI network and subnetworks were visualized using Cytoscape software. A total of 121 DEGs were obtained, of which 101 were upregulated and 20 were downregulated. The upregulated DEGs were significantly enriched in 14 pathways and 83 GO biological processes, while the downregulated DEGs were significantly enriched in 18 GO biological processes. The PPI network with 118 nodes and 1,264 edges was constructed and three subnetworks were extracted from the entire network. The significant hub DEGs with high degrees were identified, including TP53, glyceraldehyde-3-phosphate dehydrogenase, cyclin D1, HRAS and proliferating cell nuclear antigen, which were predominantly enriched in the cell cycle pathway and pathways in cancer. A number of critical genes and pathways were revealed to be associated with TNBC. The present study may provide an improved understanding of the pathogenesis of TNBC and contribute to the development of therapeutic targets for TNBC. PMID:28075450

  8. Histological Analysis of γδ T Lymphocytes Infiltrating Human Triple-Negative Breast Carcinomas.

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    Hidalgo, Jose Villacorta; Bronsert, Peter; Orlowska-Volk, Marzenna; Díaz, Liliana B; Stickeler, Elmar; Werner, Martin; Schmitt-Graeff, Annette; Kayser, Gian; Malkovsky, Miroslav; Fisch, Paul

    2014-01-01

    Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic, and prognostic factors. Triple-negative breast carcinomas (TNBCs) lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs) with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs) are somewhat less frequent. Infiltrating T-cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of γδ T-cells within CD3(+) tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs, and 12 MBCs, using immunohistochemistry for the quantity and patterns of γδ T-cell infiltrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of γδ T-cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating γδ T-cells were higher in MBCs than in IDCs. γδ T-cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most γδ T-cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient's prognosis in MBCs is better than that in IDCs. Further studies to characterize these γδ T-cells at the molecular and functional level are in progress.

  9. The contributions of the tissue inhibitor of metalloproteinase-1 genotypes to triple negative breast cancer risk.

    Science.gov (United States)

    Chang, Wen-Shin; Liu, Liang-Chih; Hsiao, Chieh-Lun; Su, Chen-Hsien; Wang, Hwei-Chung; Ji, Hong-Xue; Tsai, Chia-Wen; Maa, Ming-Chei; Bau, Da-Tian

    2016-03-01

    The tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins which have been shown to be upregulated in various types of cancers. However, the contribution of TIMPs in breast cancer is not fully understood, not to mention triple negative breast cancer (TNBC). This study's aim was to evaluate the contribution of TIMP-1 rs4898, rs6609533, and rs2070584 genotypes to the risk of breast cancer, especially the subtype of TNBC. The contributions of these TIMP-1 genotypes to cancer risk were examined among 1232 breast cancer patients and 1232 healthy controls, and several clinicopathologic factors were also analyzed. The results showed that the percentages of CC, CT, and TT of TIMP-1 rs4898 were differentially distributed at 28.5%, 33.1% and 38.4% in the breast cancer patient group and 34.5%, 41.0% and 24.5% in the control group, respectively (P for trend = 7.99*10(-13)). It was also found that the CC genotype carriers were of increased risk for breast cancer (odds ratio = 1.90, 95% confidence interval = 1.55-2.33, P = 0.0001) than the TT genotype carriers. In addition, we analyzed the allelic frequency distributions of all three TIMP-1s, and the results showed that the C allele of TIMP-1 rs4898 contributes to an increase in breast cancer susceptibility (P = 2.41*10(-12)). On the other hand, there was no difference found in the distribution of genotypic or allelic frequencies among the patients and the controls for TIMP-1 rs6609533 and rs2070584. Thus, it is our conclusion that the CC genotype of TIMP-1 rs4898 compared to the TT wild-type genotype may increase the risk for breast cancer, especially TNBC in Taiwan, and may serve as an early detective and predictive marker.

  10. The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics.

    Science.gov (United States)

    Anders, Carey K; Abramson, Vandana; Tan, Tira; Dent, Rebecca

    2016-01-01

    Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as "immune-activated," consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

  11. Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer.

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    Mahavir B Chougule

    Full Text Available BACKGROUND: The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC. METHODS: TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. RESULTS: Noscapine inhibited growth of MDA-MB-231 and MDA-MB-468 cells with the IC(50 values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59 were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150-550 mg/kg/day compared to controls. Noscapine (300 mg/kg, Doxorubicin (1.5 mg/kg and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups. CONCLUSIONS: Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC.

  12. Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer

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    Doddapaneni, Ravi; Patel, Ketan; Chowdhury, Nusrat; Singh, Mandip

    2016-01-01

    Chemosensitization and enhanced delivery to solid tumor are widely explored strategies to augment the anticancer efficacy of existing chemotherapeutics agents. The aim of current research was to investigate the role of low dose Noscapine (Nos) in potentiating docetaxel cytotoxicity and enhancing tumor penetration of nanocarriers. The objectives are; (1) To evaluate the chemo-sensitizing effect of Nos in combination with docetaxel (DTX), and to elucidate the possible mechanism (2) To investigate the effect of low dose Nos on tumor stroma and enhancing nanocarrier uptake in triple negative breast cancer (TNBC) bearing nude mice. Cytotoxicity and flow cytometry analysis of DTX in Nos (4 µM) pre-treated MDA-MB-231 cells showed 3.0-fold increase in cell killing and 30% increase in number of late apoptotic cells, respectively. Stress transducer p38 phosphorylation was significantly upregulated with Nos exposure. DTX showed remarkable downregulation in expression of bcl-2, survivin and pAKT in Nos pre-treated MDA-MB-231 cells. Nos pre-sensitization significantly (p < 0.02) enhanced the anti-migration effect of DTX. In vivo studies in orthotopic TNBC tumor bearing mice showed marked reduction in tumor collagen-I levels and significantly (p < 0.03) higher intra-tumoral uptake of coumarin-6 loaded PEGylated liposomes (7-fold) in Nos treated group. Chemo-sensitization and anti-fibrotic effect of Nos could be a promising approach to increase anticancer efficacy of DTX which can be used for other nanomedicinal products. PMID:27177833

  13. Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.

    Science.gov (United States)

    Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane; Wong-Goodrich, Sarah J; Kramp, Tamalee; Gril, Brunilde; Shukla, Sudhanshu; Lyle, Tiffany; Hua, Emily; Cameron, Heather A; Camphausen, Kevin; Steeg, Patricia S

    2015-10-01

    Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

  14. Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer.

    Science.gov (United States)

    Bramante, Simona; Koski, Anniina; Liikanen, Ilkka; Vassilev, Lotta; Oksanen, Minna; Siurala, Mikko; Heiskanen, Raita; Hakonen, Tiina; Joensuu, Timo; Kanerva, Anna; Pesonen, Sari; Hemminki, Akseli

    2016-02-01

    Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage. Therefore, the combination of oncolytic immuno-virotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and in vivo in an orthotopic xenograft mouse model, in combination with low-dose CP or its main active metabolite 4-hydroperoxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data on this virus from the Advanced Therapy Access Program (ATAP). Low-dose CP increased the efficacy of Ad5/3-D24-GMCSF in vitro and in a TNBC mouse model. In ATAP, treatments appeared safe and well-tolerated. Thirteen out of 16 breast cancer patients treated were evaluable for possible benefits with modified RECIST 1.1 criteria: 1 patient had a minor response, 2 had stable disease (SD), and 10 had progressive disease (PD). One patient is alive at 1,771 d after treatment. Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.

  15. Maspin expression is frequent and correlates with basal markers in triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Sagara Yasuaki

    2011-04-01

    Full Text Available Abstract Background Maspin is a unique member of the serine protease inhibitor superfamily and its expression is found in myoepithelial cells of normal mammary glands; therefore, it has been considered to be a myoepithelial marker. We previously reported that maspin was frequently expressed in biologically aggressive breast cancers. In turn, triple-negative (TN breast cancer is a subtype of tumor with aggressive clinical behavior and shows frequent expression of basal markers. We hypothesized that maspin expression may be frequent and correlate with basal rather than myoepithelial markers in TN breast cancer. Methods Paraffin-embedded 135 TN invasive ductal carcinoma tissue samples were immunohistochemically investigated using the Dako Envision+ kit and primary antibodies for maspin, basal (CK5/6, EGFR, CK14 and myoepithelial markers (p63, CD10. The correlation between maspin expression and relapse-free survival (RFS was investigated by the log-rank test. Results The positive rate for maspin was 85.9% and significantly correlated with younger age (P = 0.0015, higher histological grade (P = 0.0013, CK5/6 positivity (P P = 0.0034 and the basal-like subtype defined by CK5/6, EGFR and CK14 positivity (P = 0.013. The positive rates for CK5/6, EGFR, CK14, CD10 and p63 were 59.2%, 48.9%, 34.1%, 17.8% and 12.6%, respectively. There was no significant correlation between maspin expression and RFS. Conclusions The positive rate for maspin is the highest among known basal and myoepithelial markers, and strongly correlates with basal markers in TN breast cancer. These results suggested that maspin could be a candidate for a therapeutic target for TN breast cancer.

  16. Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer.

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    Malathi Banda

    Full Text Available TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR or amplified human epidermal growth factor receptor type 2 (HER2, and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1 in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy.

  17. RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer.

    Science.gov (United States)

    Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge; Ertel, Adam; Fortina, Paolo; Witkiewicz, Agnieszka K

    2015-01-01

    Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC.

  18. Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants.

    Science.gov (United States)

    Pareja, Fresia; Geyer, Felipe C; Marchiò, Caterina; Burke, Kathleen A; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Nonetheless, TNBC has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well-characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Secretory and adenoid cystic carcinomas are two histologic types of TNBCs underpinned by specific fusion genes; these tumors have an indolent clinical behavior and lack all of the cardinal molecular features of high-grade triple-negative disease. Recent studies of rare entities, including lesions once believed to constitute mere benign breast disease (e.g., microglandular adenosis), have resulted in the identification of potential precursors of TNBC and suggested the existence of a family of low-grade triple-negative lesions that, despite having low-grade morphology and indolent clinical behavior, have been shown to harbor the complex genomic landscape of common forms of TNBC, and may progress to high-grade disease. In this review, we describe the heterogeneity of TNBC and focus on the histologic and molecular features of low-grade forms of TNBC. Germane to addressing the challenges posed by the so-called triple-negative disease is the realization that TNBC is merely a descriptive term, and that low-grade types of TNBC may be driven by distinct sets of genetic alterations.

  19. Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.

    Directory of Open Access Journals (Sweden)

    Nicholas C D'Amato

    Full Text Available Breast cancers with a basal-like gene signature are primarily triple-negative, frequently metastatic, and carry a poor prognosis. Basal-like breast cancers are enriched for markers of breast cancer stem cells as well as markers of epithelial-mesenchymal transition (EMT. While EMT is generally thought to be important in the process of metastasis, in vivo evidence of EMT in human disease remains rare. Here we report a novel model of human triple-negative breast cancer, the DKAT cell line, which was isolated from an aggressive, treatment-resistant triple-negative breast cancer that demonstrated morphological and biochemical evidence suggestive of phenotypic plasticity in the patient. The DKAT cell line displays a basal-like phenotype in vitro when cultured in serum-free media, and undergoes phenotypic changes consistent with EMT/MET in response to serum-containing media, a unique property among the breast cancer cell lines we tested. This EMT is marked by increased expression of the transcription factor Zeb1, and Zeb1 is required for the enhanced migratory ability of DKAT cells in the mesenchymal state. DKAT cells also express progenitor-cell markers, and single DKAT cells are able to generate tumorspheres containing both epithelial and mesenchymal cell types. In vivo, as few as ten DKAT cells are capable of forming xenograft tumors which display a range of epithelial and mesenchymal phenotypes. The DKAT model provides a novel model to study the molecular mechanisms regulating phenotypic plasticity and the aggressive biology of triple-negative breast cancers.

  20. Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer

    OpenAIRE

    Kim, Ji Young; Lee, Hyebin; Woo, Jongmin; Yue, Wang; Kim, Kwangsoo; Choi, Seongmin; Jang, Ja-June; Kim, Youngsoo; Park, In Ae; Han, Dohyun; Ryu, Han Suk

    2017-01-01

    Triple negative breast cancer (TNBC) is characterized by an aggressive biological behavior in the absence of a specific target agent. Nicotinamide has recently been proven to be a novel therapeutic agent for skin tumors in an ONTRAC trial. We performed combinatory transcriptomic and in-depth proteomic analyses to characterize the network of molecular interactions in TNBC cells treated with nicotinamide. The multi-omic profiles revealed that nicotinamide drives significant functional alteratio...

  1. Antitumor Activity of KW-2450 Against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases

    OpenAIRE

    Kai, Kazuharu; Kondo, Kimie; Wang, Xiaoping; Xie, Xuemei; Pitner, Mary K.; Reyes, Monica E.; Torres-Adorno, Angie M.; Masuda,Hiroko; Hortobagyi, Gabriel N.; Bartholomeusz, Chandra; Saya, Hideyuki; Tripathy, Debu; Sen, Subrata; Ueno, Naoto T

    2015-01-01

    Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and since Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of...

  2. Transcriptome analysis of Wnt3a-treated triple-negative breast cancer cells.

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    Sylvie Maubant

    Full Text Available The canonical Wnt/β-catenin pathway is activated in triple-negative breast cancer (TNBC. The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change > 1.3 of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGFβ, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change >1.3 which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors.

  3. Development of triple-negative breast cancer%三阴乳腺癌研究进展

    Institute of Scientific and Technical Information of China (English)

    王晓兰

    2008-01-01

    Triple-negative breast cancer is defined as one of the subtypes of breast cancer recently. At present, no effective tailored therapies have been developed for patients with triple-negative breast cancer, chemotherapy is the main modality of systemic therapy for patients of this subtype. However, compared with non-TNBC, sueh treatment has a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal- like subgroup of breast cancers. Triple- negative breast cancers have many similarities to BRCA1-associated breast cancers.%三阴乳腺癌(TNBC)是最近才分出来的乳腺癌亚型,目前尚无有效的个体化治疗方案,全身化疗还是该亚型患者的主要治疗模式,并且与非TNBC相比,该亚型患者使用常用的治疗方案具有较高的局部复发和远处转移率.TNBC组织学分化差,大部分可以归类于basal-like乳腺癌,且其与BRCA1相关的乳腺癌有许多相似之处.

  4. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition.

    Science.gov (United States)

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients.

  5. Cadmium promotes the proliferation of triple-negative breast cancer cells through EGFR-mediated cell cycle regulation

    Science.gov (United States)

    Wei, Zhengxi; Song, Xiulong; Shaikh, Zahir A.

    2015-01-01

    Cadmium (Cd) is a carcinogenic metal which is implicated in breast cancer by epidemiological studies. It is reported to promote breast cancer cell growth in vitro through membrane receptors. The study described here examined Cd-mediated growth of non-metastatic human breast cancer derived cells that lack receptors for estrogen, progesterone, and HER2. Treatment of triple-negative HCC 1937 cells with 0.1–0.5 μM Cd increased cell growth by activation of AKT and ERK. Accelerated cell cycle progression was achieved by increasing the levels of cyclins A, B, and E, as well as those of CDKs 1 and 2. Although triple negative cells lack estrogen receptor, they express high levels of EGFR. Therefore, further studies on HCC 1937 and another triple-negative cell line, HCC 38, were conducted using specific siRNA and an inhibitor of EGFR to determine whether EGFR was responsible for mediating the effect of Cd. The results revealed that in both cell types EGFR was not only activated upon Cd treatment, but was also essential for the downstream activation of AKT and ERK. Based on these observations, it is concluded that, in breast cancer cells lacking estrogen receptor, sub-micromolar concentration of Cd can promote cells proliferation. Furthermore, that EGFR plays a critical role in this process. PMID:26385184

  6. Anticancer and Anti-Inflammatory Properties of Ganoderma lucidum Extract Effects on Melanoma and Triple-Negative Breast Cancer Treatment

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    Antonio Barbieri

    2017-02-01

    Full Text Available Among the most important traditional medicinal fungi, Ganoderma lucidum has been used as a therapeutic agent for the treatment of numerous diseases, including cancer, in Oriental countries. The aim of this study is to investigate the anti-inflammatory, anticancer and anti-metastatic activities of Ganoderma lucidum extracts in melanoma and triple-negative breast cancer cells. Ganoderma lucidum extracts were prepared by using common organic solvents; MDA-MB 231 and B16-F10 cell lines were adopted as cellular models for triple-negative breast cancer and melanoma and characterized for cell viability, wound-healing assay and measurement of cytokines secreted by cancer cells under pro-inflammatory conditions (incubation with lipopolysaccharide, LPS and pretreatment with Ganoderma lucidum extract at different concentrations. Our study demonstrates, for the first time, how Ganoderma lucidum extracts can significantly inhibit the release of IL-8, IL-6, MMP-2 and MMP-9 in cancer cells under pro-inflammatory condition. Interestingly, Ganoderma lucidum extracts significantly also decrease the viability of both cancer cells in a time- and concentration-dependent manner, with abilities to reduce cell migration over time, which is correlated with a lower release of matrix metalloproteases. Taken together, these results indicate the possible use of Ganoderma lucidum extract for the therapeutic management of melanoma and human triple-negative breast cancer.

  7. Cadmium promotes the proliferation of triple-negative breast cancer cells through EGFR-mediated cell cycle regulation.

    Science.gov (United States)

    Wei, Zhengxi; Song, Xiulong; Shaikh, Zahir A

    2015-11-15

    Cadmium (Cd) is a carcinogenic metal which is implicated in breast cancer by epidemiological studies. It is reported to promote breast cancer cell growth in vitro through membrane receptors. The study described here examined Cd-mediated growth of non-metastatic human breast cancer derived cells that lack receptors for estrogen, progesterone, and HER2. Treatment of triple-negative HCC 1937 cells with 0.1-0.5 μM Cd increased cell growth by activation of AKT and ERK. Accelerated cell cycle progression was achieved by increasing the levels of cyclins A, B, and E, as well as those of CDKs 1 and 2. Although triple negative cells lack estrogen receptor, they express high levels of EGFR. Therefore, further studies on HCC 1937 and another triple-negative cell line, HCC 38, were conducted using specific siRNA and an inhibitor of EGFR to determine whether EGFR was responsible for mediating the effect of Cd. The results revealed that in both cell types EGFR was not only activated upon Cd treatment, but was also essential for the downstream activation of AKT and ERK. Based on these observations, it is concluded that, in breast cancer cells lacking estrogen receptor, sub-micromolar concentration of Cd can promote cell proliferation. Furthermore, that EGFR plays a critical role in this process.

  8. A phase 1/2 of a combination of cetuximab and taxane for "triple negative" breast cancer patients.

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    Nechushtan, Hovav; Vainer, Gilad; Stainberg, Hana; Salmon, Asher Y; Hamburger, Tamar; Peretz, Tamar

    2014-08-01

    50-70% of tumors of the so called "triple negative" subtype of breast cancer express EGFR. We hypothesized that addition of anti EGFR to Taxanes will result in increased effectiveness in EGFR expressing tumors. Here we set out to obtain data regarding the safety, tolerability and also the effectivity of the combination of weekly Taxane treatments with Cetuximab -an anti EGFR antibody in this subgroup of breast cancer. 18 triple negative breast cancer patients were treated with weekly Cetuximab and Taxane therapy. Addition of Cetuximab resulted in controllable Dermatologic toxicity in most patients -with grade 3 in two patients. Some impressive results were noted including one CR, one near CR and regression of chemotherapy and radiation resistance skin metastasis. Median TTF -and overall survival -6 and 12 months. Administration of Taxane Cetuximab weekly therapy for triple negative breast cancer patients is feasible. Use of anti EGFR-Taxane combinations should be assessed in larger clinical trials in this patient population perhaps in a similar manner to the lung cancer patients only in those with strong EGFR expression.

  9. FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma.

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    Perez-Balaguer, Ariadna; Ortiz-Martínez, Fernando; García-Martínez, Araceli; Pomares-Navarro, Critina; Lerma, Enrique; Peiró, Gloria

    2015-09-01

    The FOXA family of transcription factors regulates chromatin structure and gene expression especially during embryonic development. In normal breast tissue FOXA1 acts throughout mammary development; whereas in breast carcinoma its expression promotes luminal phenotype and correlates with good prognosis. However, the role of FOXA2 has not been previously studied in breast cancer. Our purpose was to analyze the expression of FOXA2 in breast cancer cells, to explore its role in breast cancer stem cells, and to correlate its mRNA expression with clinicopathological features and outcome in a series of patients diagnosed with breast carcinoma. We analyzed FOXA2 mRNA expression in a retrospective cohort of 230 breast cancer patients and in cell lines. We also knocked down FOXA2 mRNA expression by siRNA to determine the impact on cell proliferation and mammospheres formation using a cancer stem cells culture assay. In vitro studies demonstrated higher FOXA2 mRNA expression in Triple-Negative/Basal-like cells. Further, when it was knocked down, cells decreased proliferation and its capability of forming mammospheres. Similarly, FOXA2 mRNA expression was detected in 10% (23/230) of the tumors, especially in Triple-Negative/Basal-like phenotype (p Triple-Negative/Basal-like tumors, and is associated with increase relapses.

  10. 三阴乳腺癌与非三阴乳腺癌预后的比较分析%Comparison of survival in patients with breast cancer of triple-negative versus non-triple-negative

    Institute of Scientific and Technical Information of China (English)

    章克毅; 吴智勇; 张仕义

    2009-01-01

    目的 比较三阴乳腺癌与非三阴乳腺癌预后的不同及其影响因素.方法 回顾性分析1998年12月至2007年6月收治的684例临床可手术乳腺癌患者的临床资料,其中107例为三阴乳腺癌患者(三阴组),577例为非三阴乳腺癌患者(非三阴组).应用Kaplan-Meier法进行生存分析,组间比较用log-rank检验,多因素分析采用COX比例风险模型.结果 三阴组与非三阴组总的7年生存率分别为51.4%(55/107)及74.2%(428/577),差异有统计学意义(P<0.01).Her-2表达阳性患者总的7年生存率为53.1%(43/81),与三阴组比较差异无统计学意义(P>0.05).单因素分析结果显示患者的年龄、月经状态、肿瘤大小、腋窝淋巴结状态及受体状况均为预后影响因素.多因素分析结果表明肿瘤大小、腋窝淋巴结状态及受体状况为预后的独立影响因素.结论 三阴乳腺癌和Her-2表达阳性的乳腺癌患者治疗效果均较差,三阴乳腺癌是一个独立的预后影响因素.%Objective To assess whether survival differed among patients who had triple-negative breast cancers compared with patients who had non-triple-negative breast cancers.Methods The clinicopathologic data of 684 patients with operable breast cancer,who were treated with multimodal therapy from December 1998 to June 2007 were analyzed.Of these patients,107 cases were confirmed to have triple-negative tumor histology(triple-negative group),577 cases were confirmed to have non-triple-negative tumor histology(non-triple-negative group).The 7 years cumulative survival and disease-free survival were analyzed by Kaplan-Meier method and compared by Log-rank test.The prognosis Was analyzed by COX regression model.Results The 7 years overall survival rates for triple-negative group and non-triple-negative group were 51.4%(55/107),74.2%(428/577),respectively,there Was significant difference between the two groups(P<0.01).However,the 7 years overall survival rates of patients with

  11. Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.

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    Shan, Naing Lin; Wahler, Joseph; Lee, Hong Jin; Bak, Min Ji; Gupta, Soumyasri Das; Maehr, Hubert; Suh, Nanjoo

    2017-10-01

    Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH)2D3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH)2D3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest that

  12. Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer

    Science.gov (United States)

    2017-02-28

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer

  13. Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

    Science.gov (United States)

    2017-01-19

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  14. The fate of BRCA1-related germline mutations in triple-negative breast tumors

    Science.gov (United States)

    Kotoula, Vassiliki; Fostira, Florentia; Papadopoulou, Kyriaki; Apostolou, Paraskevi; Tsolaki, Eleftheria; Lazaridis, Georgios; Manoussou, Kyriaki; Zagouri, Flora; Pectasides, Dimitrios; Vlachos, Ioannis; Tikas, Ioannis; Lakis, Sotiris; Konstantopoulou, Irene; Pentheroudakis, George; Gogas, Helen; Papakostas, Pavlos; Christodoulou, Christos; Bafaloukos, Dimitrios; Razis, Evangelia; Karavasilis, Vasilios; Bamias, Christina; Yannoukakos, Drakoulis; Fountzilas, George

    2017-01-01

    The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001); PIK3CA mutations were exclusively present in non-carriers (P=0.007). Germline BRCA1/2 mutations were not detected in matched tumors and breast tissues from 14 out of 33 (42%) evaluable carriers. Microsatellite markers revealed tumor loss of the germline mutant allele in one case only. Tumors that had lost the germline mutation demonstrated a higher incidence of somatic TP53 mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumor TP53 mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumor TP53 mutations did not affect outcome; In carriers, those with mutated TP53 tumors experienced more relapses compared to those with wild-type TP53 tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germline BRCA1/2 mutations is not a rare event in TNBC. This finding, the observed differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and

  15. Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

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    Nivine Gado

    2016-06-01

    Full Text Available Purpose: Triple negative breast cancer (TNBC is an aggressive subtype of breast cancer with poor prognosis despite the high rates of response to chemotherapy. We aim to study the clinical features, factors influencing recurrence and survival outcomes of TNBC patients.Methods: We retrospectively studied the charts of patients with biopsy proven TNBC treated at The Clinical Oncology Department Ain-Shams University between 2009 and 2012.Results: One hundred and forty five patients fulfilled the eligibility criteria. The incidence of TNBC was 10.5% - 15% with a mean of 12% of all breast cancer patients. The follow-up duration ranged from six months to four years. The age range was 26 to 78 years. Infiltrating ductal carcinoma represented 93.1% of the pathologic types. 87% of patients were free of metastases (M0 at presentation. Clinical stages II and III represented 38 and 39.5% of the patients. 66% of patients had modified radical mastectomy. Following surgery, 77.5% of patients received adjuvant chemotherapy while 61% of the patients had adjuvant radiation therapy. Anthracyclines based chemotherapy was given to 52% of patients. Disease-free survival (DFS of the M0 patients at 20 and 30 months was 92% and 80% respectively. Relapse occurred in 23% of M0 patients. After a mean duration of DFS of 15.1 months, the most common sites of metastases for relapsed M0 patients were pulmonary (44.8%, bone (41.4%, and locoregional (13.8%. The median overall survival (ORS of patients was 18 months (1 - 45 months, whereas for the M1 group of patients the median ORS was 9 months (2 - 29 months.Conclusion: The incidence, pathological characteristics, and clinical behavior of TNBC were similar to what is mentioned in the literature. Adding taxanes to the chemotherapy protocols and using postoperative radiotherapy were both associated with a significant increase in the mean period of DFS, while did not significantly affect the ORS.

  16. Expression and significance of EZH2 and DNMT1 in triple-negative breast cancer

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    Ping-ping WU

    2015-04-01

    Full Text Available Objective To probe into the expression features of EZH2 and DNMT1 in triple-negative breast cancer (TNBC, and the relations between the expression and the main clinical pathological parameters of TNBC. Methods The clinical and pathological data of 209 cases of breast cancer (including 131 cases of TNBC and 78 cases of non-TNBC in Guangzhou Kingmed Center for Clinical Laboratory from Jan. 2008 to May 2013 were retrospectively analyzed. Immunohistochemistry SP assay was performed to determine the expressions of EZH2 and DNMT1 in 209 paraffin-embedded specimens of breast cancer and 65 specimens of normal tissue (more than 4cm away from tumor. The differences of protein expression in the specimens were compared, and correlation analysis was performed to disclose the relationship between protein expression and clinico-pathological indices. Multivariate logistic regression analysis was applied to analyze the positive expression-related factor of EZH2 and DNMT1. Spearman rank correlation analysis was used to analyse the interrelation of EZH2 and DNMT1 in TNBC. Results The positive expression rates of EZH2 in TNBC, non-TNBC and adjacent breast tissue were 86.3%, 89.7% and 40.0%, respectively, while the positive expression rates of DNMT1 were 63.4%, 66.6% and 44.6%, respectively. The positive expression rates of EZH2 and DNMT1 were higher in both TNBC and non-TNBC tissues than in adjacent breast tissue (P0.05, but the positive expression of EZH2 in TNBC was related to the pathological grade, tumor size and lymph node metastasis (P<0.05, and the positive expression of DNMT1 was related to the pathological grade and lymph node metastasis (P<0.05. Multivariate logistic regression analysis demonstrated that the pathological grade of tumor was the main factor affecting the expressions of EZH2 and DNMT1, and the expressions of EZH2 and DNMT1 in TNBC were positively correlated (r=0.34, P<0.01. Conclusion The high expressions of EZH2 and DNMT1 are

  17. Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer.

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    Satoshi Inoue

    Full Text Available Treatment options for triple negative breast cancer (TNBC are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid (PMLA nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON to inhibit EGFR synthesis. The nanobioconjugates variants were: (1 P (BioPolymer with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR, and (2 P with AON and 2C5 (P/AON/2C5. Controls included (3 P with 2C5 but without AON (P/2C5, (4 PBS, and (5 P with PEG and leucine ester (LOEt for endosomal escape (P/mPEG/LOEt. Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1 [P = 0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2]. Lead nanobioconjugate (1 also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate

  18. Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

    Science.gov (United States)

    Castaneda, Carlos A; Mittendorf, Elizabeth; Casavilca, Sandro; Wu, Yun; Castillo, Miluska; Arboleda, Patricia; Nunez, Teresa; Guerra, Henry; Barrionuevo, Carlos; Dolores-Cerna, Ketty; Belmar-Lopez, Carolina; Abugattas, Julio; Calderon, Gabriela; De La Cruz, Miguel; Cotrina, Manuel; Dunstan, Jorge; Gomez, Henry L; Vidaurre, Tatiana

    2016-01-01

    AIM To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC). METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR. CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related. PMID:27777881

  19. Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

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    Aiyu Zhu

    2016-03-01

    Full Text Available Background/Aims: Androgen receptor (AR, a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC. However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC

  20. Epidemiological and clinical profile of triple negative breast cancer at a cancer hospital in North India

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    P Suresh

    2013-01-01

    Full Text Available Background: Triple negative breast cancer (TNBC is a recent concept and the burning topic of research today. Various studies have been reported in western literature on TNBCs or the similar group of basal like cancers, all highlighting the poor prognostic features of this molecular subtype in comparison to the other types of breast cancers. However extensive data from India is lacking. The aim of this study was to analyze the epidemiological and clinical profile of TNBcs at our institute. Materials and Methods: Data on 171 patients of TNBCs registered at this hospital between 2005 and 2008 and followed up until December 2010 was collected and reviewed for epidemiological and clinical features. Results: The median age at presentation was 49 years (22-75 years. Sixty eight patients (40% had lump in the breast of less than 1 month duration. Fourteen (8% were nulliparous and 10 (7% patients had crossed the age of 30 years at first full-term pregnancy, 89 (52% were pre or peri-menopausal at presentation. Only 8 (5% patients had a family history of breast or ovarian cancer. One hundred and six (62% patients were stage II, 26 (15% stage III, 21 (12% stage I and 18 (10% stage IV at presentation. One hundred and twenty eight patients (75% had early breast cancer eligible for surgery at presentation, 25 (15% were locally advanced and received neoadjuvant chemotherapy (NACT and 18 (10% were found to be metastatic. Modified radical mastectomy was the preferred surgical option by most patients (76% who underwent upfront surgery in our study. The pathological overall response rates (complete and partial response after NACT was 75% with complete response rate of 25% and there were no relapses in the complete responders. The median follow-up was 30 months (9-70 months. One hundred and twenty two patients (71% were alive at last follow-up, 34 (22% had relapsed, 18 (11% had died due to progressive disease. Thirty one patients (18% were lost to follow-up. Most of

  1. Does obesity have an effect on outcomes in triple-negative breast cancer?

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    Mowad, Ronny; Chu, Quyen D; Li, Benjamin D L; Burton, Gary V; Ampil, Frederico L; Kim, Roger H

    2013-09-01

    Among patients with breast cancer, obesity has been associated with an increased likelihood of having triple-negative breast cancer (TNBC). This association has been thought to be due to the antiapoptotic effects of obesity-related proteins. However, the effect of obesity on the outcomes in patients with TNBC remains unclear. We hypothesized that obesity would be associated with decreased overall survival and disease-free survival in these patients. A retrospective review of a prospectively maintained database was conducted of patients treated for breast cancer at an academic medical center from March 1998 to September 2011. The body mass index (BMI) of patients with TNBC was calculated at diagnosis. The patients were categorized as normal (BMI obese (BMI > 30 kg/m(2)). The endpoints of overall survival and disease-free survival were analyzed. A total of 183 patients with TNBC were included for analysis. Of the 183 patients, 24 (13.1%) were normal (BMI obese (BMI > 30 kg/m(2)). The median follow-up period was 42.5 months. Of the 183 patients, 2 (9.1%) died in the normal group, 10 (23.1%) died in the overweight group, and 25 (21.4%) died in the obese group (P = 0.28). The patients who were overweight or obese had larger tumors (P = 0.02), a higher T stage (P = 0.001), and higher tumor grade (P = 0.01) than the normal BMI patients. By Kaplan-Meier analysis, normal patients had higher overall survival than the overweight or obese patients, but this difference was not statistically significant (P = 0.29). Disease-free survival was also not significantly different (P = 0.91). Despite an increased frequency of larger tumors, higher T stage, and higher tumor grade, obesity was not associated with decreased overall or disease-free survival in patients with TNBC. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

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    Tingting Jiang

    2016-12-01

    Full Text Available Triple negative breast cancer (TNBC is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR from standard-of-care anthracycline/taxane (ACT chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC selected because they had either pCR (n = 18 or extensive residual disease (n = 11 after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144 and METABRIC (n = 278 cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02 and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05. Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021, and they had significantly higher mutation burden (p < 0.001 and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009. As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort

  3. Opioid growth factor receptor (OGFR expression is downregulated with progression of triple negative breast cancer

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    Beth Worley

    2015-12-01

    Full Text Available Purpose: Triple negative breast cancer (TNBC is an aggressive form of breast cancer that accounts for approximately 15% of the newly diagnosed cancers worldwide, and disproportionately affects younger women and women of color. Although many forms of breast cancer are successfully treated, new therapies are needed for TNBC. A novel regulatory system, the opioid growth factor (OGF – opioid growth factor receptor (OGFr axis, plays a determining role in neoplasia. OGF is an endogenous peptide that binds specifically to OGFr to inhibit cell replication. As some human cancers grow, OGFr expression is diminished, thus limiting the therapeutic efficacy of OGF. The OGF-OGFr axis is present in human TNBC cell line MDA-MB-231 and OGF  inhibits cell replication in a dosage-related, receptor-mediated manner. Methods: The present study investigated whether OGFr protein expression in human breast cancer cell lines grown in vitro or transplanted into nude mice, changed with the stage of proliferation or size of tumor using western blotting, semi-quantitative immunohistochemistry, and DNA synthesis techniques. Results: Comparison of log and confluent TNBC cultures revealed that OGF expression was significantly decreased in confluent cultures relative to levels in log-phase cells. Western blot analyses confirmed that OGFr was reduced in confluent TNBC and MCF-7 breast cancer cells in comparison to corresponding log-phase cells. Moreover, BrdU labeling was reduced in confluent cells. Small (<500 mm3 and large (>1000 mm3 TNBC tumors grown in nude mice were processed for semiquantitative   measurement of OGF and OGFr. The expression of both peptide and receptor in large tumors was downregulated relative to small tumors. Conclusion: The reduced expression of the inhibitory peptide and receptor diminishes the efficacy of the OGF-OGFr axis as a biotherapy. These data suggest that the OGF-OGFr pathway is altered with cancer progression and one or more elements of

  4. DUSP1 promoter methylation in peripheral blood leukocyte is associated with triple-negative breast cancer risk.

    Science.gov (United States)

    Li, Jing; Chen, Yanbo; Yu, Hongyuan; Tian, Jingshen; Yuan, Fengshun; Fan, Jialong; Liu, Yupeng; Zhu, Lin; Wang, Fan; Zhao, Yashuang; Pang, Da

    2017-02-21

    DNA methylation is one of the most common epigenetic alterations, providing important information regarding cancer risk and prognosis. A case-control study (423 breast cancer cases, 509 controls) and a case-only study (326 cases) were conducted to evaluate the association of DUSP1 promoter methylation with breast cancer risk and clinicopathological characteristics. No significant association between DUSP1 methylation in peripheral blood leukocyte (PBL) DNA and breast cancer risk was observed. DUSP1 methylation was significantly associated with ER/PR-negative status; in particular, triple-negative breast cancer patients showed the highest frequency of DUSP1 methylation in both tumour DNA and PBL DNA. Soybean intake was significantly correlated with methylated DUSP1 only in ER-negative (OR 2.978; 95% CI 1.245-7.124) and PR negative (OR 2.735; 95% CI 1.315-5.692) patients. Irregular menstruation was significantly associated with methylated DUSP1 only in ER-positive (OR 3.564; 95% CI 1.691-7.511) and PR-positive (OR 3.902, 95% CI 1.656-9.194) patients. Thus, DUSP1 methylation is a cancer-associated hypermethylation event that is closely linked with triple-negative status. Further investigations are warranted to confirm the association of environmental factors, including fruit and soybean intake, irregular menstruation, and ER/PR status, with DUSP1 methylation in breast tumour DNA.

  5. DUSP1 promoter methylation in peripheral blood leukocyte is associated with triple-negative breast cancer risk

    Science.gov (United States)

    Li, Jing; Chen, Yanbo; Yu, Hongyuan; Tian, Jingshen; Yuan, Fengshun; Fan, Jialong; Liu, Yupeng; Zhu, Lin; Wang, Fan; Zhao, Yashuang; Pang, Da

    2017-01-01

    DNA methylation is one of the most common epigenetic alterations, providing important information regarding cancer risk and prognosis. A case-control study (423 breast cancer cases, 509 controls) and a case-only study (326 cases) were conducted to evaluate the association of DUSP1 promoter methylation with breast cancer risk and clinicopathological characteristics. No significant association between DUSP1 methylation in peripheral blood leukocyte (PBL) DNA and breast cancer risk was observed. DUSP1 methylation was significantly associated with ER/PR-negative status; in particular, triple-negative breast cancer patients showed the highest frequency of DUSP1 methylation in both tumour DNA and PBL DNA. Soybean intake was significantly correlated with methylated DUSP1 only in ER-negative (OR 2.978; 95% CI 1.245–7.124) and PR negative (OR 2.735; 95% CI 1.315–5.692) patients. Irregular menstruation was significantly associated with methylated DUSP1 only in ER-positive (OR 3.564; 95% CI 1.691–7.511) and PR-positive (OR 3.902, 95% CI 1.656–9.194) patients. Thus, DUSP1 methylation is a cancer-associated hypermethylation event that is closely linked with triple-negative status. Further investigations are warranted to confirm the association of environmental factors, including fruit and soybean intake, irregular menstruation, and ER/PR status, with DUSP1 methylation in breast tumour DNA. PMID:28220843

  6. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.

    Science.gov (United States)

    Colleoni, Marco; Cole, Bernard F; Viale, Giuseppe; Regan, Meredith M; Price, Karen N; Maiorano, Eugenio; Mastropasqua, Mauro G; Crivellari, Diana; Gelber, Richard D; Goldhirsch, Aron; Coates, Alan S; Gusterson, Barry A

    2010-06-20

    Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease). The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

  7. Stratification of Prognosis of Triple-Negative Breast Cancer Patients Using Combinatorial Biomarkers.

    Directory of Open Access Journals (Sweden)

    Yong Yue

    Full Text Available Triple-negative breast cancer (TNBC is highly diverse group of cancers, and generally considered an aggressive disease associated with poor survival. Stratification of TNBC is highly desired for both prognosis and treatment decisions to identify patients who may benefit from less aggressive therapy.This study retrieved 192 consecutive non-metastasis TNBC patients who had undergone a resection of a primary tumor from 2008 to 2012. All samples were negative for ER, PR, and HER2/neu. Disease-free-survival (DFS and overall-survival (OS were evaluated for expression of immunohistochemical biomarkers (P53, Ki-67, CK5/6 and EGFR, as well as clinicopathological variables including age, tumor size, grade, lymph node status, pathologic tumor and nodal stages. The cutoff values of the basal biomarkers, EGFR and CK5/6, were estimated by time-dependent ROC curves. The prognostic values of combinatorial variables were identified by univariate and multivariate Cox analysis. Patients were stratified into different risk groups based on expression status of identified prognostic variables.Median age was 57 years (range, 28-92 years. Patients' tumor stage and nodal stage were significantly associated with OS and DFS. EGFR and CK5/6 were significant prognostic variables at cutoff points of 15% (p = 0.001, AUC = 0.723, and 50% (p = 0.006, AUC = 0.675, respectively. Multivariate Cox analysis identified five significant variables: EGFR (p = 0.016, CK5/6 (p = 0.018, Ki-67 (p = 0.048, tumor stage (p = 0.010, and nodal stage (p = 0.003. Patients were stratified into low basal (EGFR≤15% and CK5/6≤50% and high basal (EGFR>15% and/or CK5/6>50% expression groups. In the low basal expression group, patients with low expressions of Ki-67, low tumor and nodal stage had significantly better survival than those with high expressions/stages of three variables, log-rank p = 0.015 (100% vs 68% at 50 months. In the high basal expression group, patient with high basal expression

  8. Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Kim Dong-Wan

    2007-11-01

    Full Text Available Abstract Background Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy. Methods A total of 145 stage II and III breast cancer patients received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We examined the clinical and biological factors (ER, PR, p53, c-erbB2, bcl-2, and Ki-67 by immunohistochemistry. We analyzed clinical outcome and their correlation with clinicopathologic parameters. Results Among the clinicopathologic parameters investigated, none of the marker was correlated with response rate (RR except triple negative phenotype. Patients with triple negative phenotype showed higher RR (83.0% in triple negative vs. 62.2% in non-triple negative, p = 0.012 and pathologic complete RR (17.0% in triple negative vs. 3.1% in non-triple negative, p = 0.005. However, relapse free survival (RFS and overall survival (OS were significantly shorter in triple negative breast cancer patients (p p = 0.021, respectively. Low histologic grade, positive hormone receptors, positive bcl-2 and low level of Ki-67 were associated with prolonged RFS. In addition, positive ER and positive bcl-2 were associated with prolonged OS. In our homogeneous patient population, initial clinical stage reflects RFS and OS more precisely than pathologic stage. In multivariate analysis, initial clinical stage was the only significant independent prognostic factor to impact on OS (hazard ratio 3.597, p = 0.044. Conclusion Several molecular markers provided useful predictive and prognostic information in stage II and III breast cancer patients treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Triple negative phenotype was associated with shorter survival, even though it was associated

  9. Impact of type 2 diabetes mellitus on the prognosis of early stage triple-negative breast cancer in People’s Republic of China

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    Ma FJ

    2014-11-01

    significantly lower DFS than patients without T2DM (log-rank P<0.001. Similar results were observed when patients with positive lymph nodes were compared with patients with negative lymph nodes (log-rank P=0.003. T2DM was independently associated with a lower DFS after adjustments of other variables (adjusted hazard ratio, 7.719; 95% confidence interval, 4.304–13.843; P<0.001 and adjustments of lymph node positivity (adjusted hazard ratio, 2.407; 95% confidence interval, 1.391–4.166; P=0.002. The DFS rates at 2 years for the T2DM group and the non-T2DM group were 78% and 97%, respectively. The prognostic influence of T2DM was consistent across the subgroups, including subgroups by age (>50 or ≤50, menopausal status (post- or premenopausal, tumor size (>5 cm or ≤5 cm, lymph node involvement (positive or negative, and adjuvant chemotherapy (received or not using the Kaplan–Meier method (log-rank P<0.05.Conclusion: In the People’s Republic of China, T2DM is an independent prognostic risk factor that indicates an increased likelihood of recurrence and metastasis in patients with early stage TNBC. The presence of T2DM should be taken into account when evaluating the risk for an early stage TNBC patient. More effective therapeutic regimens are needed for early stage TNBC patients with T2DM. Keywords: disease-free survival, hyperglycemia, highly aggressive breast cancer

  10. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

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    Danica L. Rowe

    2009-09-01

    Full Text Available In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.

  11. The role of neoadjuvant chemotherapy of triple-negative breast cancer in St. Petersburg City Clinical Oncological Dispensary

    Directory of Open Access Journals (Sweden)

    A. G. Manikhas

    2016-01-01

    Full Text Available Introduction. Triple-negative breast cancer (BC is very aggressive form of breast malignancies with high levels of dissemination, frequent ecurrence and poor survival rate, as compared to other breast cancer subtypes.Aim of the study – development and introduction of optimized treatment strategy of patients with triple-negative breast cancer into the clinical practice of City Clinical Oncological Dispensary.Materials and methods. The study included 201 patients (21–90 years, mean age 52 years who were treated in the first departmentof St. Petersburg City Clinical Oncological Dispensary from 2005 to 2011. Stage IА–IIIC invasive breast cancer with triple-negative phenotype according to immunohistochemical study of the tumor material was verified in all the patients before beginning of the treatment. Standard chemotherapy by FAC, CMF and taxane-containing regimen was used as neoadjuvant chemotherapy. The degree of therapeutic pathomorphism was evaluated according to Miller-Payne (2003 classification, which was designed taking into account an overall survival rate of patients, depending on the degree of pathologic tumor regression. Results. We performed evaluation of 3-year relapse-free survival, depending on the degree of pathomorphological regression and histological degree of malignancy. There is a clear dependence of the 3-year relapse-free survival on the degree of histological differentiation of the tumor. We noted an inverse correlation between high degree of histological malignancy with a short relapse-free period. The disease progressed in patients who have a high degree of histological malignancy.Conclusion. The highest efficiency was achieved in patients receiving chemotherapy with the addition of taxanes. It is advantageous to include taxane-containing chemotherapy regimens in the treatment of patients with a high degree of histological malignancy.

  12. 三阴性乳腺癌超声特征%Sonographic feathers of triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    崔志英; 张桦; 严梦寒

    2015-01-01

    目的:探讨三阴性乳腺癌超声声像图特征。方法回顾性分析129例女性浸润性乳腺癌患者的超声及病理资料,根据免疫组化结果分为43例三阴性乳腺癌(TNBC)和86例非三阴性乳腺癌(non-TNBC),比较两组超声图像的差别。结果 TNBC 与 non-TNBC 比较,肿瘤形态规整、周边高回声晕、钙化、肿块后方回声衰减、2~3级血流和阻力指数≥0.7比较差异有统计学意义(P 0.05)。结论 TNBC 肿瘤形态规整,缺少周边高回声晕及实质钙化,后方回声增强,血流不丰富。%Objective To investigate the sonographic features of triple-negative breast cancer (TNBC). Methods One hundred and twenty-nine famale invasive breast cancer were divided into triple-negative breast cancer( TNBC) group( n = 43) and non-triple-negative breast cancer( non-TNBC) group (n = 86)according to immunohistochemistry. Ultrasonic and pathological characteristics were studied and compared. Results There were significant differences between TNBC group and non-TNBC group in regular morphology, hyper halo echo, calcification, posterior echo attenuation, blood stream grade 2 - 3 and RI≥0. 7(P 0. 05) . Conclusions TNBC mass are regular, lack of hyper halo echo, calcification and posterior echo attenuation. Blood stream grade 2 - 3 and RI≥0. 7 are fewer too.

  13. Efficacy of RG7787, a Next Generation Mesothelin-targeted Immunotoxin, Against Triple-negative Breast and Gastric Cancers

    Science.gov (United States)

    Alewine, Christine; Xiang, Laiman; Yamori, Takao; Niederfellner, Gerhard; Bosslet, Klaus; Pastan, Ira

    2014-01-01

    The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24-kD fragment of Pseudomonas exotoxin A for cell killing. Compared to prior RITs, RG7787 has improved properties for clinical development including decreased non-specific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced >95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC50 < 100 pM. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45 and MKN74 in vitro, with subnanomolar IC50’s. In a nude mouse model, RG7787 treatment (2.5 mg/kg I.V. qod x3-4) resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (p < 0.0001) and an 18% decrease in MKN28 tumors (p < 0.0001). Pre-treatment with paclitaxel (50 mg/kg ip) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (p < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers. PMID:25239937

  14. Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation.

    Science.gov (United States)

    Miles, Wayne O; Lembo, Antonio; Volorio, Angela; Brachtel, Elena; Tian, Bin; Sgroi, Dennis; Provero, Paolo; Dyson, Nicholas

    2016-12-15

    Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3' untranslated region (3' UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3' UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231-41. ©2016 AACR.

  15. Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation

    Science.gov (United States)

    Miles, Wayne O.; Lembo, Antonio; Volorio, Angela; Brachtel, Elena; Tian, Bin; Sgroi, Dennis; Provero, Paolo; Dyson, Nicholas

    2017-01-01

    Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype–specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. PMID:27758885

  16. PIM kinase inhibition presents a novel targeted therapy against triple-negative breast tumors with elevated MYC expression

    Science.gov (United States)

    Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y.; Yau, Christina; Momcilovic, Olga; Balakrishnan, Sanjeev; Corella, Alexandra N.; Eyob, Henok; Kessenbrock, Kai; Lawson, Devon A.; Marsh, Lindsey A.; Anderton, Brittany N.; Rohrberg, Julia; Kunder, Ratika; Bazarov, Alexey V.; Yaswen, Paul; McManus, Michael T.; Rugo, Hope S.; Werb, Zena; Goga, Andrei

    2017-01-01

    Triple-negative breast cancer (TNBC), which lacks the expression of the estrogen, progesterone, and HER2 receptors, represents the breast cancer subtype with the poorest outcome1. No targeted therapy is available against this subtype due to lack of validated molecular targets. We previously reported that MYC signaling is disproportionally elevated in triple-negative (TN) tumors compared to receptor-positive (RP) tumors2. MYC is an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes3. Direct inhibition of oncogenic MYC transcriptional activity has remained challenging4,5. The present study conducted an shRNA screen against all kinases to uncover novel MYC-dependent synthetic lethal combinations, and identified PIM1, a non-essential kinase. Here we demonstrate that PIM1 expression was elevated in TN tumors and was associated with poor prognosis in patients with hormone and HER2 receptor-negative tumors. Small molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic breast cancer models by inhibiting oncogenic transcriptional activity of MYC while simultaneously restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that exhibit elevated MYC expression. PMID:27775705

  17. Phosphorylated eIF2α predicts disease-free survival in triple-negative breast cancer patients.

    Science.gov (United States)

    Guo, Liang; Chi, Yayun; Xue, Jingyan; Ma, Linxiaoxi; Shao, Zhiming; Wu, Jiong

    2017-03-15

    Phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), which functions as a marker of endoplasmic reticulum stress, has been reported to be associated with patient prognosis in various cancers. However, little is known about the prognostic value of p-eIF2α in breast cancer, particularly in different breast cancer subtypes. An immunohistochemistry screen for p-eIF2α was performed using a tissue microarray containing 233 tumors and paired peritumoral tissues from female patients diagnosed with breast cancer. The staining results were scored semiquantitatively, and the p-eIF2α expression level in breast cancer and its potential prognostic value were investigated. In this retrospective cohort study, we found that p-eIF2α levels were significantly upregulated in breast cancer (P < 0.001). p-eIF2α level was negatively correlated with lymph node status (P = 0.039). Survival analysis by Kaplan-Meier estimation and Cox regression showed that p-eIF2α level was correlated with better disease free survival (P = 0.026) and served as an independent prognostic factor (P = 0.046) in patients with triple-negative breast cancer. Our study revealed that p-eIF2α was upregulated in breast cancer and represented a novel predictor of prognosis in patients with triple-negative subtype.

  18. CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Xiang, Jingyu; Hurchla, Michelle A; Fontana, Francesca; Su, Xinming; Amend, Sarah R; Esser, Alison K; Douglas, Garry J; Mudalagiriyappa, Chidananda; Luker, Kathryn E; Pluard, Timothy; Ademuyiwa, Foluso O; Romagnoli, Barbara; Tuffin, Gérald; Chevalier, Eric; Luker, Gary D; Bauer, Michael; Zimmermann, Johann; Aft, Rebecca L; Dembowsky, Klaus; Weilbaecher, Katherine N

    2015-11-01

    The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. ©2015 American Association for Cancer Research.

  19. Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.

    Science.gov (United States)

    Maiti, Aparna; Takabe, Kazuaki; Hait, Nitai C

    2017-04-01

    About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies.

  20. Targeting triple negative breast cancer cells by N3-substituted 9,10-Phenanthrenequinone thiosemicarbazones and their metal complexes

    Science.gov (United States)

    Afrasiabi, Zahra; Stovall, Preston; Finley, Kristen; Choudhury, Amitava; Barnes, Charles; Ahmad, Aamir; Sarkar, Fazlul; Vyas, Alok; Padhye, Subhash

    2013-10-01

    Novel N3-substituted 9,10-Phenanthrenequinone thiosemicarbazones and their copper, nickel and palladium complexes are structurally characterized and reported along with the single crystal X-ray structures of three ligands and one nickel complex. All compounds were evaluated for their antiproliferative potential against Triple Negative Breast Cancer (TNBC) cells which have poor prognosis and no effective drugs to treat with. All compounds exhibited antiproliferative activity against these cells. Among the metal complexes evaluated, redox active copper complexes were found to be more potent. The possible mechanism for such enhanced activity can be attributed to the generation of oxidative stress, which was amenable for targeting through metal complexation.

  1. Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less

    Directory of Open Access Journals (Sweden)

    Kim Tae-You

    2010-10-01

    Full Text Available Abstract Background Whether a systemic adjuvant treatment is needed is an area of controversy in patients with node-negative early breast cancer with tumor size of ≤1 cm, including T1mic. Methods We performed a retrospective analysis of clinical and pathology data of all consecutive patients with node-negative T1mic, T1a, and T1b invasive ductal carcinoma who received surgery between Jan 2000 and Dec 2006. The recurrence free survival (RFS and risk factors for recurrence were identified. Results Out of 3889 patients diagnosed with breast cancer, 375 patients were enrolled (T1mic:120, T1a:93, T1b:162. Median age at diagnosis was 49. After a median follow up of 60.8 months, 12 patients developed recurrences (T1mic:4 (3.3%, T1a:2 (2.2%, T1b:6 (3.7%, with a five-year cumulative RFS rate of 97.2%. Distant recurrence was identified in three patients. Age younger than 35 years (HR 4.91; 95% CI 1.014-23.763, p = 0.048 and triple negative disease (HR 4.93; 95% CI 1.312-18.519, p = 0.018 were significantly associated with a higher rate of recurrence. HER2 overexpression, Ki-67, and p53 status did not affect RFS. Conclusions Prognosis of node-negative breast cancer with T1mic, T1a and T1b is excellent, but patients under 35 years of age or with triple negative disease have a relatively high risk of recurrence.

  2. Claudin 4 expression in triple-negative breast cancer: correlation with androgen receptors and Ki-67 expression.

    Science.gov (United States)

    Abd-Elazeem, Mona A; Abd-Elazeem, Marwa A

    2015-02-01

    Breast cancer is the most common malignancy in women and the leading cause of cancer mortality worldwide. Triple-negative breast cancer (TNBC) is an important phenotype of breast cancer that accounts for a relatively small number of breast cancer cases but still represent a focus of increasing interest at the clinical, biological, and epidemiological level. Claudins are the major component of the tight junction, and only a few studies have addressed the role of claudins in breast cancer, especially TNBC. Androgen receptors (ARs), as members of the nuclear receptor superfamily, are known to be involved in a complex network of signaling pathways that collectively regulate cell proliferation. However, roles of AR in breast cancer development and progression have not been very clearly understood. The proliferation marker Ki-67 has been confirmed as an independent predictive and prognostic factor in early breast cancer. The aims of this study are to identify the clinicopathologic associations and prognostic value of claudin 4 expression in TNBC and to correlate claudin 4 expression with AR status and Ki-67 expression. Paraffin blocks obtained from 56 female patients with triple-negative primary invasive ductal breast carcinomas were analyzed for claudin 4, AR, and Ki-67 immunohistochemical expression. High levels of claudin 4 expression were detected in 66.1% of TNBC cases. There was a significant positive correlation with age, tumor size, grade, nodal status, metastasis, and Ki-67 expression (all P negative correlation with AR status (P negative correlation with the all the studied clinicopathologic parameters, claudin 4 and Ki-67 expression. High claudin 4 expression, negative AR expression, and high Ki-67 index would provide a strong prognostic power to differentiate the patients with worse outcome among TNBC patients. Moreover, target treatment for TNBC cells expressing claudin 4 or AR enriched would be valuable for future therapies. Copyright © 2014 Elsevier Inc

  3. Clinical Initial Response of Neoadjuvant Chemotheraphy in Triple Negative, HER-2, and Luminal Types of Breast Cancer in Denpasar (A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Kristianto Yuli Yarso

    2012-01-01

    Full Text Available Objectives: Triple Negative, Luminal, HER-2 subtypes of breast cancer are markers to predict behavior, aggressiveness, and response to chemotherapy. The aim of this study is to understand character and response to standard neoadjuvant chemotherapy in different subtypes of breast cancer. Method: This is a descriptive study of breast cancer subtypes. From 687 patients (2003-2010 351 patients have IHC data which divided into 3 groups, Triple negative, Luminal, and HER-2. We used 10% as a cut off point for ER, PR, while 30% & positive 3 for HER-2. We determined initial clinical response after 3 cycles of neoadjuvant chemotherapy although only 77 got standard neoadjuvant chemotherapy and had clinical response data. We used 50% diameters depreciation & no metastasis as cut off point for respond group. Results: There were 116 (33% Triple Negative, 60 (17% HER-2, and 175 (50% Luminal Subtypes. The mean of age for 351 patients are 48.32 (23-82 years. In this study, it was obtained that no significant difference of means of age (p=0.24 in these 3 groups. Triple negative group significantly more advance in grade if compared with the other two groups (p=0.02. HER-2 group had highest response with standard neoadjuvant chemotherapy (50%, Luminal group had (49%, and Triple negative group had only (15% response. One pCR in HER-2 group. There were no difference ages in subtypes. Triple negative has more advances in grade. HER-2 group has highest response to standard neoadjuvant chemotherapy and Triple negative has lowest response to standard neoadjuvant chemotherapy.

  4. Clinical Initial Response of Neoadjuvant Chemotheraphy in Triple Negative, HER-2, and Luminal Types of Breast Cancer in Denpasar (A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Kristianto Yuli Yarso

    2012-01-01

    Full Text Available Objectives: Triple Negative, Luminal, HER-2 subtypes of breast cancer are markers to predict behavior, aggressiveness, and response to chemotherapy. The aim of this study is to understand character and response to standard neoadjuvant chemotherapy in different subtypes of breast cancer. Method: This is a descriptive study of breast cancer subtypes. From 687 patients (2003-2010 351 patients have IHC data which divided into 3 groups, Triple negative, Luminal, and HER-2. We used 10% as a cut off point for ER, PR, while 30% & positive 3 for HER-2. We determined initial clinical response after 3 cycles of neoadjuvant chemotherapy although only 77 got standard neoadjuvant chemotherapy and had clinical response data. We used 50% diameters depreciation & no metastasis as cut off point for respond group. Results: There were 116 (33% Triple Negative, 60 (17% HER-2, and 175 (50% Luminal Subtypes. The mean of age for 351 patients are 48.32 (23-82 years. In this study, it was obtained that no significant difference of means of age (p=0.24 in these 3 groups. Triple negative group significantly more advance in grade if compared with the other two groups (p=0.02. HER-2 group had highest response with standard neoadjuvant chemotherapy (50%, Luminal group had (49%, and Triple negative group had only (15% response. One pCR in HER-2 group. There were no difference ages in subtypes.  Triple negative has more advances in grade. HER-2 group has highest response to standard neoadjuvant chemotherapy and Triple negative has lowest response to standard neoadjuvant chemotherapy.

  5. Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells.

    Science.gov (United States)

    Xu, Hui; Qian, Mingping; Zhao, Bingkun; Wu, Chenyang; Maskey, Niraj; Song, Hongming; Li, Dengfeng; Song, Jialu; Hua, Kaiyao; Fang, Lin

    2017-03-01

    RAB1A acts as an oncogene in various cancers, and emerging evidence has verified that RAB1A is an mTORC1 activator in hepatocellular and colorectal cancer, but the role of RAB1A in breast cancer remains unclear. In this investigation, RAB1A siRNA was successfully transfected in MDA-MB-231 and BT-549 human triple-negative breast cancer cells, and verified by real‑time quantitative polymerase chain reaction and western blotting. Then, MTT cell proliferation, colony formation, cell invasion and wound healing assays were performed to characterize the function of RAB1A in the breast cancer cell lines. Downregulation of RAB1A inhibited cellular growth, cell migration, cell invasion and cell epithelial-mesenchymal transition. Furthermore, compared with NC siRNA transfected cells, RAB1A siRNA transfected breast cancer cells inhibited the phosphorylation of S6K1, the effector molecular of mTORC1. Collectively, our data suggested that RAB1A acts as an oncogene by regulating cellular proliferation, growth, invasion and metastasis via activation of mTORC1 pathway in triple-negative breast cancer.

  6. Noninvasive in vivo multispectral optoacoustic imaging of apoptosis in triple negative breast cancer using indocyanine green conjugated phosphatidylserine monoclonal antibody

    Science.gov (United States)

    Kannadorai, Ravi Kumar; Udumala, Sunil Kumar; Sidney, Yu Wing Kwong

    2016-12-01

    Noninvasive and nonradioactive imaging modality to track and image apoptosis during chemotherapy of triple negative breast cancer is much needed for an effective treatment plan. Phosphatidylserine (PS) is a biomarker transiently exposed on the outer surface of the cells during apoptosis. Its externalization occurs within a few hours of an apoptotic stimulus by a chemotherapy drug and leads to presentation of millions of phospholipid molecules per apoptotic cell on the cell surface. This makes PS an abundant and accessible target for apoptosis imaging. In the current work, we show that PS monoclonal antibody tagged with indocyanine green (ICG) can help to track and image apoptosis using multispectral optoacoustic tomography in vivo. When compared to saline control, the doxorubicin treated group showed a significant increase in uptake of ICG-PS monoclonal antibody in triple negative breast tumor xenografted in NCr nude female mice. Day 5 posttreatment had the highest optoacoustic signal in the tumor region, indicating maximum apoptosis and the tumor subsequently shrank. Since multispectral optoacoustic imaging does not involve the use of radioactivity, the longer the circulatory time of the PS antibody can be exploited to monitor apoptosis over a period of time without multiple injections of commonly used imaging probes such as Tc-99m Annexin V or F-18 ML10. The proposed apoptosis imaging technique involving multispectral optoacoustic tomography, monoclonal antibody, and near-infrared absorbing fluorescent marker can be an effective tool for imaging apoptosis and treatment planning.

  7. Progress on chemotherapy for triple negative breast cancer%三阴性乳腺癌化疗进展

    Institute of Scientific and Technical Information of China (English)

    倪晨; 李婷; 吴振华; 胡夕春

    2014-01-01

    三阴性乳腺癌作为乳腺癌的一种特殊亚型,对内分泌治疗和现有靶向治疗无效,并且通常复发较早、进展迅速、预后较差。现就三阴性乳腺癌的分子分型及其临床价值、化疗药物和化疗方案以及化疗和潜在的新靶点药物联合方面的最新进展作一综述。%Triple negative breast cancer (TNBC), as a special molecular subtype of breast cancer, is non-responsive to endocrine therapy or commercially available targeted therapy. It is characterized by early recurrence, rapid progression and poor prognosis. This systemic and comprehensive overview was focused on recent progress on molecular subtyping of triple negative breast cancer and its possible clinical value, chemotherapeutic agents and chemotherapy regimens, and combination of chemotherapy with potential molecular targeting agents.

  8. Integrated analysis of expression profiling data identifies three genes in correlation with poor prognosis of triple-negative breast cancer.

    Science.gov (United States)

    Zhang, Cheng; Han, Yong; Huang, Hao; Min, Li; Qu, Like; Shou, Chengchao

    2014-06-01

    Triple-negative breast cancer (TNBC) shows more aggressive clinical behavior and poorer outcome than non-triple-negative breast cancer (NTNBC), and cannot be treated either via endocrine therapy or by Trastuzumab. For TNBC, chemotherapy is currently the mainstay of systemic medical treatment, the lack of more efficient options of treatment has been a problem in breast cancer prevention. In this study, we aimed to find genes related to prognosis in TNBC by bioinformatic analysis and to provide therapeutic candidates for TNBC treatment. We compared the differences in gene expression levels between cancer patients and healthy individuals across five breast cancer microarray databases to generate a gene cohort specifically upregulated in the NTNBC subtype, whose expression levels are ≥2-fold higher in TNBC compared to NTNBC and healthy individuals. Another two databases with clinical information were applied for following Kaplan-Meier analysis, and high expression of BIRC5, CENPA and FAM64A in this cohort were found to be related to poor survival (OS, DMFS, DFS and RFS). This correlation was also seen in patients at early stages and grades. On the other hand, the outcome of patients with synchronous upregulation of these three genes was the worst, while those with synchronous low gene level was the best. In conclusion, BIRC5, CENPA and FAM64A are specifically upregulated in TNBC, and the high expression of these three genes is associated with poor breast cancer prognosis, suggesting their clinical implication as therapeutic targets in TNBC.

  9. Androgen Receptor Expression and its Correlation with Other Risk Factors in Triple Negative Breast Cancers: a Report from Western Iran.

    Science.gov (United States)

    Payandeh, Mehrdad; Shazad, Babak; Madani, SeyedHamid; Ramezani, Mazaher; Sadeghi, Masoud

    2016-01-01

    Androgen receptors (ARs) are expressed in more than 70% of breast cancers (BCs) and have been implicated in BC pathogenesis. Some triple negative (TN)BC tumors express AR and may benefit from ARtargeted therapies. The aim of this study was to evaluate survival and the prevalence of AR expression and its correlation with other risk factors in triple negative BCs in women from Western Iran. In a retrospective study between 20092015, 41 patients with TNBC were referred to the Private Clinic of Oncology, Kermanshah city, Iran. ER, PR and ARpositive expression was defined as ≥10% nuclear staining and also HER2 (2+), FISH was performed. Nuclear staining was considered representative for Ki67 and P53. The mean followup for the patients was 25 months. In this time, 5 patients died and 4 lost to followup were censored from survival analysis. The mean age at diagnosis was 46.9 years (range, 2471 years) and all patients were female. The OS rates for ARpositive and ARnegative patients were 90% and 85.1%, respectively, and the mean OS was 26.3 and 23.2 months. Therefore, there was no significant difference between the two groups (Hazard ratio: 0.580, 95% CI: 0.0863.893, P=0.575). In TNBC patients, evaluation of AR status may provide additional information on prognosis and treatment. The results of studies showed that the prevalence AR expression may differ in the world and probably ethnicity can be an influencing factor.

  10. Melanin-originated carbonaceous dots for triple negative breast cancer diagnosis by fluorescence and photoacoustic dual-mode imaging.

    Science.gov (United States)

    Xiao, Wei; Li, Yuan; Hu, Chuan; Huang, Yuan; He, Qin; Gao, Huile

    2017-07-01

    Carbonaceous dots exhibit increasing applications in diagnosis and drug delivery due to excellent photostability and biocompatibility properties. However, relative short excitation and emission of melanin carbonaceous dots (MCDs) limit the applicability in fluorescence bioimaging. Furthermore, the generally poor spatial resolution of fluorescence imaging limits potential in vivo applications. Due to a variety of beneficial properties, in this study, MCDs were prepared exhibiting great potential in fluorescence and photoacoustic dual-mode bioimaging. The MCDs exhibited a long excitation peak at 615nm and emission peak at 650nm, further highlighting the applicability in fluorescence imaging, while the absorbance peak at 633nm renders MCDs suitable for photoacoustic imaging. In vivo, the photoacoustic signal of MCDs was linearly correlated with the concentration of MCDs. Moreover, the MCDs were shown to be taken up into triple negative breast cancer cell line 4T1 in both a time- and concentration-dependent manner. In vivo fluorescence and photoacoustic imaging of subcutaneous 4T1 tumor demonstrated that MCDs could passively target triple negative breast cancer tissue by enhanced permeability and retention effects and may therefore be used for tumor dual-mode imaging. Furthermore, fluorescence distribution in tissue slices suggested that MCDs may distribute in 4T1 tumor with high efficacy. In conclusion, the MCDs studied offer potential application in fluorescence and photoacoustic dual-mode imaging.

  11. Methylation of the BRCA1 promoter in peripheral blood DNA is associated with triple-negative and medullary breast cancer.

    Science.gov (United States)

    Gupta, Satish; Jaworska-Bieniek, Katarzyna; Narod, Steven A; Lubinski, Jan; Wojdacz, Tomasz K; Jakubowska, Anna

    2014-12-01

    It has been proposed that methylation signatures in blood-derived DNA may correlate with cancer risk. In this study, we evaluated whether methylation of the promoter region of the BRCA1 gene detectable in DNA from peripheral blood cells is a risk factor for breast cancer, in particular for tumors with pathologic features characteristic for cancers with BRCA1 gene mutations. We conducted a case-control study of 66 breast cancer cases and 36 unaffected controls. Cases were triple-negative or of medullary histology, or both; 30 carried a constitutional BRCA1 mutation and 36 did not carry a mutation. Blood for DNA methylation analysis was taken within three months of diagnosis. Methylation of the promoter of the BRCA1 gene was measured in cases and controls using methylation-sensitive high-resolution melting (MS-HRM). A sample with any detectable level of methylation was considered to be positive. Methylation of the BRCA1 promoter was detected in 15 of 66 cases and in 2 of 36 controls (OR 5.0, p = 0.03). Methylation was present in 15 of 36 women with breast cancer and without germline BRCA1 mutation, but in none of 30 women with breast cancer and a germline mutation (p blood DNA may be a marker of increased susceptibility to triple-negative or medullary breast cancer.

  12. Noninvasive in vivo multispectral optoacoustic imaging of apoptosis in triple negative breast cancer using indocyanine green conjugated phosphatidylserine monoclonal antibody.

    Science.gov (United States)

    Kannadorai, Ravi Kumar; Udumala, Sunil Kumar; Sidney, Yu Wing Kwong

    2016-12-01

    Noninvasive and nonradioactive imaging modality to track and image apoptosis during chemotherapy of triple negative breast cancer is much needed for an effective treatment plan. Phosphatidylserine (PS) is a biomarker transiently exposed on the outer surface of the cells during apoptosis. Its externalization occurs within a few hours of an apoptotic stimulus by a chemotherapy drug and leads to presentation of millions of phospholipid molecules per apoptotic cell on the cell surface. This makes PS an abundant and accessible target for apoptosis imaging. In the current work, we show that PS monoclonal antibody tagged with indocyanine green (ICG) can help to track and image apoptosis using multispectral optoacoustic tomography triple negative breast tumor xenografted in NCr nude female mice. Day 5 posttreatment had the highest optoacoustic signal in the tumor region, indicating maximum apoptosis and the tumor subsequently shrank. Since multispectral optoacoustic imaging does not involve the use of radioactivity, the longer the circulatory time of the PS antibody can be exploited to monitor apoptosis over a period of time without multiple injections of commonly used imaging probes such as Tc-99m Annexin V or F-18 ML10. The proposed apoptosis imaging technique involving multispectral optoacoustic tomography, monoclonal antibody, and near-infrared absorbing fluorescent marker can be an effective tool for imaging apoptosis and treatment planning.

  13. Heterogeneity between triple negative breast cancer cells due to differential activation of Wnt and PI3K/AKT pathways.

    Science.gov (United States)

    Martínez-Revollar, Gabriela; Garay, Erika; Martin-Tapia, Dolores; Nava, Porfirio; Huerta, Miriam; Lopez-Bayghen, Esther; Meraz-Cruz, Noemí; Segovia, José; González-Mariscal, Lorenza

    2015-11-15

    The lack of a successful treatment for triple-negative breast cancer demands the study of the heterogeneity of cells that constitute these tumors. With this aim, two clones from triple negative breast MDA-MB-231 cancer cells were isolated: One with fibroblast-like appearance (F) and another with semi-epithelial (SE) morphology. Cells of the F clone have a higher migration and tumorigenesis capacity than SE cells, suggesting that these cells are in a more advanced stage of epithelial to mesenchymal transformation. In agreement, F cells have a diminished expression of the tight junction proteins claudins 1 and 4, and an increased content of β-catenin. The latter is due to an augmented activity of the canonical Wnt route and of the EGFR/PI3K/mTORC2/AKT pathway favoring the cytoplasmic accumulation of β-catenin and its transcriptional activity. In addition, F cells display increased phosphorylation of β-catenin at Tyr654 by Src. These changes favor in F cells, the over-expression of Snail that promotes EMT. Finally, we observe that both F and SE cells display markers of cancer stem cells, which are more abundant in the F clone.

  14. Histological features of medullary carcinoma and prognosis in triple-negative basal-like carcinomas of the breast.

    Science.gov (United States)

    Marginean, Felicia; Rakha, Emad A; Ho, Bernard C; Ellis, Ian O; Lee, Andrew H S

    2010-10-01

    Medullary carcinomas have a better prognosis than other grade 3 mammary carcinomas, but they typically show basal-like biological features, which are associated with a poor prognosis. In this study we examined the associations and prognostic relevance of medullary histological features in a series of 165 invasive carcinomas with a basal-like phenotype: triple-negative (oestrogen receptor, progesterone receptor, HER2) and expressing at least one basal marker (CK5/6, CK14, CK17 or EGFR). The following histological features were associated with each other: prominent inflammation, anastomosing sheets, absence of fibrosis, absence of infiltrative margin and absence of gland formation. Prominent inflammation and anastomosing sheets in at least 30% of the tumour were associated with a better prognosis on univariate analysis. The combination of these two features (a simplified definition of medullary-like type) was present in 17% of tumours and was an independent prognostic factor on multivariate analysis. This simplified definition had good inter-observer reproducibility (κ=0.61) and is worthy of more detailed assessment in an unselected group of mammary carcinomas. A fibrotic focus was present in 36% of carcinomas. Only 3% of tumours with a fibrotic focus had features of medullary-like carcinomas. Fibrotic focus of greater than 30% of the tumour was associated with a poor prognosis. This study emphasizes the heterogeneity of morphology and behaviour of triple-negative basal-like carcinomas.

  15. Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles.

    Science.gov (United States)

    Liu, Yang; Zhu, Yan-Hua; Mao, Cheng-Qiong; Dou, Shuang; Shen, Song; Tan, Zi-Bin; Wang, Jun

    2014-10-28

    There is no effective clinical therapy yet for triple-negative breast cancer (TNBC) without particular human epidermal growth factor receptor-2, estrogen and progesterone receptor expression. In this study, we report a molecularly targeted and synthetic lethality-based siRNA therapy for TNBC treatment, using cationic lipid assisted poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the siRNA carrier. It is demonstrated that only in c-Myc overexpressed TNBC cells, while not in normal mammary epithelial cells, delivery of siRNA targeting cyclin-dependent kinase 1 (CDK1) with the nanoparticle carrier (NPsiCDK1) induces cell viability decreasing and cell apoptosis through RNAi-mediated CDK1 expression inhibition, indicating the synthetic lethality between c-Myc with CDK1 in TNBC cells. Moreover, systemic delivery of NPsiCDK1 is able to suppress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxicity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer.

  16. Current Status of Poly(ADP-ribose Polymerase Inhibitors as Novel Therapeutic Agents for Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    David J. Hiller

    2012-01-01

    Full Text Available Triple-negative breast cancer (TNBC is an aggressive type of breast cancer that is clinically defined as lacking estrogen and progesterone receptors, as well as being ERBB2 (HER-2 negative. Without specific therapeutic targets, TNBC carries a worse prognosis than other types of breast cancer in the absence of therapy. Research has now further differentiated breast cancer into subtypes based on genetic expression patterns. One of these subtypes, basal-like, frequently overlaps with the clinical picture of TNBC. Additionally, both TNBC and basal-like breast cancer link to BRCA mutations. Recent pharmaceutical advances have created a class of drugs, poly(ADP-ribose polymerase (PARP inhibitors, which are showing potential to effectively treat these patients. The aim of this paper is to summarize the basis behind PARP inhibitors and update the current status of their development in clinical trials for the treatment of TNBC.

  17. Identification of Novel Biomarkers and Targeting Tumor-Initiating Cell Clones of the Triple-Negative Breast Cancer Subtype

    DEFF Research Database (Denmark)

    Ehmsen, Sidse

    Brystkræft påvirker mere end 10% af kvinderne i vestlige lande og er den hyppigste årsag til kræftrelateret dødelighed blandt kvinder på verdensplan. Den triple-negative brystkræft-subtype (TNBC, (ER-/PR-/HER2normal)) udgør ca. 10% af alle brystkræfttilfældene, samtidig er den aggressiv og...... kræft-negative lymfeknuder (N-), men med kræftknuder, der har højt udtryk af S100A14, som har den samme dårlig prognose som N+ gruppen. For at opnå yderligere indsigt i den cellulære funktion af S100A14 blev cellelinjer med stabil fjernelse af S100A14-genet genereret for to TNBC-cellelinjer. Disse...

  18. S100A14 is a novel independent prognostic biomarker in the triple-negative breast cancer subtype

    DEFF Research Database (Denmark)

    Ehmsen, Sidse; Hansen, Lea Tykgaard; Bak, Martin

    2015-01-01

    Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein...... as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors...... with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor-negative axillary lymph nodes (N...

  19. 三阴乳腺癌保乳治疗的疗效分析%Efficacy of conservative surgery on triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    李永强; 苏逢锡

    2011-01-01

    Objective To compare the prognosis of triple negative and non-triple negative breast cancer after conservative surgery. Methods 593 patients with breast cancer were studied. All patients underwent conservative surgery therapy. All the patients' ER, PR, HER2/neu were available. The patients were classified as triple negative if all three markers were negative and non-triple negative if not. Ninty-two cases were classified as triple negative and 501 as non-triple negative. Results Till Nov. 2010, the median follow-up time of the 593 patients was 52 months. There was 11 in-breast relapses, 28 distant relapses, and 16 deaths. The triple negative cohort had a poorer distant metastasis-free rate compared with the non-triple negative cohort. But there was no significant difference in local control between the triple negative and the non-triple negative. Conclusions Triple-negative breast cancer has a more aggressive clinical course than non-triple negative breast cancer. However, there is no evidence that these patients are at higher risk for local relapse after conservative surgery therapy. Triple-negative breast cancer is still the candidate for conservative surgery therapy.%目的 探讨三阴乳腺癌行保乳治疗后的疗效观察.方法 行保乳手术治疗的乳腺癌患者593例,所有病例的ER、PR、HER2/neu状态均经病理证实,根据ER、PR、HER2/neu的状态分为三阴乳腺癌(ER、PR、HER2/neu 均为阴性)及非三阴乳腺癌(ER、PR、HEE2/neu其中任何一项为阳性)两组.其中三阴乳腺癌92例,非三阴乳腺癌501例.结果 截止2009年11月,共随访593例,中位随访时间为52月,出现局部复发病例11例,远处转移28例,死亡16例.三阴乳腺癌组比非三阴乳腺癌组有较高的远处转移率,预后较差.但三阴乳腺癌和非三阴乳腺癌患者在术后的局部复发率上无明显差异.结论 三阴乳腺癌相较非三阴乳腺癌总体预后差,但没有证据说明三阴乳腺癌行保乳手术后局

  20. Lymph node-positive prostate cancer: current issues, emerging technology and impact on clinical outcome.

    Science.gov (United States)

    Adams, Julia; Cheng, Liang

    2011-09-01

    Lymph node metastasis in patients with prostate cancer indicates a poorer prognosis compared with patients without lymph node metastasis; however, some patients with node-positive disease have long-term survival. Many studies have attempted to discern what characteristics of lymph node metastasis are prognostically significant. These characteristics include nodal tumor volume, number of positive lymph nodes, lymph node density, extranodal extension, lymphovascular invasion and tumor dedifferentiation. Favorable characteristics of regional lymph node involvement included a smaller tumor size and smaller tumor volume. However, the current staging system for prostate cancer does not provide different subclassifications for patients with node-positive prostate cancer. In recent years numerous advanced technologies for the detection of lymph node metastasis have been developed, including molecular imaging techniques and the CellSearch Circulating Tumor Cell System. With the increased detection of patients with prostate cancer, emergence of new technology to identify lymph node metastasis and the number of radical prostatectomies being performed on the rise, subclassifying patients with lymph node-positive disease is imperative. Subclassification would provide a better picture of patient prognosis and allow for a better understanding of targeted therapies to treat patients with lymph node metastasis.

  1. Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from (18)F-FDG PET/CT in operable triple-negative breast cancer.

    Science.gov (United States)

    Kim, Yong-Il; Kim, Yong Joong; Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo; Chung, June-Key; Kang, Keon Wook

    2017-06-14

    Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. A total of 228 patients with triple-negative breast cancer (mean age 47.0 ± 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P triple-negative breast cancer after surgery. Lymph node metabolic and volumetric parameters were useful parameters for evaluating prognosis in patients with triple-negative breast cancer by (18)F-FDG PET/CT, rather than tumor parameters.

  2. MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer.

    Science.gov (United States)

    Zhu, Zhengzhi; Wang, Shengying; Zhu, Jinhai; Yang, Qifeng; Dong, Huiming; Huang, Jiankang

    2016-10-01

    Triple negative breast cancer lacking estrogen receptor (ER), progesterone receptor and Her2 account for account for the majority of the breast cancer deaths, due to the lack of specific gene targeted therapy. Our current study aimed to investigate the role of miR-544 in triple negative breast cancer. Endogenous levels of miR-544 were significantly lower in breast cancer cell lines than in human breast non-tumorigenic and mammary epithelial cell lines. We found that miR-544 directly targeted the 3'-untranslated region (UTR) on both Bcl6 and Stat3 mRNAs, and overexpression of miR-544 in triple negative breast cancer cells significantly down-regulated expressions of Bcl6 and Stat3, which in turn severely inhibited cancer cell proliferation, migration and invasion in vitro. Employing a mouse xenograft model to examine the in vivo function of miR-544, we found that expression of miR-544 significantly repressed the growth of xenograft tumors. Our current study reported miR-544 as a tumor-suppressor microRNA particularly in triple negative breast cancer. Our data supported the role of miR-544 as a potential biomarker in developing gene targeted therapies in the clinical treatment of triple negative breast cancer.

  3. [Effect of miR-342-3p on chemotherapy sensitivity in triple-negative breast cancer].

    Science.gov (United States)

    Ma, Tao; Zhang, Junying; Wu, Jianzhong; Tang, Jinhai

    2014-05-01

    To study the effect of miR-342-3p on the chemotherapy sensitivity in triple-negative breast cancer (TNBC). Tissue samples were collected from January 2011 to August 2013 samples in Jiangsu Cancer Hospital from a total of 32 triple-negative breast cancer patients with preoperative chemotherapy, with 5 cases of complete response (CR) and 27 cases of partial response (PR). We detected miR-342-3p expression of TNBC with RT-PCR. We transfected has-miR-342-3p mimic and inhibitor into breast cancer cell lines MDA-MB-231 by lipofection transfection and set up negative control mim-NC and inhi-NC. Group of mimic, mim-NC, inhibitor and inhi-NC were cultivated with 2 μmol /L paclitaxel, cisplatin or 4 μmol/L doxorubicin for 48 h. The cell growth rates were measured by CCK8 reagent kit, and the cell apoptosis rate by flow cytometry. The expressions of miRNA-342-3p in TNBC tissue of CR were higher than those of PR. The cell growth rates of mimic were lower and cell apoptosis rates were higher than those of min- NC after cultivating with paclitaxel or cisplatin for 48 h, with significant difference (P0.05). TNBC with high expression of miR-342-3p are more sensitive to chemotherapy. miRNA-342-3p may regulate the sensitivity of breast cancer cell line MDA-MB-231 to chemotherapy drugs paclitaxel and cisplatin, but can not affect the chemotherapy sensitivity of doxorubicin.

  4. Prognostic value of androgen receptor expression in triple negative breast carcinomas: personal experience and comments on a review about “Triple-negative breast cancer: treatment challenges and solutions” by Collignon et al

    Directory of Open Access Journals (Sweden)

    Ieni A

    2016-08-01

    Full Text Available Antonio Ieni,1 Valeria Barresi,1 Giuseppina Rosaria Rita Ricciardi,2 Barbara Adamo,3 Vincenzo Adamo,2 Giovanni Tuccari11Department of Human Pathology of Adult and Evolutive Age “Gaetano Barresi”, Section of Pathology, University of Messina, AOU “Policlinico G Martino”; 2Medical Oncology Unit AOOR Papardo-Piemonte, Department of Human Pathology of Adult And Evolutive Age “Gaetano Barresi”, University of Messina, Messina, Italy; 3Medical Oncology Hospital Clinic, Barcelona, SpainRecently, we read with great interest the review by Collignon et al entitled “Triplenegative breast cancer: treatment challenges and solutions”,1 which appeared in the last issue of Breast Cancer: Targets and Therapy. In this article, the authors extensively reviewed studies concerning the opportunity to identify triple negative breast carcinoma (TNBC subtypes by newly proposed markers, taking into account their biological heterogeneity on the light of clinical implications.View original paper by Collignon et al.

  5. The value of level III clearance in patients with axillary and sentinel node positive breast cancer.

    LENUS (Irish Health Repository)

    Dillon, Mary F

    2012-02-01

    BACKGROUND: The value of level III axillary clearance is contentious, with great variance worldwide in the extent and levels of clearance performed. OBJECTIVE: To determine rates of level III positivity in patients undergoing level I-III axillary clearance, and identify which patients are at highest risk of involved level III nodes. METHODS: From a database of 2850 patients derived from symptomatic and population-based screening service, 1179 patients who underwent level I-III clearance between the years 1999-2007 were identified. The pathology, surgical details, and prior sentinel nodes biopsies of patients were recorded. RESULTS: Eleven hundred seventy nine patients had level I-III axillary clearance. Of the patients, 63% (n = 747) were node positive. Of patients with node positive disease, 23% (n = 168) were level II positive and 19% (n = 141) were level III positive. Two hundred fifty patients had positive sentinel node biopsies prior to axillary clearance. Of these, 12% (n = 30) and 9% (n = 22) were level II and level III positive, respectively. On multivariate analysis, factors predictive of level III involvement in patients with node positive disease were tumor size (P < 0.001, OR = 1.36; 95% CI: 1.2-1.5), invasive lobular disease (P < 0.001, OR = 3.6; 95% CI: 1.9-6.95), extranodal extension (P < 0.001, OR = 0.27; 95% CI: 0.18-0.4), and lymphovascular invasion (P = 0.04, OR = 0.58; 95% CI: 0.35-1). Lobular invasive disease (P = 0.049, OR = 4.1; 95% CI: 1-16.8), extranodal spread (P = 0.003, OR = 0.18; 95% CI: 0.06-0.57), and having more than one positive sentinel node (P = 0.009, OR = 4.9; 95% CI: 1.5-16.1) were predictive of level III involvement in patients with sentinel node positive disease. CONCLUSION: Level III clearance has a selective but definite role to play in patients who have node positive breast carcinoma. Pathological characteristics of the primary tumor are of particular use in identifying those who are at various risk of level III nodal

  6. Mammographic features of triple negative breast cancer%三阴性乳腺癌X线特征分析

    Institute of Scientific and Technical Information of China (English)

    梁晓燕; 马少君; 康晓丽; 王涛; 黄范利

    2014-01-01

    目的:探讨三阴性乳腺癌的 X 线特征。方法:收集经手术病理证实为乳腺癌的202例患者资料,根据雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体(HER -2)表达情况将其分为三阴性乳腺癌(TNBC)与非三阴性乳腺癌(NTNBC),比较两组病例腺体分型、病灶是否单发、肿块情况及有无钙化。结果:202例乳腺癌TNBC 有34例,NTNBC 有168例。两组病例肿块边缘及有无钙化差异有统计学意义(P均﹤0.05)。腺体分型、是否单发、肿块的大小、肿块的形态、肿块的密度差异无统计学意义。结论:TNBC 有一定特征,大多为单发肿块,与 NTNBC 相比肿块边缘更易表现为清晰光滑,钙化相对少见的征象。%To analyze the X - ray findings of triple negative breast cancer. Methods:The results of 202 cases of breast cancer identified by postoperative pathology were collected,which distinguished to triple negative breast cancer(TNBC)and non - triple negative breast cancer(NTNBC)by immunohistochemologic receptor status of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(HER - 2). The re-sults of mammary gland type,mass's number,margin and calcification on mammograms were compared. Results:Of 202 cases breast cancer included 34 cases TNBC and 168 cases NTNBC,the differences between mass margins and calcification incidence were statistically significant(P ﹤ 0. 05),and there were no statistically significant differences among mass's number,size,shape,density and mammary gland type(P ﹥ 0. 05). Conclusion:TNBC shows merely a mass with indistinct margins and less calcifications than NTNBC.

  7. Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer.

    Science.gov (United States)

    Dong, Tieying; Kang, Xinmei; Liu, Zhaoliang; Zhao, Shu; Ma, Wenjie; Xuan, Qijia; Liu, Hang; Wang, Zhipeng; Zhang, Qingyuan

    2016-06-01

    Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic

  8. Heterogeneity of triple-negative breast cancer: mammographic, US, and MR imaging features according to androgen receptor expression

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Min Sun; Song, Sung Eun; Kim, Won Hwa; Lee, Su Hyun; Moon, Woo Kyung [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, So Yeon; Park, In-Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Han, Wonshik; Noh, Dong-Young [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of)

    2014-09-16

    Our aim was to determine whether triple-negative breast cancers (TNBCs) with and without androgen receptor (AR) expression have distinguishing imaging features on mammography, breast ultrasound (US), and magnetic resonance (MR) imaging. AR expression was assessed immunohistochemically in 125 patients with TNBC from a consecutive series of 1,086 operable invasive breast cancers. Two experienced radiologists blinded to clinicopathological findings reviewed all imaging studies in consensus using the BI-RADS lexicon. The imaging and pathological features of 33 AR-positive TNBCs were compared with those of 92 AR-negative TNBCs. The presence of mammographic calcifications with or without a mass (p < 0.001), non-mass enhancement on MR imaging (p < 0.001), and masses with irregular shape or spiculated margins on US (p < 0.001 and p = 0.002) and MR imaging (p = 0.001 and p < 0.001) were significantly associated with AR-positive TNBC. Compared with AR-negative TNBC, AR-positive TNBC was more likely to have a ductal carcinoma in situ component (59.8 % vs. 90.9 %, p = 0.001) and low Ki-67 expression (30.4 % vs. 51.5 %, p = 0.030). AR-positive and AR-negative TNBCs have different imaging features, and certain imaging findings can be useful to predict AR status in TNBC. (orig.)

  9. Triple-beam negative hydrogen-ion source based on water vapor

    Energy Technology Data Exchange (ETDEWEB)

    Parkomchuk, V.V.; Kot, N.K.

    1985-07-01

    A Penning three-beam source of negative hydrogen-ions has been devised, which works with water vapor. The steady negative hydrogen-ion current in each beam is less than 4 microamps, but the negative hydrogen-ions constitute 92% of the beam current, while the water vapor consumption is 2.5 cm/sup 3//h and the distance between the beams is 20 mm. The source has been set up on an EG-1.5 accelerator, where it has worked without fail for over 400 h at 1 MeV.

  10. The correlation between triple negative breast cancer and androgen%三阴性乳腺癌与雄激素的相关性研究

    Institute of Scientific and Technical Information of China (English)

    庞华靖

    2015-01-01

    Objective To investigate the difference of serum testosterone and androgen receptor(AR)concentrations between triple negative breast cancer patients and non-triple negative breast cancer patients and its clinical significance.differences and clini-cal significance.Methods According to the inclusion criteria,a total of 92 female patients were enrolled in the study including 42 patients with triple negative breast cancer and 50 patients with non-triple negative breast cancer.The patients recruited all seeked medical advice in hospital and diagnosed with primary breast cancer by using pathological method.Age,histological grade,patholog-ical stage,serum testosterone and AR concentrations were compared between triple negative breast and non-triple-negative group and statistically analyzed.Results Compared between triple negative breast and non-triple-negative group,the serum testosterone concentrations of triple negative breast was lower and the difference were statistically different(P <0.05);AR-positive rate of triple negative breast cancer group was 57%,AR-positive rate of non-triple-negative breast cancer was 82%,the difference was statistical-ly significant(P <0.05).Conclusion Androgen and AR may be a prognostic therapeutic target in triple negative breast cancer.%目的:探讨三阴性乳腺癌与非三阴性乳腺癌患者间睾酮和雄激素受体(AR)水平的差异及临床意义。方法按照纳入标准选取该院经病理确证为原发性乳腺癌的患者,共92例女性患者,其中三阴性乳腺癌42例,非三阴性乳腺癌50例,统计分析三阴性与非三阴性乳腺组患者年龄、组织学分级、病理分期、血清睾酮水平和 AR 的差异。结果三阴性乳腺癌组和非三阴性乳腺癌组比较,三阴性乳腺癌组血清睾酮水平低于非三阴性乳腺癌组,差异有统计学意义(P <0.05);三阴性乳腺癌组 AR 阳性率为57%,非三阴性乳腺癌 AR 阳性率为82%,

  11. Neoadjuvant chemotherapy for triple-negative breast cancer:a meta-analysis with 7168 cases

    Institute of Scientific and Technical Information of China (English)

    Guojing Zhang; Xiaodong Xie; Wanqing Xie Co-first author; Chao Lin; Zhaozhe Liu; Long Xu; Guanzhong Zhang; Fang Guo; Yaling Han; Hongxin Zheng

    2014-01-01

    Objective:The pathological complete response (pCR) rates of neoadjuvant chemotherapy (NAC) in triple-nega-tive breast cancer (TNBC) was reported higher than that in non-TNBC but ranged from 12%to 48%. pCR was reported to be a predictor of long overal survival and exact pCR rate of NAC in TNBC would give us some hints on how to improve outcomes of TNBC patients. The meta-analysis was conducted to estimate the pCR rate of NAC for TNBC through contrasting the pCR rates of TNBC and non-TNBC tumors in NAC. Methods:Studies were selected from the PubMed database and Cochrane Col aboration Library. pCR rates were col ected in groups of TNBC and non-TNBC tumors. Review Manager 4.2 was used to perform forest plots and funnel plots. Results:The analysis included 22 studies with 7168 patients, the aggregate pCR rate was 29.5%in TNBC group, which was 17.7%higher than non-TNBC. The summary relative risk (RR) for pCR rate of TNBC group with that of non-TNBC group was 2.55. No obvious statistical heterogeneity and publication bias was detected. Conclu-sion:This meta-analysis demonstrated that NAC showed a higher pCR rate in TNBC than non-TNBC.

  12. Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jun Hyoung Park

    2016-03-01

    Full Text Available Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC. Analysis of cybrids and established breast cancer (BC cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1 and 2 (CPT2, the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.

  13. Identifying gaps and relative opportunities for discovering membrane proteomic biomarkers of triple-negative breast cancer as a translational priority

    Directory of Open Access Journals (Sweden)

    Bhooma Venkatraman

    2016-01-01

    Full Text Available Triple-negative breast cancer (TNBC remains a significant clinical and scientific challenge. The classification of TNBC is based on the lack of expression of the human epidermal growth factor 2, the estrogen receptor, and the progesterone receptor. TNBC accounts for more than 20% of all breast cancers (BCs, has a poorer prognosis compared to other BC subtypes, and has no targeted therapeutics. Primarily, this review focuses on the heterogeneity of BC and the importance of molecular subtyping for the accurate classification of TNBC. Further, it seeks to identify the molecular "omic" gaps in subtyping TNBC and the role of membrane protein biomarkers that could potentially advance clinical and translational research in BC.

  14. Polypyrrole-based nanotheranostics for activatable fluorescence imaging and chemo/photothermal dual therapy of triple-negative breast cancer

    Science.gov (United States)

    Park, Dongjin; Ahn, Kyung-Ohk; Jeong, Kyung-Chae; Choi, Yongdoo

    2016-05-01

    Here, we fabricated polypyrrole nanoparticles (PPys) (termed HA10-PPy, HA20-PPy, and HA40-PPy) doped with different average molecular weight hyaluronic acids (HAs) (10, 20, and 40 kDa, respectively), and evaluated the effect of molecular weight of doped HA on photothermal induction, fluorescence quenching, and drug loading efficiencies. Doxorubicin-loaded HA-doped PPys (DOX@HA-PPys) could be used for imaging and therapy of triple-negative breast cancer (TNBC). Fluorescence turn-on, stimuli-responsive drug release, and photo-induced heating of DOX@HA-PPys enabled not only activatable fluorescence imaging but also subsequent chemo/photothermal dual therapy for TNBC. In particular, we illustrated the potential usefulness of the photothermal effect of the nanoparticles for overcoming chemoresistance in TNBC.

  15. Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Park, Jun Hyoung; Vithayathil, Sajna; Kumar, Santosh; Sung, Pi-Lin; Dobrolecki, Lacey Elizabeth; Putluri, Vasanta; Bhat, Vadiraja B; Bhowmik, Salil Kumar; Gupta, Vineet; Arora, Kavisha; Wu, Danli; Tsouko, Efrosini; Zhang, Yiqun; Maity, Suman; Donti, Taraka R; Graham, Brett H; Frigo, Daniel E; Coarfa, Cristian; Yotnda, Patricia; Putluri, Nagireddy; Sreekumar, Arun; Lewis, Michael T; Creighton, Chad J; Wong, Lee-Jun C; Kaipparettu, Benny Abraham

    2016-03-08

    Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.

  16. Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells.

    Science.gov (United States)

    Kwak, Jin Ho; Park, Jun Yeon; Lee, Dahae; Kwak, Jae Young; Park, Eun Hwa; Kim, Ki Hyun; Park, Hye-Jin; Kim, Hyun Young; Jang, Hyuk Jai; Ham, Jungyeob; Hwang, Gwi Seo; Yamabe, Noriko; Kang, Ki Sung

    2014-12-01

    Because of poor prognosis, clinical treatment of triple-negative (TN) breast cancer remains the most challenging factor in cancer treatment. Extensive research into alternative cancer therapies includes studying the naturopathic effects of the medicinal herb ginseng. This study investigates the anti-neoplastic properties of ginseng sapogenins and the derivatives: (1) (20(S)-protopanaxadiol (PPD), (2) 20(S)-protopanaxatriol), (3) (20(S)-dihydroprotopanaxadiol, and (4) 20(S)-dihydroprotopanaxatriol). These compounds were found to prevent the proliferation of MDA-MB-231 human breast cancer cells. PPD was the most potent inhibitor, exhibiting an IC₅₀ (5.87 μM) comparable to that of the chemotherapeutic drug taxol. Furthermore, PPD induced dose-dependent cleavage of caspase-8, caspase-3, and PARP in MDA-MB-231 cells. Thus, we propose that PPD acts as anti-cancer agent by stimulating caspase-dependent apoptosis in breast cancer cells.

  17. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer.

    Science.gov (United States)

    Xu, Jie; Wu, Xing; Zhou, Wei-hua; Liu, An-wen; Wu, Jian-bing; Deng, Jin-yun; Yue, Cai-feng; Yang, Shao-bing; Wang, Jing; Yuan, Zhong-yu; Liu, Quentin

    2013-01-01

    Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (Pprognosis compared with low expression of both Aur-A and Ki-67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy.

  18. Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Vincent K. Tuohy

    2016-06-01

    Full Text Available We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC.

  19. Selective, nontoxic CB(2) cannabinoid o-quinone with in vivo activity against triple-negative breast cancer.

    Science.gov (United States)

    Morales, Paula; Blasco-Benito, Sandra; Andradas, Clara; Gómez-Cañas, María; Flores, Juana María; Goya, Pilar; Fernández-Ruiz, Javier; Sánchez, Cristina; Jagerovic, Nadine

    2015-03-12

    Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (10) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB2 cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound 10 exerts antitumor effect by inducing cell apoptosis through activation of CB2 receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC.

  20. Clinicopathologic features and prognosis of triple negative breast cancer%三阴性乳腺癌临床病理特征及预后分析

    Institute of Scientific and Technical Information of China (English)

    史立晖; 张晓君; 张晓耀; 李智; 王景; 屈翔

    2010-01-01

    目的 分析三阴性乳腺癌的临床病理特征及与预后的关系. 方法 回顾性分析2002年1月-2007年2月北京通州妇幼保健院收治的乳腺癌患者196例,进行免疫组织化学法测定Her-2、ER、PR蛋白表达,并分为两组,一组为三阴性(triple-negative)乳腺癌,即Her2(-),ER(-),PR(-),另一组为非三阴性乳腺癌.分析三阴性和非三阴性乳腺癌的临床病理特征,比较三阴性乳腺癌患者术后的3年无瘤生存率. 结果 三阴性乳腺癌在所有患者中所占比例为13.27%(26/196),其肿瘤大小情况、组织学Ⅲ级的比例高于非三阴性乳腺癌(P<0.05).三阴性乳腺癌和非三阴性乳腺癌3年无瘤生存率分别为84.62%(22/26)和92.94%(158/170). 结论 三阴性乳腺癌较非三阴性乳腺癌易发生局部复发和远处转移,预后差.%Objective To analyze the relationship of clinicopathologic Features and prognosis of triple negative breast cancer. Methods A total of 196 cases with operable breast cancer received in our hospital between January 2002 and February 2007 were analyzed. We used immunohistochemistry to determine Her2, ER, and PR status. The patients were divided into the triple negative breast cancer group (ER negative,PR negative, and Her-2 negative)and the non-triple negative breast cancer group. The clinicopathologic features of the two groups were compared. The 3-year disease-free survival (DFS) was analyzed. Results Of the 196 patients, 13.27% (26/196) had triple negative breast cancer. The percentage of cases with tumor exceeded 5 cm or grade Ⅲ was higher in the triple negative group than in the non-triple negative group (P < 0.05 ). No significant difference was found in other clinicopathologic features between the two groups.The 3-year DFS was 84.62% (22/26) in the triple negative group and 92.94% ( 158/170)in the non-triple negative group. Conclusion Compared with non triple negative breast cancer, triple negative breast cancer has an increased

  1. Identifying Triple-Negative Breast Cancer Using Background Parenchymal Enhancement Heterogeneity on Dynamic Contrast-Enhanced MRI: A Pilot Radiomics Study.

    Directory of Open Access Journals (Sweden)

    Jeff Wang

    Full Text Available To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE MRI at 3.0 Tesla in identifying "triple-negative" breast cancers.In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other subtypes, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC using cross-validation.Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01. Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement.Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple-negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly associated with the triple-negative subtype

  2. Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?

    Science.gov (United States)

    Synnott, N C; Murray, A; McGowan, P M; Kiely, M; Kiely, P A; O'Donovan, N; O'Connor, D P; Gallagher, W M; Crown, J; Duffy, M J

    2017-01-01

    The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1(MET) (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1(MET) was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1(MET) than p53 WT cells (p = 0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p = 0.0089, r=-0.57, n = 19). In addition to inhibiting cell proliferation, PRIMA-1(MET) induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1(MET) is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.

  3. Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in human triple-negative breast cancer cells.

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    Luan, Yun-Yan; Liu, Zi-Min; Zhong, Jin-Yi; Yao, Ru-Yong; Yu, Hong-Sheng

    2015-01-01

    Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenesis, which was associated with invasion and metastasis. The grape seed proanthocyanidins (GSPs) had attracted much attention as a potential bioactive anti-carcinogenic agent. However, GSPs regulation of VM and its possible mechanisms in a triple-negative breast cancer cells (TNBCs) remain not clear. Therefore, we examined the effect of GSPs on VM information in HCC1937 cell model. In this study, we identified the VM structure via the three-dimensional (3D) matrix in vitro. Cell viability was measured using the CCK8 assay. The effects of GSPs on human triple-negative breast cancer cells (TNBCs) HCC1937 in terms of related proteins of VM information were determined using western blot analysis. In vitro, the tubular networks were found in highly invasive HCC1937 cells but not in the non-invasive MCF-7 cells when plated on matrigel. The number of vascular channels was significantly reduced when cells were exposed in GSPs (100 μg/ml) and GSPs (200 μg/ml) groups (all p<0.001). Furthermore, we found that treatment with GSPs promoted transition of the mesenchymal state to the epithelial state in HCC1937 cells as well as reducing the expression of Twist1 protein, a master EMT regulator.GSPs has the ability to inhibit VM information by the suppression of Twist1 protein that could be related to the reversal of epithelial-to-mesenchymal (EMT) process. It is firstly concluded that GSPs may be an potential anti-VM botanical agent for human TNBCs.

  4. MiRNAs Predict the Prognosis of Patients with Triple Negative Breast Cancer: A Meta-Analysis

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    Liu, Yanli; Zhang, Yuchao; Li, Qingfu; Li, Junfang; Ma, Xiaotian; Xing, Jinfang; Rong, Shouhua; Wu, Zhong; Tian, Yuan; Li, Jing; Jia, Liting

    2017-01-01

    Purpose miRNAs are stable and can be extracted from tissues, blood and other body fluid without degradation. miRNAs are abnormally expressed in the presence of a pathological status, including cancer. Therefore, miRNAs are ideal biomarkers for cancer diagnosis and prognosis. Patients with triple negative breast cancer (TNBC) suffer the worst prognosis, although great efforts have been made. Many studies have investigated the role of miRNAs in predicting the outcomes of TNBC patients for better adjustment of treatment. However, results were inconsistent. Thus, we performed a meta-analysis to summarize the published studies for conclusive results. Methods Eligible studies from different database were retrieved from the online databases, and we used STSTA 12.0 to analysis the prognostic role of miRNAs in triple negative breast cancer. Results Overall high miRNA expression indicated a worse survival with HR value of 1.78 (95% CI: 0.97–3.25). However, subtotal HRs of oncogenic miRNAs and tumor suppressive miRNAs were 2.73 (95% CI: 2.08–3.57; P<0.001) and 0.44 (95% CI: 0.21–0.90; P = 0.024), respectively, and no heterogeneity was observed within the subgroups. Conclusions The miRNAs showed a slightly stronger prognostic value for disease-free survival, relapse-free survival and distant metastasis-free survival compared to the overall survival of TNBC patients. Circulating miRNAs could serve as potential biomarkers for the prognosis of TNBC patients and need further investigation. PMID:28085956

  5. Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4.

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    Astrid Grottke

    Full Text Available Treatment of breast cancer patients with distant metastases represents one of the biggest challenges in today's gynecological oncology. Therefore, a better understanding of mechanisms promoting the development of metastases is of paramount importance. The serine/threonine kinase AKT was shown to drive cancer progression and metastasis. However, there is emerging data that single AKT isoforms (i.e. AKT1, AKT2 and AKT3 have different or even opposing functions in the regulation of cancer cell migration in vitro, giving rise to the hypothesis that inhibition of distinct AKT isoforms might have undesirable effects on cancer dissemination in vivo.The triple negative breast cancer cell line MDA-MB-231 was used to investigate the functional roles of AKT in migration and metastasis. AKT single and double knockdown cells were generated using isoform specific shRNAs. Migration was analyzed using live cell imaging, chemotaxis and transwell assays. The metastatic potential of AKT isoform knockdown cells was evaluated in a subcutaneous xenograft mouse model in vivo.Depletion of AKT3, but not AKT1 or AKT2, resulted in increased migration in vitro. This effect was even more prominent in AKT2,3 double knockdown cells. Furthermore, combined downregulation of AKT2 and AKT3, as well as AKT1 and AKT3 significantly increased metastasis formation in vivo. Screening for promigratory proteins revealed that downregulation of AKT3 increases the expression of S100A4 protein. In accordance, depletion of S100A4 by siRNA approach reverses the increased migration induced by knockdown of AKT3.We demonstrated that knockdown of AKT3 can increase the metastatic potential of triple negative breast cancer cells. Therefore, our results provide a rationale for the development of AKT isoform specific inhibitors.

  6. Identification, validation, and targeting of the mutant p53-PARP-MCM chromatin axis in triple negative breast cancer.

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    Qiu, Wei-Gang; Polotskaia, Alla; Xiao, Gu; Di, Lia; Zhao, Yuhan; Hu, Wenwei; Philip, John; Hendrickson, Ronald C; Bargonetti, Jill

    2017-01-01

    Over 80% of triple negative breast cancers express mutant p53. Mutant p53 often gains oncogenic function suggesting that triple negative breast cancers may be driven by p53 protein type. To determine the chromatin targets of this gain-of-function mutant p53 we used inducible knockdown of endogenous gain-of-function mtp53 in MDA-MB-468 cells in conjunction with stable isotope labeling with amino acids in cell culture and subcellular fractionation. We sequenced over 70,000 total peptides for each corresponding reciprocal data set and were able to identify 3010 unique cytoplasmic fraction proteins and 3403 unique chromatin fraction proteins. The present proteomics experiment corroborated our previous experiment-based results that poly ADP-ribose polymerase has a positive association with mutant p53 on the chromatin. Here, for the first time we report that the heterohexomeric minichromosome maintenance complex that participates in DNA replication initiation ranked as a high mutant p53-chromatin associated pathway. Enrichment analysis identified the minichromosome maintenance members 2-7. To validate this mutant p53- poly ADP-ribose polymerase-minichromosome maintenance functional axis, we experimentally depleted R273H mutant p53 and found a large reduction of the amount of minichromosome maintenance complex proteins on the chromatin. Furthermore a mutant p53-minichromosome maintenance 2 direct interaction was detected. Overexpressed mutant p53, but not wild type p53, showed a protein-protein interaction with minichromosome maintenance 2 and minichromosome maintenance 4. To target the mutant p53- poly ADP-ribose polymerase-minichromosome maintenance axis we treated cells with the poly ADP-ribose polymerase inhibitor talazoparib and the alkylating agent temozolomide and detected synergistic activation of apoptosis only in the presence of mutant p53. Furthermore when minichromosome maintenance 2-7 activity was inhibited the synergistic activation of apoptosis was blocked

  7. Jadomycins inhibit type II topoisomerases and promote DNA damage and apoptosis in multidrug resistant triple negative breast cancer cells.

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    Hall, Steven R; Toulany, Jay; Bennett, Leah G; Martinez-Farina, Camilo F; Robertson, Andrew W; Jakeman, David L; Goralski, Kerry B

    2017-09-13

    Jadomycins are natural products that kill drug-sensitive and multidrug resistant (MDR) breast cancer cells. To date the cytotoxic activity of jadomycins has never been tested in MDR breast cancer cells that are also triple-negative. Additionally, there is only a rudimentary understanding of how jadomycins cause cancer cell death, which includes the induction of intracellular reactive oxygen species (ROS). We first created a paclitaxel-resistant, triple-negative breast cancer cell line (231-TXL) from drug-sensitive MDA-MB-231 cells (231-CON). Using MTT cell viability measuring assays, jadomycins B, S, and F were found to be equipotent in drug-sensitive 231-CON and MDR 231-TXL cells, and using ROS-detecting assays these jadomycins were determined to increase ROS activity in both cell lines by up to 7.3-fold. Jadomycins caused DNA double strand breaks in 231-CON and 231-TXL cells as measured by γH2AX western blotting. Co-incubation with the antioxidant N-acetyl cysteine (NAC) or pro-oxidant auranofin did not affect jadomycin-mediated DNA damage. Jadomycins induced apoptosis in 231-CON and 231-TXL cells as measured by annexin V affinity assays, a process which was retained when ROS were inhibited. This indicated that jadomycins are capable of inducing MDA-MB-231 apoptotic cell death independently of ROS activity. Using qPCR, western blotting, and direct topoisomerase inhibition assays, it was determined that jadomycins inhibit type II topoisomerases and that jadomycins B and F selectively poison topoisomerase IIβ. We therefore propose novel mechanisms through which jadomycins induce breast cancer cell death independently of ROS-activity, through inhibition or poisoning of type II topoisomerases, and induction of DNA damage and apoptosis. The American Society for Pharmacology and Experimental Therapeutics.

  8. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

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    Zhang, Wenwen; Xu, Jing; Fang, Hehui; Tang, Lin; Chen, Weiwei; Sun, Qian; Zhang, Qun; Yang, Fang; Sun, Zijia; Cao, Lulu; Wang, Yucai; Guan, Xiaoxiang

    2017-09-12

    Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs-when mixed with TNBC cells-could increase TNBC cell metastatic potency. After treatment with TGF-β to induce endothelial-mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stimulate the expression and secretion of the chemokine, CCL5, from ECs, which then acts in a paracrine fashion on TNBC cells to enhance their migration, invasion, and metastasis. CCL5, in turn, accelerates TNBC cell secretion of PAI-1 and promotes TNBC cell metastasis, thus forming a positive feedback loop. Moreover, this enhanced metastatic ability is reversible and dependent on CCL5 signaling via the chemokine receptor, CCR5. Of importance, key features of this pathway are manifested in patients with TNBC and in The Cancer Genome Atlas database. Taken together, our results suggest that ECs enhance EMT-induced TNBC cell metastasis via PAI-1 and CCL5 signaling and illustrate the potential of developing new PAI-1- and CCL5-targeting therapy for patients with TNBC.-Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. © FASEB.

  9. Current data of targeted therapies for the treatment of triple-negative advanced breast cancer: empiricism or evidence-based?

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    Petrelli, Fausto; Cabiddu, Mary; Ghilardi, Mara; Barni, Sandro

    2009-10-01

    Approximately 10 - 15% of breast carcinomas (BCs) are known to be 'triple-negative (TN) receptor' (i.e., not expressing ER or PR and not exhibiting overexpression and/or gene amplification of HER2-neu). Triple-negative BCs comprise approximately 85% of all basal-type tumours. Classically, basal-like BCs have been characterised by low expression of ER, PR, and HER2 neu and high expression of CK5, CK14, caveolin-1, CAIX, p63, and EGFR (HER1), which reflects the mammary gland basal/myoepithelial cell component. Although there is no standard first-line chemotherapy regimen for metastatic TN BCs, anthracycline- and taxane-containing regimens are acceptable treatments. A large number of agents, including DNA-damaging agents, EGFR inhibitors, antiangiogenic agents and novel taxane formulations are currently being tested in clinical trials for first-line and pretreated patients. Limited experiences with platinum salts, poly(ADP-ribose) polymerase (PARP) inhibitors, cetuximab, bevacizumab and ixabepilone have been published in recent years and will be reported. Novel immunohistochemistry analysis for identification of basal like/TN phenotype are awaited to correctly select this population. The clinical trials investigating new agents have to be designed for a specific (and possibly large) subset of patients with BC. In the future, a gene array platform with greater sensitivity for distinguishing the various BC subtypes, as well as having the power to predict the molecular biology of the disease, will be an indispensible tool for treatment selection. Currently, treatment of TN BC is more empirical than evidence-based. The cornerstone of treatment is chemotherapy, but in the near future, novel target agents will emerge as possible partners.

  10. Pharmacological levels of Withaferin A (Withania somnifera trigger clinically relevant anticancer effects specific to triple negative breast cancer cells.

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    Katarzyna Szarc vel Szic

    Full Text Available Withaferin A (WA isolated from Withania somnifera (Ashwagandha has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8, cell adhesion molecules (integrins, laminins, pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1. In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors

  11. Stem cell marker aldehyde dehydrogenase 1 (ALDH1)-expressing cells are enriched in triple-negative breast cancer.

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    Li, Huihui; Ma, Fei; Wang, Haijuan; Lin, Chen; Fan, Ying; Zhang, Xueyan; Qian, Haili; Xu, Binghe

    2013-12-17

    The stem cell marker ALDH1 has been of particular interest to scientists since it has been successfully used as a marker to isolate cancer stem cells from breast cancers. However, little is known, especially in Chinese breast cancer patients, on whether ALDH1 enrichment is prevalent in certain subtypes of breast cancer. In this study, we performed flow cytometry and immunohistochemistry to measure the expression of ALDH1 in 10 breast cancer cell lines and in a set of tissue microarrays consisting of 101 breast cancer tissues from the Chinese population. The 101 breast cancer tissues included 4 cancer subtypes defined on bases of their ER, PR, and HER2 statuses: triple-negative (25 cases), luminal A (33 cases), luminal B (16 cases) and HER2-overexpressing (HER2-OE, 27 cases). We found that ALDH1 was expressed in 25 of the 101 cases of breast cancer tissues. When the analysis was stratified, we found that the expression of ALDH1 varied significantly among the 4 subtypes, with a higher expression in triple-negative breast cancer (TNBC, p=0.003) than in the other 3 subtypes. In a series of breast cancer cell lines, we also confirmed that ALDH1 activity was mainly found in TNBC cell lines compared with non-TNBC ones (15.6% ± 2.45% vs 5.5% ± 2.58%, p=0.026). These data support the concept that the expression of ALDH1 is higher in TNBC than non-TNBC, which may be clinically meaningful for a better understanding of the poor prognosis of TNBC patients.

  12. Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines.

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    Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

    2015-04-01

    Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers.

  13. Novel treatment strategies in triple-negative breast cancer: specific role of poly(adenosine diphosphate-ribose polymerase inhibition

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    Audeh MW

    2014-10-01

    Full Text Available M William Audeh Division of Medical Oncology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abstract: Inhibitors of the poly(adenosine triphosphate-ribose polymerase (PARP-1 enzyme induce synthetic lethality in cancers with ineffective DNA (DNA repair or homologous repair deficiency, and have shown promising clinical activity in cancers deficient in DNA repair due to germ-line mutation in BRCA1 and BRCA2. The majority of breast cancers arising in carriers of BRCA1 germ-line mutations, as well as half of those in BRCA2 carriers, are classified as triple-negative breast cancer (TNBC. TNBC is a biologically heterogeneous group of breast cancers characterized by the lack of immunohistochemical expression of the ER, PR, or HER2 proteins, and for which the current standard of care in systemic therapy is cytotoxic chemotherapy. Many “sporadic” cases of TNBC appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of TNBC. Significant genetic heterogeneity has been observed within the TNBC cohort, creating challenges for interpretation of prior clinical trial data, and for the design of future clinical trials. Several PARP inhibitors are currently in clinical development in BRCA-mutated breast cancer. The use of PARP inhibitors in TNBC without BRCA mutation will require biomarkers that identify cancers with homologous repair deficiency in order to select patients likely to respond. Beyond mutations in the BRCA genes, dysfunction in other genes that interact with the homologous repair pathway may offer opportunities to induce synthetic lethality when combined with PARP inhibition. Keywords: PARP, triple negative breast cancer, PARP inhibitors

  14. Profile of molecular subtypes of breast cancer with special reference to triple negative: A study from Northeast India

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    Gayatri Gogoi

    2016-01-01

    Full Text Available Background: Different molecular classes of breast cancer (BRCA correlate with prognosis and response to therapy. Triple-negative breast cancer (TNBC is a newer concept and very limited studies were carried out in India. The aim of this study was to profile the molecular types with a particular emphasis on TNBCs. Materials and Methods: Prospectively evaluated descriptive study for 2 years from June 2014 to March 2016, was carried out in the Department of Pathology and Surgery in a tertiary care institute. Cases included were of invasive breast carcinoma in females, confirmed by histopathology. Ethical clearance was received. Data were analyzed using Statistical SAS software. Results: A total of 123 cases of invasive BRCA were studied and mean age was 44.64 years. The peak age group was 36–45 years (43.9%. Tumor sizes ≥2 cm was 30%, between 2 and 5 cm was 50.40%, over 5 cm was 19.51%. Invasive duct carcinoma was 82.11% and invasive lobular carcinoma 8.13%. Only 21% of subjects presented as early breast carcinoma. Cases of 1–3 nodes were 22.8%, 4–5 nodes 21.1%, more than five nodes were 34%. Histologic Grade 3 was 50.4%, Grade 2 was 41%, and Grade 1 was only 8.1. The American Joint Committee on Cancer, Stage 1 (17.9% in Stage 2 (29.3% Stage 3 was 46.3%, Stage 4 was 6.5%. Estrogen receptor was in 40.62%, progesterone receptor 35.77%, Her2/Neu 18.69% luminal A (19.51%, luminal B (21.13%, Her2/Neu type (17.88%, and triple negatives (38.21. Conclusion: The present study showed significantly higher TNBC with poor prognostic factors in younger women in a background of peculiar ethic spectrum in this geographical region.

  15. Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival.

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    Gary Tozbikian

    Full Text Available Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006, and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients' race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.

  16. Adjuvant endocrine therapy alone in patients with node-positive, luminal A type breast cancer.

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    Park, Sungmin; Lee, Se Kyung; Paik, Hyun-June; Ryu, Jai Min; Kim, Isaac; Bae, Soo Youn; Yu, Jonghan; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin

    2017-06-01

    Luminal A breast cancer has a much better prognosis than other subtypes, with a low risk of local or regional recurrence. However, there is controversy around under- versus overtreatment with regard to adjuvant treatment of node-positive, luminal A breast cancer. The purpose of this study was to identify whether adjuvant systemic chemotherapy has any benefit in node-positive, luminal A breast cancer and to evaluate feasibility of endocrine therapy without chemotherapy in this group.This was a retrospective study of 11,025 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between January 2004 and December 2013. Luminal A subtype was defined as ER+, HER2-, and Ki-67 < 14%. We compared AC based (AC: doxorubicin or epirubicin, plus cyclophosphamide) adjuvant chemotherapy versus endocrine therapy without chemotherapy in patients with node-positive, luminal A breast cancer.We performed 1: n matching, with a maximum n of 8 on endocrine therapy group (n = 50) to chemotherapy group (n = 642). The median age of the patients in each group at the time of surgery was 58.3 ± 9.5 years in the chemotherapy group and 58.7 ± 11.7 in the endocrine therapy only group. The median follow-up time was 51.9 months (range, 1-125 months). In multivariable analysis, omission of adjuvant chemotherapy in luminal A cancer had no influence on OS and DFS. Axillary lymph node metastasis and progesterone receptor (PR) status were significantly different between the endocrine therapy alone group and the chemotherapy group in terms of OS. Nuclear grade, PR status, and adjuvant radiotherapy were significantly different between the endocrine therapy alone group and the chemotherapy group with regard to DFS. In survival analysis, there were no differences in OS (P = .137) and DFS (P = .225) between the 2 groups.Adjuvant chemotherapy could provide little benefit to postmenopausal patients with luminal A, node-positive breast cancer, and

  17. Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition.

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    Su, Chih-Ming; Lee, Wei-Hwa; Wu, Alexander T H; Lin, Yen-Kuang; Wang, Liang-Shun; Wu, Chih-Hsiung; Yeh, Chi-Tai

    2015-06-01

    Breast cancer is the leading cause of cancer-related deaths among females in economically developing countries. Greater than 95% of breast malignancies are of epithelial origin; the induction of epithelial-to-mesenchymal transition (EMT) has been shown to initiate the metastatic process in breast carcinoma and remains the key target for drug development. Here, we examine the anti-metastatic potential of pterostilbene in modulating EMT process in breast cancer cells both in vitro and in vivo. The differential invasive ability among MCF7, Hs578t and MDA-MB-231 breast cancer cell lines were closely correlated with the expression of EMT markers, determined by Western blots and Matrigel-coated transwells assay. Pterostilbene inhibited the migratory and invasive potential of triple-negative MDA-MB-231 and Hs578t cells, accompanied by the up-regulation of E-cadherin and down-regulation of Snail, Slug, vimentin and ZEB1. Mechanistic investigations revealed a significant up-regulation of miR-205, which resulted in the reduction of Src expression in pterostilbene-treated breast cancer cells. Importantly, pterostilbene suppressed tumor growth and metastasis in MDA-MB-231-bearing NOD/SCID mice by reducing Src/Fak signaling; this observation was consistent with the negative correlations between miR-205 and Src expression in both normal and malignant breast tissues. Our findings provide supports for the usage of pterostilbene as an inhibitor of EMT process and potential candidate for adjuvant therapy.

  18. Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor.

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    Al-Ejeh, Fares; Shi, Wei; Miranda, Mariska; Simpson, Peter T; Vargas, Ana Cristina; Song, Sarah; Wiegmans, Adrian P; Swarbrick, Alex; Welm, Alana L; Brown, Michael P; Chenevix-Trench, Georgia; Lakhani, Sunil R; Khanna, Kum Kum

    2013-06-01

    Triple-negative breast cancer (TNBC) is associated with poor survival. Chemotherapy is the only standard treatment for TNBC. The prevalence of BRCA1 inactivation in TNBC has rationalized clinical trials of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Similarly, the overexpression of epidermal growth factor receptor (EGFR) rationalized anti-EGFR therapies in this disease. However, clinical trials using these 2 strategies have not reached their promise. In this study, we used EGFR as a target for radioimmunotherapy and hypothesized that EGFR-directed radioimmunotherapy can deliver a continuous lethal radiation dose to residual tumors that are radiosensitized by PARP inhibitors and chemotherapy. We analyzed EGFR messenger RNA in published gene expression array studies and investigated EGFR protein expression by immunohistochemistry in a cohort of breast cancer patients to confirm EGFR as a target in TNBC. Preclinically, using orthotopic and metastatic xenograft models of EGFR-positive TNBC, we investigated the effect of the novel combination of (177)Lu-labeled anti-EGFR monoclonal antibody, chemotherapy, and PARP inhibitors on cell death and the survival of breast cancer stem cells. In this first preclinical study of anti-EGFR radioimmunotherapy in breast cancer, we found that anti-EGFR radioimmunotherapy is safe and that TNBC orthotopic tumors and established metastases were eradicated in mice treated with anti-EGFR radioimmunotherapy combined with chemotherapy and PARP inhibitors. We showed that the superior response to this triple-agent combination therapy was associated with apoptosis and eradication of putative breast cancer stem cells. Our data support further preclinical investigations toward the development of combination therapies using systemic anti-EGFR radioimmunotherapy for the treatment of recurrent and metastatic TNBC.

  19. 三阴乳腺癌与非三阴乳腺癌X线及病理特征分析%Mammographic features and histopathological characteristics of triple negative breast cancer and non-triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    李丽娟; 黎庶

    2012-01-01

    目的 与非三阴乳腺癌(non-TNBC)比较,探讨三阴乳腺癌(TNBC)的X线表现及病理特征.方法 回顾性分析经病理证实的574例乳腺癌患者资料,对比分析81例TNBC(TNBC组)与493例non-TNBC患者(non-TNBC组)的临床、病理特征及X线表现.结果 TNBC组织学分级以中、高级别为主,其中53.09%(43/81)发生腋窝淋巴结转移,高于non-TNBC组(39.96%,197/493,P<0.05).与non-TNBC组相比,TNBC病变体积较大,多为单纯肿块型,少见钙化(P<0.05),肿块型TNBC瘤体多为类圆形,边缘光滑,较少见不规则形及毛刺(P<0.05).结论 TNBC与non-TNBC在X线表现及病理特征方面存在一定差异,了解其特征有助于诊断TNBC.%Objective To explore the mammographic features and histpathological characteristics of triple negative breast cancer (TNBC) compared with non-triple negative breast cancer (non-TNBC). Methods A total of 574 patients with his-topathologieally confirmed breast cancer were analyzed retrospectively. The clinical, histopathological and mammographic imaging characteristics of TNBC patients (n=81) were analyzed and compared with those of non-TNBC patients (n = 493). Results Most of TNBC showed intermediate and high histological grade. The percentage of lymph node metastasis in TNBC group (43/81, 53. 09%) was higher than that of non-TNBC group (197/493, 39. 96%, P<0. 05). Tumors in TNBC group were larger than non-TNBC group, usually presented as a mass with less calcifications (P<0. 05). The masses of TNBC frequently presented as oval and smooth margin, with less irregular and burr (P<0. 05). Conclusion There are some differences between TNBC and non-TNBC in pathology and radiology. Understanding these characters might be useful to diagnose TNBC.

  20. miRNA-21 promotes proliferation and invasion of triple-negative breast cancer cells through targeting PTEN

    Science.gov (United States)

    Fang, Hong; Xie, Jiping; Zhang, Min; Zhao, Ziwei; Wan, Yi; Yao, Yongqiang

    2017-01-01

    MicroRNAs (miRNAs) are small single-stranded RNAs that bind to the 3’UTR of the mRNAs of target genes. They can target multiple genes and regulate translation or degradation of the mRNA. miRNAs target genes in a tissue-specific manner, and the role of a particular miRNA varies according to tumor origin or even subtype within the same cancer. This study evaluated the effect of miR-21 expression in triple-negative breast cancer (TNBC) tissues and MDA-MB-468, a cell line derived from TNBC tissues. miR-21 was consistently upregulated in TNBC and MDA-MB-468 cells compared to normal tissues. Inhibition of miR-21 by miR-21 antisense oligonucleotides decreased the proliferation, viability, and invasiveness of MDA-MB-468 cells and enhanced apoptosis. Furthermore, we confirmed that PTEN was downregulated by miR-21 in MDA-MB-468 cells. The results indicated that PTEN may mediate the oncogenic properties of miR-21 in TNBC. In summary, miR-21 was upregulated in TNBC tissues and cells, and promoted the proliferation and invasion of MDA-MB-468 cells, but negatively regulated the expression of PTEN protein. Inhibition of miR-21 or overexpression of PTEN protein could be promising strategies for the treatment of patients with TNBC.

  1. Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity.

    Science.gov (United States)

    Roberts, Lindsay S; Yan, Peter; Bateman, Leslie A; Nomura, Daniel K

    2017-03-08

    Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map additional metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.

  2. Current status of treatment of triple-negative breast cancer%三阴乳腺癌治疗现状

    Institute of Scientific and Technical Information of China (English)

    钟辉凤; 陈晓品

    2015-01-01

    Triple-negative breast cancer (TNBC) means the breast cancer with estrogen receptor,progestrone receptor, human epidermal growth factor receptor 2(Her-2) being negative,accounting for about 15.0%-25.0% of breast cancers. It is charaterized with tending to recrudesce,metastasis and being poor in prognosis,which didit benefit from adjusting Endocrine level and Her-2 targeted drugs. It′s treatment is comprehensive including chemotherapy,surgery and radiotherapy,while the effective targeted therapy is in process. This article focuses on the local and general therapies as well as prognosis.%三阴乳腺癌(TNBC),即雌激素受体、孕激素受体、人表皮生长因子受体-2(Her-2)均为阴性的乳腺癌,约占乳腺癌的15.0%~25.0%,具有易复发、易转移和预后差的特点,且不能从内分泌治疗和Her-2靶向药物治疗获益。其治疗为化疗、手术及放疗的综合治疗,有效的靶向治疗正在探索中。该文主要就TNBC的局部治疗、全身治疗及预后进行了综述。

  3. Correlation of Physical Activities and Breast Cancer Characteristics: A Prospective Analysis with Special Focus on Triple Negative Breast Cancer.

    Science.gov (United States)

    Vallard, Alexis; Falk, Alexander Tuan; Antoine, Pascale; Guy, Jean-Baptiste; Guichard, Jean-Baptiste; Espenel, Sophie; Langrand-Escure, Julien; Trone, Jane-Chloé; Méry, Benoîte; Ben Mrad, Majed; Diao, Peng; Wang, Guoping; Roche, Frédéric; Bosacki, Claire; Chargari, Cyrus; Bourmaud, Aurélie; Magné, Nicolas

    2015-01-01

    Several studies have demonstrated that daily physical activity (PA) prevents the development of breast cancer. Our objective was to examine the relationship between PA and clinical and biological tumor characteristics in breast cancer patients in order to determine the impact of energy expenditure (EE) on tumor prognosis. We pooled data from two prospective studies, including a total of 121 breast cancer patients. The measure of PA was done using the self-completion Population Physical Activity Questionnaire, which was answered by each patient. Ten patients harbored triple negative (TN) tumors. The mean body mass index (BMI) in the general population and in patients with TN tumors was 24.3 and 25.6, respectively. The mean daily EE (DEE) was 10,266 kJ×24 h(-1) in the general population and 11,212 kJ×24 h(-1) in patients with TN tumors. In the whole population, there was an inverse statistical correlation between BMI and DEE, rest, low PA, and high PA (p=0.0002, p=0.003, pcorrelation between negative estrogen receptor status and intensive PA (p=0.041) and DEE (p=0.007). For TN tumors, there was no significant correlation between BMI and categories of EE. Lifestyle (weight regulation, PA) should be adapted and personalized according to biological, clinical, and epidemiological characteristics of the tumors. © 2015 S. Karger AG, Basel.

  4. Progesterone suppresses triple-negative breast cancer growth and metastasis to the brain via membrane progesterone receptor α.

    Science.gov (United States)

    Zhou, Li; Zhou, Wei; Zhang, Hongwei; Hu, Yan; Yu, Lei; Zhang, Yufei; Zhang, Yanli; Wang, Shuang; Wang, Peng; Xia, Wei

    2017-09-01

    Progesterone plays an important role in mammary epithelial cell proliferation and differentiation. Evidence from experimental and clinical studies indicates that progesterone is a risk factor for breast cancer under certain conditions through binding nuclear progesterone receptor (PR). These mechanisms, however, are not applicable to triple-negative breast cancer (TNBC) due to the lack of PR in these cancers. In this study, we demonstrate that membrane progesterone receptor α (mPRα) is expressed in TNBC tissues and the expression level of mPRα is negatively associated with the TNM stage. We found that progesterone suppressed the growth, migration and invasion of mPRα+ human TNBC cells in vitro, which was neither mediated by PR nor by PR membrane component 1 (PGRMCl). Notably, these effects exerted by progesterone were significantly blocked by shRNA specific to mPRα. Moreover, the knockdown of mPRα expression impaired the inhibitory effects of progesterone on mPRα+ tumor growth and metastasis in vivo. These data collectively indicate that progesterone suppresses TNCB growth and metastasis via mPRα, which provides evidence of the anti-neoplastic effects of progesterone-mPRα pathway in the treatment of human TNBC.

  5. Being Overweight or Obese Increases the Risk of Progression in Triple-Negative Breast Cancer after Surgical Resection.

    Science.gov (United States)

    Choi, Yunseon; Park, Sung Kwang; Ahn, Ki Jung; Cho, Heunglae; Kim, Tae Hyun; Yoon, Hye Kyoung; Lee, Yun-Han

    2016-06-01

    This study aimed to evaluate the association between body mass index (BMI) and progression in triple-negative breast cancer (TNBC). We retrospectively reviewed the medical records of 50 patients with TNBC who underwent breast-conserving surgery or mastectomy between 2007 and 2014. All patients were classified according to BMI (median 23.5 kg/m(2), range 17.2-31.6 kg/m(2)): 31 patients (62%) were classified as being overweight or obese (BMI ≥ 23 kg/m(2)) and 19 patients (38%) were classified as having a normal body weight (BMI overweight or obese patients (P = 0.035), while none of the normal weight patients showed progression. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 85.0% and 87.7%, respectively. DFS was significantly reduced in overweight or obese patients compared to that in normal weight patients (P = 0.035). However, OS was not significantly compromised by being overweight or obese (P = 0.134). In conclusion, being overweight or obese negatively affects DFS in TNBC patients.

  6. Inference of the Basal epithelial phenotype in breast carcinoma from differential marker expression, using tissue microarrays in triple negative breast cancer and women younger than 35.

    Science.gov (United States)

    Nassar, Aziza; Sussman, Zachary M; Lawson, Diane; Cohen, Cynthia

    2012-09-01

    Basal-cell phenotype breast carcinoma has been associated with high-grade and metaplastic morphology, expression of basal-type cytokeratins, uniform negativity for ER and HER2, and decreased overall survival. Breast cancers occurring in young women are usually T2 disease at presentation, high-grade and of poor prognosis. We compared two groups of breast cancers, (a) ER-, PR-, HER2- (triple negative) [TNBrCa] and (b) non-triple negative breast cancers (non-TNBrCa) occurring in women under 35, using tissue microarray technology to characterize expression of the basal/myoepithelial cytokeratins (CK5/6, CK7, and CK14), luminal cytokeratins (CK8, CK18, and CK19), EGFR, p-cadherin, c-kit, p63, and p53. We also sought to identify characteristic histomorphologic features indicative of basal-like phenotype. The triple negative group showed preferential staining versus the age triple negative patients (p = 0.006). The TNBrCa have characteristic histologic features including higher tumor grade, pushing tumor border, geographic necrosis, syncytial growth pattern, brisk mitotic activity, lack of/minimal in situ component, medullary-like and metaplastic differentiation. Invasive carcinomas in women younger than 35 usually have an associated in situ component, prominent nucleoli, central acellular fibrotic zone, and infiltrative tumor border. Triple negativity for ER/PR/HER2 coupled with EGFR, c-kit, and basal/myoepithelial cytokeratins (CK5/6, CK14) expression, and distinctive histomorphologic features predict morphology consistent with basal-cell phenotype. © 2012 Wiley Periodicals, Inc.

  7. Triple-negative breast cancer with brain metastases: a comparison between basal-like and non-basal-like biological subtypes

    NARCIS (Netherlands)

    A. Niwińska (Anna); W. Olszewski (Wojciech); M. Murawska (Magdalena); K. Pogoda (Katarzyna)

    2011-01-01

    textabstractThe aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive t

  8. Elucidation of epithelial-mesenchymal transition-related pathways in a triple-negative breast cancer cell line model by multi-omics interactome analysis

    DEFF Research Database (Denmark)

    Pauling, Josch K; Christensen, Anne G; Batra, Richa

    2014-01-01

    obtained from a triple-negative breast cancer cell line model, combining data sets of gene and protein expression as well as protein phosphorylation. We focus on alterations associated with the phenotypical differences arising from epithelial-mesenchymal transition in two breast cancer cell lines...

  9. IP-10 is an important chemokine secreted by tumor infiltrating lymphocytes and is an independent prognostic factor in triple-negative breast cancer patients

    DEFF Research Database (Denmark)

    Elias, Daniel; Ditzel, Henrik; Kupisiewicz, Kasia

    Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs)1, particularly CD8+T cells2 , are associated with improved disease-free and overall survival in triple-negative breast cancer (TNBC3). To evaluate the functions of TILs in breast cancer, we performed gene expression analysis...

  10. A novel approach for targeted elimination of CSPG4-positive triple-negative breast cancer cells using a MAP tau-based fusion protein

    NARCIS (Netherlands)

    Amoury, Manal; Mladenov, Radoslav; Nachreiner, Thomas; Pham, Anh-Tuan; Hristodorov, Dmitrij; Di Fiore, Stefano; Helfrich, Wijnand; Pardo, Alessa; Fey, Georg; Schwenkert, Michael; Thepen, Theophilus; Kiessling, Fabian; Hussain, Ahmad F.; Fischer, Rainer; Kolberg, Katharina; Barth, Stefan

    2016-01-01

    Chondroitin sulfate proteoglycan 4 (CSPG4) has been identified as a highly promising target antigen for immunotherapy of triple-negative breast cancer (TNBC). TNBC represents a highly aggressive heterogeneous group of tumors lacking expression of estrogen, progesterone and human epidermal growth fac

  11. Triple-negative breast cancer with brain metastases: a comparison between basal-like and non-basal-like biological subtypes

    NARCIS (Netherlands)

    A. Niwińska (Anna); W. Olszewski (Wojciech); M. Murawska (Magdalena); K. Pogoda (Katarzyna)

    2011-01-01

    textabstractThe aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive

  12. Identification, validation, and targeting of the mutant p53-PARP-MCM chromatin axis in triple negative breast cancer

    Science.gov (United States)

    Qiu, Wei-Gang; Polotskaia, Alla; Xiao, Gu; Di, Lia; Zhao, Yuhan; Hu, Wenwei; Philip, John; Hendrickson, Ronald C.; Bargonetti, Jill

    2017-01-01

    Over 80% of triple negative breast cancers express mutant p53. Mutant p53 often gains oncogenic function suggesting that triple negative breast cancers may be driven by p53 protein type. To determine the chromatin targets of this gain-of-function mutant p53 we used inducible knockdown of endogenous gain-of-function mtp53 in MDA-MB-468 cells in conjunction with stable isotope labeling with amino acids in cell culture and subcellular fractionation. We sequenced over 70,000 total peptides for each corresponding reciprocal data set and were able to identify 3010 unique cytoplasmic fraction proteins and 3403 unique chromatin fraction proteins. The present proteomics experiment corroborated our previous experiment-based results that poly ADP-ribose polymerase has a positive association with mutant p53 on the chromatin. Here, for the first time we report that the heterohexomeric minichromosome maintenance complex that participates in DNA replication initiation ranked as a high mutant p53-chromatin associated pathway. Enrichment analysis identified the minichromosome maintenance members 2–7. To validate this mutant p53- poly ADP-ribose polymerase-minichromosome maintenance functional axis, we experimentally depleted R273H mutant p53 and found a large reduction of the amount of minichromosome maintenance complex proteins on the chromatin. Furthermore a mutant p53-minichromosome maintenance 2 direct interaction was detected. Overexpressed mutant p53, but not wild type p53, showed a protein-protein interaction with minichromosome maintenance 2 and minichromosome maintenance 4. To target the mutant p53- poly ADP-ribose polymerase-minichromosome maintenance axis we treated cells with the poly ADP-ribose polymerase inhibitor talazoparib and the alkylating agent temozolomide and detected synergistic activation of apoptosis only in the presence of mutant p53. Furthermore when minichromosome maintenance 2–7 activity was inhibited the synergistic activation of apoptosis was

  13. Overexpression of ETV4 protein in triple-negative breast cancer is associated with a higher risk of distant metastasis

    Directory of Open Access Journals (Sweden)

    Yuan ZY

    2014-09-01

    Full Text Available Zhong-Yu Yuan,1–3,* Ting Dai,1,2,* Shu-Sen Wang,1–3 Rou-Jun Peng,1–3 Xing-Hua Li,1,2 Tao Qin,1–3 Li-Bing Song,1,2 Xi Wang1,2,41State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China; 2Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China; 3Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China; 4Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China  *These authors contributed equally to this work Background: Patients with triple-negative breast cancer (TNBC present a higher probability of distant metastasis and lack of effective targeted therapy. ETS translocation variant 4 (ETV4 is an ETS (E-26 transcription factor and has been associated with tumor metastasis. However, the clinical and functional significance of ETV4 in TNBC still remains unclear. Methods: A human tumor metastasis polymerase chain reaction array was used to profile differential expression of tumor metastasis-related genes in TNBC tissue. Real-time reverse transcription and Western blot analyses were performed to verify ETV4 expression in TNBC cells and tissue. Immunohistochemistry was used to detect expression of ETV4 protein in 135 TNBC tissue samples for association between ETV4 protein expression and clinical outcomes. Results: A total total of eight upregulated (CCL7, KISS1, MET, MMP7, NR4A3, ETV4, TIMP3, and TSHR and three downregulated (ITGA7, SSTR, and MMP2 genes were identified between TNBC tissue and the luminal subtype of breast cancer tissue. ETV4 messenger ribonucleic acid was more than five-fold upregulated in TNBC tissue compared with the control tissue. ETV4 overexpression was found in 57.0% of 135 TNBC cases. Overexpression of ETV4 protein was associated with an advanced stage and a higher proportion of positive lymph node and lymphovascular invasion. Patients with an ETV4

  14. Genetic polymorphism in hOGG1 is associated with triple-negative breast cancer risk in Chinese Han women.

    Science.gov (United States)

    Xie, Hui; Xia, Kai; Rong, Hui; Chen, Xiaoxiang

    2013-10-01

    8-hydroxy-2'-deoxyguanine (8-OHdG), a typical product of oxidative stress-induced DNA damage, can cause a G-T transversion during DNA replication if it is not removed. Human 8-oxoguanine glycosylase 1 (hOGG1), a key DNA repair gene, recognizes and excises 8-OHdG from damaged DNA accurately; however, a c.977C>G (Ser326Cys) polymorphism in hOGG1 can inhibit the gene's ability to remove 8-OHdG. The aim of present study was to investigate the association between the c.977C>G polymorphism in hOGG1 and the risk of breast cancer in Chinese Han women. We used high-resolution melting and sequencing to analyze the genotypes of 630 patients with sporadic breast cancer patients and 777 healthy controls. We also performed risk-stratified subgroup analyses to determine the association between the c.977C>G polymorphism and other characteristics of breast cancer subgroups. Breast cancer patients and healthy controls did not have significantly different of c.977C/G genotypes (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.82-1.49, p = 0.57) and c.977G/G genotypes (OR = 1.34, 95% CI = 0.97-1.84, p = 0.09). However, the c.977G/G genotype was especially prevalent in breast cancer patients who were younger than 55 years (OR = 1.58, 95% CI = 1.05-2.39, p = 0.04), were premenopausal status (OR = 1.87, 95% CI = 1.14-3.06, p = 0.02), had triple-negative disease (OR = 2.14, 95% CI = 1.06-4.29, p = 0.04), or p53-positive disease (OR = 1.56, 95% CI = 1.14-2.12, p = 0.005). These findings suggest that the c.977C>G polymorphism in hOGG1 is associated with an increased risk of breast cancer in Chinese Han women who are younger than 55 years, premenopausal, triple-negative, or p53-positive subgroups.

  15. Dillenia suffruticosa dichloromethane root extract induced apoptosis towards MDA-MB-231 triple-negative breast cancer cells.

    Science.gov (United States)

    Foo, Jhi Biau; Saiful Yazan, Latifah; Tor, Yin Sim; Wibowo, Agustono; Ismail, Norsharina; Armania, Nurdin; Cheah, Yoke Kqueen; Abdullah, Rasedee

    2016-07-01

    Dillenia suffruticosa is traditionally used for treatment of cancerous growth including breast cancer in Malaysia. Dillenia suffruticosa is a well-known medicinal plant in Malaysia for the treatment of cancer. Nevertheless, no study has been reported the cytotoxicity of this plant towards MDA-MB-231 triple-negative breast cancer cells. The present study was designed to investigate the mode of cell death and signalling pathways of MDA-MB-231 cells treated with dichloromethane Dillenia suffruticosa root extract (DCM-DS). Extraction of Dillenia suffruticosa root was performed by the use of sequential solvent procedure. The cytotoxicity of DCM-DS was determined by using MTT assay. The mode of cell death was evaluated by using an inverted light microscope and flow cytometry analysis using Annexin-V/PI. Cell cycle analysis and measurement of reactive oxygen species level were performed by using flow cytometry. The cells were treated with DCM-DS and antioxidants α-tocopherol or ascorbic acid to evaluate the involvement of ROS in the cytotoxicity of DCM-DS. Effect of DCM-DS on the expression of antioxidant, apoptotic, growth, survival genes and proteins were analysed by using GeXP-based multiplex system and Western blot, respectively. The cytotoxicity of compounds isolated from DCM-DS was evaluated towards MDA-MB-231 cells using MTT assay. DCM-DS induced apoptosis, G2/M phase cell cycle arrest and oxidative stress in MDA-MB-231 cells. The induction of apoptosis in MDA-MB-231 cells by DCM-DS is possibly due to the activation of pro-apoptotic JNK1 and down-regulation of anti-apoptotic ERK1, which in turn down-regulates anti-apoptotic BCL-2 to increase the BAX/BCL-2 ratio to initiate the mitochondrial apoptotic pathway. The cell cycle arrest in DCM-DS-treated MDA-MB-231 cells is possibly via p53-independent but p21-dependent pathway. A total of 3 triterpene compounds were isolated from DCM-DS. Betulinic acid appears to be the most major and most cytotoxic compound in DCM

  16. RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs.

    Science.gov (United States)

    Robinson, Tyler J W; Liu, Jeff C; Vizeacoumar, Frederick; Sun, Thomas; Maclean, Neil; Egan, Sean E; Schimmer, Aaron D; Datti, Alessandro; Zacksenhaus, Eldad

    2013-01-01

    Triple negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1) tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1(met), fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ∼3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA(+)/CD24(-/low)/CD44(+) cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.

  17. RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs.

    Directory of Open Access Journals (Sweden)

    Tyler J W Robinson

    Full Text Available Triple negative breast cancer (TNBC includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1 tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP, 5-fluorouracil, idarubicin, epirubicin, PRIMA-1(met, fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ∼3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA(+/CD24(-/low/CD44(+ cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.

  18. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

    Science.gov (United States)

    Cameron, David; Brown, Julia; Dent, Rebecca; Jackisch, Christian; Mackey, John; Pivot, Xavier; Steger, Guenther G; Suter, Thomas M; Toi, Masakazu; Parmar, Mahesh; Laeufle, Rita; Im, Young-Hyuck; Romieu, Gilles; Harvey, Vernon; Lipatov, Oleg; Pienkowski, Tadeusz; Cottu, Paul; Chan, Arlene; Im, Seock-Ah; Hall, Peter S; Bubuteishvili-Pacaud, Lida; Henschel, Volkmar; Deurloo, Regula J; Pallaud, Celine; Bell, Richard

    2013-09-01

    The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy

  19. Feasibility and accuracy of sentinel lymph node biopsy in clinically node-positive breast cancer after neoadjuvant chemotherapy: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jian-Fei Fu

    Full Text Available Sentinel lymph node biopsy (SLNB has replaced conventional axillary lymph node dissection (ALND in axillary node-negative breast cancer patients. However, the use of SLNB remains controversial in patients after neoadjuvant chemotherapy (NAC. The aim of this review is to evaluate the feasibility and accuracy of SLNB after NAC in clinically node-positive patients. Systematic searches were performed in the PubMed, Embase, and Cochrane Library databases from 1993 to December 2013 for studies on node-positive breast cancer patients who underwent SLNB after NAC followed by ALND. Of 436 identified studies, 15 were included in this review, with a total of 2,471 patients. The pooled identification rate (IR of SLNB was 89% [95% confidence interval (CI 85-93%], and the false negative rate (FNR of SLNB was 14% (95% CI 10-17%. The heterogeneity of FNR was analyzed by meta-regression, and the results revealed that immunohistochemistry (IHC staining may represent an independent factor (P = 0.04. FNR was lower in the IHC combined with hematoxylin and eosin (H&E staining subgroup than in the H&E staining alone subgroup, with values of 8.7% versus 16.0%, respectively (P = 0.001. Thus, SLNB was feasible after NAC in node-positive breast cancer patients. In addition, the IR of SLNB was respectable, although the FNR of SLNB was poor and requires further improvement. These findings indicate that IHC may improve the accuracy of SLNB.

  20. DNA repair prognostic index modelling reveals an essential role for base excision repair in influencing clinical outcomes in ER negative and triple negative breast cancers

    Science.gov (United States)

    Abdel-Fatah, Tarek M.A.; Arora, Arvind; Moseley, Paul M.; Perry, Christina; Rakha, Emad A.; Green, Andrew R.; Chan, Stephen Y.T.; Ellis, Ian O.; Madhusudan, Srinivasan

    2015-01-01

    Stratification of oestrogen receptor (ER) negative and triple negative breast cancers (TNBCs) is urgently needed. In the current study, a cohort of 880 ER- (including 635 TNBCs) was immuno-profiled for a panel of DNA repair proteins including: Pol β, FEN1, APE1, XRCC1, SMUG1, PARP1, BRCA1, ATR, ATM, DNA-PKcs, Chk1, Chk2, p53, and TOPO2. Multivariate Cox proportional hazards models (with backward stepwise exclusion of these factors, using a criterion of p < 0.05 for retention of factors in the model) were used to identify factors that were independently associated with clinical outcomes. XRCC1 (p = 0.002), pol β (p = 0.032) FEN1 (p = 0.001) and BRCA1 (p = 0.040) levels were independently associated with poor BCSS. Subsequently, DNA repair index prognostic (DRPI) scores for breast cancer specific survival (BCSS) were calculated and two prognostic groups (DRPI-PGs) were identified. Patients in prognostic group 2 (DRPI-PG2) have higher risk of death (p < 0.001). Furthermore, in DRPI-PG2 patients, exposure to anthracycline reduced the risk of death [(HR (95% CI) = 0.79 (0.64–0.98), p = 0.032) by 21–26%. In addition, DRPI-PG2 patients have adverse clinicopathological features including higher grade, lympho-vascular invasion, Her-2 positive phenotype, compared to those in DRPI-PG1 (p < 0.01). Receiver operating characteristic (ROC) curves indicated that the DRPI outperformed the currently used prognostic factors and adding DRPI to lymph node stage significantly improved their performance as a predictor for BCSS [p < 0.00001, area under curve (AUC) = 0.70]. BER strongly influences pathogenesis of ER- and TNBCs. The DRPI accurately predicts BCSS and can also serve as a valuable prognostic and predictive tool for TNBCs. PMID:26267318

  1. Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Brown, Kristin K; Spinelli, Jessica B; Asara, John M; Toker, Alex

    2017-04-01

    Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC.Significance: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov; 7(4); 391-9. ©2017 AACR.See related article by Mathur et al., p. 380This article is highlighted in the In This Issue feature, p. 339.

  2. Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women.

    Science.gov (United States)

    Kabat, Geoffrey C; Kim, Mimi; Phipps, Amanda I; Li, Christopher I; Messina, Catherine R; Wactawski-Wende, Jean; Kuller, Lewis; Simon, Michael S; Yasmeen, Shagufta; Wassertheil-Smoller, Sylvia; Rohan, Thomas E

    2011-05-01

    Little is known about the risk factors for triple-negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer. Among 148,030 women enrolled in the Women's Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Cigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ≥ 40 pack-years of smoking, the HR was 1.24, 95% CI 1.06-1.44; for women consuming ≥ 7 servings of alcohol per week, the HR was 1.26, 95% CI 1.06-1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer. These findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.

  3. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance.

    Science.gov (United States)

    Robinson, Prema; Kasembeli, Moses; Bharadwaj, Uddalak; Engineer, Nikita; Eckols, Kris T; Tweardy, David J

    2016-01-01

    Doxorubicin (DOX), an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC), DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP), a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS). Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2) and a TNBC cell line (MDA-MB 231) with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance.

  4. High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells

    Science.gov (United States)

    Robinson, Tyler JW; Pai, Melody; Liu, Jeff C; Vizeacoumar, Frederick; Sun, Thomas; Egan, Sean E; Datti, Alessandro; Huang, Jing; Zacksenhaus, Eldad

    2013-01-01

    Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC50 for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA+/CD24-/low/CD44+ cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin. PMID:23974104

  5. Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells.

    Science.gov (United States)

    Burnett, Joseph P; Lim, Gi; Li, Yanyan; Shah, Ronak B; Lim, Rebekah; Paholak, Hayley J; McDermott, Sean P; Sun, Lichao; Tsume, Yasuhiro; Bai, Shuhua; Wicha, Max S; Sun, Duxin; Zhang, Tao

    2017-05-28

    Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs.

  6. Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT

    Directory of Open Access Journals (Sweden)

    Zhen-Yu He

    2017-02-01

    Full Text Available Triple-negative breast cancer (TNBC was regarded as the most aggressive and mortal subtype of breast cancer (BC since the molecular subtype system has been established. Abundant studies have revealed that epithelial-mesenchymal transition (EMT played a pivotal role during breast cancer metastasis and progression, especially in TNBC. Herein, we showed that inhibition the expression of replication factor C subunit 3 (RFC3 significantly attenuated TNBC metastasis and progression, which was associated with EMT signal pathway. In TNBC cells, knockdown of RFC3 can down-regulate mesenchymal markers and up-regulate epithelial markers, significantly attenuated cell proliferation, migration and invasion. Additionally, silencing RFC3 expression can decrease nude mice tumor volume, weight and relieve lung metastasis in vivo. Furthermore, we also demonstrated that overexpression of RFC3 in TNBC showed increased metastasis, progression and poor prognosis. We confirmed all of these results by immunohistochemistry analysis in 127 human TNBC tissues and found that RFC3 expression was significantly associated with poor prognosis in TNBC. Taken all these findings into consideration, we can conclude that up-regulation of RFC3 promotes TNBC progression through EMT signal pathway. Therefore, RFC3 could be an independent prognostic factor and therapeutic target for TNBC.

  7. 三阴乳腺癌潜在治疗靶点%Potential therapeutic target for triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    汪颖; 王宁; 王雅杰

    2009-01-01

    不表达雌、孕激素受体以及人类表皮生长因子受体-2的三阴乳腺癌,由于无法从较成熟的内分泌与赫赛汀靶向治疗中受益,成为目前乳腺癌治疗中较为棘手的亚群.识别三阴乳腺癌特异性分子生物学标志、选择适合的治疗方案及靶向治疗是目前研究的热点.%Triple negative phenotype breast cancers are characterized by lack of expression of estrogen receptor,progesterone receptor and human epithelial grouth factor receptor 2. This subgroup of cancers is insen-sitive to most available hormonal and targeted therapeutic agents. Identification of more molecular predictive sig-natures will enable us to design optimal treatment regimens and targeted therapies.

  8. Nestin expression associates with poor prognosis and triple negative phenotype in locally advanced (T4 breast cancer

    Directory of Open Access Journals (Sweden)

    F. Piras

    2011-11-01

    Full Text Available Nestin, an intermediate filament protein, has traditionally been noted for its importance as a neural stem cell marker. However, in recent years, expression of nestin has shown to be associated with general proliferation of progenitor cell populations within neoplasms. There is no reported study addressing nestin expression in T4 breast cancer patients. Thus, the aim of the present study was to investigate, through immunohistochemistry, the expression and distribution of nestin in T4 breast cancer, in order to determine its association with clinical and pathological parameters as well as with patients’ outcome. Nestin was detectable in tumoral cells and in endothelial cells of blood microvessels, and it is significantly expressed in triple-negative and in inflammatory breast cancer (IBC subgroups of T4 breast tumours. The Kaplan-Meier analysis showed that the presence of nestin in tumoral cells significantly predicted poor prognosis at 5-years survival (P=0.02 and with borderline significance at 10-years of survival (P=0.05 in T4 breast cancer patients. On the basis of these observations, we speculate that nestin expression may characterize tumours with an aggressive clinical behavior, suggesting that the presence of nestin in tumoral cells and vessels may be considered an important factor that leads to a poor prognosis. Further studies are awaited to define the biological role of nestin in the etiology of these subgroups of breast cancers.

  9. Pilot Study on MAGE-C2 as a Potential Biomarker for Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Qian Zhao

    2016-01-01

    Full Text Available Objective. In the current study, we measured the expression status of melanoma antigen gene c2 (MAGE-C2 in triple-negative breast cancer (TNBC and analyzed its prognostic with the clinical pathological features of patients with TNBC. Methods. The expressions statuses of MAGE-C2 were detected in TNBC tissues and paracarcinoma tissues by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR, and western blotting. Then, we investigated the relationship of MAGE-C2 expression status and clinicopathological parameters of TNBC patients by the chi-squared test. Finally, we discussed the relations of MAGE-C2 expression state and prognosis of patients with TNBC by Kaplan-Meier method and Cox proportional hazards model. Results. High MAGE-C2 expression was found in 38.18% (42/110 of TNBC tissues. In adjacent tissues it was 9.09% (10/110. High MAGE-C2 expression in TNBC patients was closely associated with lymph node status, tumor node metastasis (TNM stage, and lymphovascular invasion (P<0.001. TNBC patients with high MAGE-C2 expression had significantly shorter survival time than low expression patients. We also found that age, lymph node status, TNM stage, lymphovascular invasion, and MAGE-C2 expression status were closely associated with overall survival of TNBC patients (P<0.05. Conclusion. High MAGE-C2 expression may serve as an independent prognostic factor for TNBC patients.

  10. 三阴性乳腺癌的治疗%The therapy for triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    关格格; 周福祥; 周云峰

    2014-01-01

    Triple negative breast cancer (TNBC) is a special subgroup of breast cancer with more aggressive biological behavior and clinicopathological characteristics,and the therapy of TNBC has always been the research difficulty and hot spot.Currently,surgery and adjuvant radiotherapy are still the main method in local treatment,amd the research of traditional chemotherapy and targeted therapy have been made some progress.Meanwhile,new drugs continuously appear in recent years.%三阴性乳腺癌(TNBC)是具有特殊侵袭性生物学行为及临床病理特征的一个乳腺癌亚型,其治疗一直是乳腺癌中的难点和热点问题.目前,手术和辅助放疗仍是早期TNBC局部治疗的主要方式,传统化疗、靶向治疗研究在TNBC的全身治疗中取得了一定的进展,同时,近几年新药物也不断涌现出来.

  11. 三阴乳腺癌研究进展%Progression of triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    夏春强; 郑如珍; 王晓稼

    2009-01-01

    三阴乳腺癌(TNBC)具有独特的生物学行为和临床特征,目前尚没有针对TNBC的标准治疗.近年来在TNBC的流行病学、分子特征、化学治疗和靶向治疗等方面进行了许多研究与探索,特别是Ⅱ期或Ⅲ期临床研究初步结果显示,新的化疗方案和靶向治疗对TNBC可能具有很好的疗效.%Triple-negative breast cancer(TNBC) has distinct biological and clinical characteristics. Therapeutic strategies for TNBC remain a challenge. Studies about epidemiology,molecular characteristics,chemotherapy and targeted-therapy are ongoing,In particular,preliminary results of stage II or III clinical trials indicate new chemotherapy or combination targeted therapy may have a good efficacy.

  12. RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer.

    Science.gov (United States)

    Pascual-Vargas, Patricia; Cooper, Samuel; Sero, Julia; Bousgouni, Vicky; Arias-Garcia, Mar; Bakal, Chris

    2017-03-01

    In order to metastasise, triple negative breast cancer (TNBC) must make dynamic changes in cell shape. The shape of all eukaryotic cells is regulated by Rho Guanine Nucleotide Exchange Factors (RhoGEFs), which activate Rho-family GTPases in response to mechanical and informational cues. In contrast, Rho GTPase-activating proteins (RhoGAPs) inhibit Rho GTPases. However, which RhoGEFs and RhoGAPS couple TNBC cell shape to changes in their environment is very poorly understood. Moreover, whether the activity of particular RhoGEFs and RhoGAPs become dysregulated as cells evolve the ability to metastasise is not clear. Towards the ultimate goal of identifying RhoGEFs and RhoGAPs that are essential for TNBC metastasis, we performed an RNAi screen to isolate RhoGEFs and RhoGAPs that contribute to the morphogenesis of the highly metastatic TNBC cell line LM2, and its less-metastatic parental cell line MDA-MB-231. For ~6 million cells from each cell line, we measured 127 different features following the depletion of 142 genes. Using a linear classifier scheme we also describe the morphological heterogeneity of each gene-depleted population.

  13. Role of Wnt Co-receptor LRP6 in Triple Negative Breast Cancer Cell Migration and Invasion.

    Science.gov (United States)

    Ma, Jinlu; Lu, Wenyan; Chen, Dongquan; Xu, Bo; Li, Yonghe

    2017-03-01

    The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential Wnt co-receptor of the Wnt/β-catenin signaling pathway. Although studies have shown an increased expression of LRP6 in several types of cancer, its function in tumor development and progression remains to be elucidated. We herein demonstrated that LRP6 expression is up-regulated in human triple negative breast cancer (TNBC) patients and human TNBC cell lines, and that knockdown of LRP6 expression and treatment of recombinant Mesd protein (a specific inhibitor of LRP6) significantly decreased cell migration and invasion of TNBC MDA-MB-231 and BT549 cells. Interestingly, the effects of LRP6 knockdown and Mesd treatment on TNBC cell migration and invasion were more prominent than on TNBC cell proliferation/viability. Mechanistically, LRP6 knockdown and Mesd treatment inhibited Wnt/β-catenin signaling and decreased the expression of S100A4, a mediator of cancer metastasis and a specific target of Wnt/β-catenin signaling, in TNBC cells. Together, our data suggest that LRP6 promotes TNBC cell migration and invasion by regulating the expression and function of S100A4 via the Wnt/β-catenin signaling pathway. This article is protected by copyright. All rights reserved.

  14. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Jie Xu

    Full Text Available Triple negative breast cancer (TNBC acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025, the proliferation marker Ki-67 (P = 0.001, and the recurrence rate of TNBC patients (P<0.001. In TNBC patients with Aur-A high expression, the risk of distant recurrence peaked at the first 3 years and declined rapidly thereafter, whereas patients with Aur-A low expression showed a relatively constant risk of recurrence during the entire follow-up period. Univariate and multivariate analysis showed that overexpression of Aur-A predicted poor overall survival (P = 0.002 and progression-free survival (P = 0.012 in TNBC. Furthermore, overexpression of Aur-A, associated with high Ki-67, predicted an inferior prognosis compared with low expression of both Aur-A and Ki-67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy.

  15. Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nalo Hamilton

    2015-01-01

    Full Text Available Triple-negative breast cancer (TNBC occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2, along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

  16. 三阴乳腺癌研究进展%Research advancement on triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    刘璐

    2010-01-01

    三阴乳腺癌是指雌激素受体(ER)、孕激素受体(PR)、人类表皮生长因子受体-2(Her-2)均不表达的乳腺癌,是乳腺癌的一种特殊亚型,有着特殊的生物学特性和临床病理特征,对内分泌治疗及针对Her-2的靶向药物赫赛汀无效,对化疗敏感,但是远期疗效不佳.三阴乳腺癌的特点,以及治疗方案的选择,是近年研究的热点.%Triple negative breast cancer(TNBC) is defined by the lack of estrogen receptor (ER) , progesterone receptor (PR) and human epidermal growth factor receptor-2 ( Her-2) expression. It is a subtype of tumor with distinct clinical and pathologic features and lacks effective targeted therapies. It is non - sensitive to endocrine therapy and targeted therapy drug herceptin, leaving chemotherapy as the mainstay of treatment The feature and the treatment of TNBC is the hotspot of resent research.

  17. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity.

    Science.gov (United States)

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R; Bollig-Fischer, Aliccia

    2017-03-10

    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.

  18. 钙黏蛋白与三阴乳腺癌%Cadherins and triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    施学兵; 王潞

    2012-01-01

    Cadherins that mediate the adhesion of the same type of cells by specific binding to calciumdependent adhesions of the same type with cadherins mainly consist of three subtypes including E-cadberin,P-cadherin and N-cadherin.In recent years,more and more studies have indicated that cadherins are closely related to triple-negative breast cancer(TNBC)and play an important role in prognosis and treatment of TNBC.%钙黏蛋白与自身同型的钙依赖性黏附素特异性结合从而介导同型细胞间的黏附作用,主要包括上皮型、胎盘型及神经型3种亚型.近年来,国内外越来越多的研究报道表明钙黏蛋白与三阴乳腺癌(TNBC)密切相关,钙黏蛋白对TNBC的预后判断及治疗具有重要的意义.

  19. The role of ELK3 to regulate peritumoral lymphangiogenesis and VEGF-C production in triple negative breast cancer cells.

    Science.gov (United States)

    Oh, Nuri; Park, Ji-In; Park, Ji-Hoon; Kim, Kwang-Soo; Lee, Dong Ryul; Park, Kyung-Soon

    2017-03-18

    Tumor-induced lymphangiogenesis, a major conduit for cancer cell dissemination from the primary tumor site to lymph nodes and beyond, eventually leads to metastasis in cancer patients. Given the recent evidence revealing that the suppression of ELK3 inhibits the metastasis of triple-negative breast cancer cells, we aimed to study the underlying mechanism of impaired metastasis in ELK3-suppressed MDA-MB-231 cells (ELK3 KD) with regard to lymphangiogenesis. We found that the secretome of ELK3 KD cells inhibited tube formation, whereas it promoted the migration and invasion of lymphatic endothelial cells (LECs) in vitro. In vivo analysis revealed that peritumoral lymphatic vessels were not developed around the xenografted tumors of ELK3 KD. We further revealed that the suppression of NF-κB signaling in ELK3 KD was the primary cause of the reduced VEGFC expression. Taken together, we suggest that ELK3 is an upstream regulator of the NF-κB signaling pathway, the inhibition of which leads to the suppression of peritumoral lymphatic vessel development, possibly due to a low VEGFC expression.

  20. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancer patients.

    Science.gov (United States)

    Lefort, S; Thuleau, A; Kieffer, Y; Sirven, P; Bieche, I; Marangoni, E; Vincent-Salomon, A; Mechta-Grigoriou, F

    2017-03-02

    The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties. We observed that two CXCR4 inhibitors, AMD3100 and TN14003, efficiently impair tumor growth and metastasis dissemination in both Herceptin-sensitive and Herceptin-resistant HER2 BC. Conversely, blocking CXCR4/CXCL12 pathway in triple-negative (TN) BC does not reduce tumor growth, and can even increase metastatic spread. Moreover, although CXCR4 inhibitors significantly reduce myofibroblast content in all BC subtypes, they decrease angiogenesis only in HER2 BC. Thus, our findings suggest that targeting CXCR4 could provide some therapeutic interest for HER2 BC patients, whereas it has no impact or could even be detrimental for TN BC patients.

  1. In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer.

    Science.gov (United States)

    Hamilton, Amanda M; Foster, Paula J

    2017-02-01

    Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

  2. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes.

    Science.gov (United States)

    Ponente, Manfredi; Campanini, Letizia; Cuttano, Roberto; Piunti, Andrea; Delledonne, Giacomo A; Coltella, Nadia; Valsecchi, Roberta; Villa, Alessandra; Cavallaro, Ugo; Pattini, Linda; Doglioni, Claudio; Bernardi, Rosa

    2017-02-23

    Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.

  3. Identification of recurrent BRCA1 mutation and its clinical relevance in Chinese Triple-negative breast cancer cohort.

    Science.gov (United States)

    Liu, Xiaoran; Li, Huiping; Shao, Bin; Wu, Jianmin; Kong, Weiyao; Song, Guohong; Jiang, Hanfang; Wang, Jing; Wan, Fengling

    2017-03-01

    Triple-negative breast cancer (TNBC) accounts for 15-20% of all newly diagnosed breast cancers, and is enriched for germline mutation of BRCA. In Asian patients diagnosed with breast cancer, 268 deleterious mutations of BRCA1 and 242 of BRCA2 have been identified so far, including a reported BRCA1 frameshift mutation (rs80350973), apparently found only in Asian people, with a low prevalence of 0.3-1.7% in different breast cancer cohorts. Here, we reported the high prevalence (7.2%) of rs80350973 among 125 Chinese patients with TNBC, which implies its mutational predilection for certain breast cancer subtypes. Although its low prevalence had not indicated any particular clinical significance in previous studies, our results associated rs80350973 mutation with cell checkpoint malfunction, and was found to be more common in TNBC patients with high Ki-67 indices (P = 0.004). As Ki-67 overexpression is a predictor of poor prognosis in TNBC, inclusion of this mutation into genetic assessments may improve the clinical management of Chinese patients with TNBC.

  4. Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.

    Science.gov (United States)

    Zhao, Chunyan; Qiao, Yichun; Jonsson, Philip; Wang, Jian; Xu, Li; Rouhi, Pegah; Sinha, Indranil; Cao, Yihai; Williams, Cecilia; Dahlman-Wright, Karin

    2014-07-15

    Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

  5. Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances.

    Science.gov (United States)

    Miller-Kleinhenz, Jasmine M; Bozeman, Erica N; Yang, Lily

    2015-01-01

    Effective treatment of triple-negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle-based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor-associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in-depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic.

  6. Comparative Profiling of Triple-Negative Breast Carcinomas Tissue Glycoproteome by Sequential Purification of Glycoproteins and Stable Isotope Labeling

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    Xiang Chen

    2016-01-01

    Full Text Available Background: Women with triple negative breast cancers (TNBCs have a poor prognosis due to lack of suitable targeted therapies. Changes in the protein glycosylation are increasingly being recognized as an important modification associated with cancer etiology. Methods: In an attempt to identify TNBC biomarkers with greater diagnostic and prognostic capabilities, hydrazide- based chemistry method combined with LC-MS/MS were used to purify and identify N-linked glycopeptides or glycoproteins of tissues from TNBC patients. Results: A total of 550 unique N-linked glycoproteins were identified, among these proteins, 72 unique N-linked glycoproteins were significantly regulated in tumor tissues, of which 56 proteins were upregulated and 16 proteins were downregulated. To assess the validity of the results, three selected proteins including Vascular endothelial growth factor receptor 1, Insulin receptor, Tissue factor pathway inhibitor were selected for western blot analysis, and these proteins were found as potential biomarkers of TNBC. The top three pathways of differentially expressed glycoproteins participated in were caveolar-mediated endocytosis signaling, agrin interactions at neuromuscular junction and LXR/RXR activation. Conclusion: This work provides potential glycoprotein markers to function as a novel tissue-based biomarker for TNBC.

  7. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancer patients

    Science.gov (United States)

    Lefort, S; Thuleau, A; Kieffer, Y; Sirven, P; Bieche, I; Marangoni, E; Vincent-Salomon, A; Mechta-Grigoriou, F

    2017-01-01

    The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties. We observed that two CXCR4 inhibitors, AMD3100 and TN14003, efficiently impair tumor growth and metastasis dissemination in both Herceptin-sensitive and Herceptin-resistant HER2 BC. Conversely, blocking CXCR4/CXCL12 pathway in triple-negative (TN) BC does not reduce tumor growth, and can even increase metastatic spread. Moreover, although CXCR4 inhibitors significantly reduce myofibroblast content in all BC subtypes, they decrease angiogenesis only in HER2 BC. Thus, our findings suggest that targeting CXCR4 could provide some therapeutic interest for HER2 BC patients, whereas it has no impact or could even be detrimental for TN BC patients. PMID:27669438

  8. The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

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    Kristen L. Karlin

    2014-11-01

    Full Text Available Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 (“STP axis” cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

  9. Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity

    Directory of Open Access Journals (Sweden)

    Giovanna Ferrari-Amorotti

    2014-12-01

    Full Text Available Most triple-negative breast cancers (TNBCs exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT, a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1; thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.

  10. Expression of C-myc and β-catenin and their correlation in triple negative breast cancer.

    Science.gov (United States)

    Wang, Jiankui; Li, Mei; Chen, Dedian; Nie, Jianyun; Xi, Yan; Yang, Xiaojuan; Chen, Yun; Yang, Zhuanqing

    2017-09-08

    The present study was planned to study the expression of C-myc and β- catenin in triple negative breast cancer (TNBC) tissue. Furthermore, their relations to clinical features of the tumor and the survival prognosis were also studied. Additionally, correlation was evaluated between the expression of C-myc and β- catenin to provide the theoretical basis for the targeted therapy of TNBC. 60 cases of patients diagnosed with TNBC for the first time were selected for the study. The immumo-histochemical staining was employed to detect the positive expression rates of C-myc and β-catenin in cancer tissues and normal mammary tissues 3 cm away from the carcinoma. Fluorescence in situ hybridization (FISH) was used to test the gene amplification of C-myc in order to analyze the relation between C-myc and the protein expression of β-catenin. Further, kept the median follow-up time to 25.0 months in order to compare the survival prognosis. The positive expression rates of C-myc and β-catenin in cancer tissues were significantly higher than those in precancerous normal tissues (Pcorrelated with clinical features of cancer and the survival prognosis.

  11. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity

    Science.gov (United States)

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L.; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R.; Bollig-Fischer, Aliccia

    2017-01-01

    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30–60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL—a re-engineered protein form of the antioxidant enzyme catalase—inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c. PMID:28281569

  12. Array-based identification of triple-negative breast cancer cells using fluorescent nanodot-graphene oxide complexes.

    Science.gov (United States)

    Tao, Yu; Auguste, Debra T

    2016-07-15

    Early and accurate diagnosis of breast cancer holds great promise to improve treatability and curability. Here, we report the usage of six luminescent nanodot-graphene oxide complexes as novel fluorescent nanoprobes in a sensing array capable of effectively identifying healthy, cancerous, and metastatic human breast cells. The sensory system is based on the utilization of nanoprobe-graphene oxide sensor elements that can be disrupted in the presence of breast cells to give fluorescent readouts. Using this multichannel sensor, we have successfully identified breast cancer cells and distinguished between estrogen receptor positive, human epidermal growth factor receptor-2 positive, and triple negative phenotypes. This approach also allows cell identification at high sensitivity (200 cells) with high reproducibility. The unknown cell sample analysis indicates that the sensor is able to identify 49 out of 50 breast cell samples correctly, with a detection accuracy of 98%. Taken together, this array-based luminescent nanoprobe-graphene oxide sensing platform presents a useful cell screening tool with potential applications in biomedical diagnostics.

  13. Demethoxycurcumin inhibits energy metabolic and oncogenic signaling pathways through AMPK activation in triple-negative breast cancer cells.

    Science.gov (United States)

    Shieh, Jiunn-Min; Chen, Yung-Chan; Lin, Ying-Chao; Lin, Jia-Ni; Chen, Wei-Chih; Chen, Yang-Yuan; Ho, Chi-Tang; Way, Tzong-Der

    2013-07-03

    Demethoxycurcumin (DMC), curcumin (Cur), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in the rhizomes of turmeric. This study examined the effects of three curcuminoid analogues on breast cancer cells. The results revealed that DMC demonstrated the most potent cytotoxic effects on breast cancer MDA-MB-231 cells. Compared with estrogen receptor (ER)-positive or HER2-overexpressing breast cancer cells, DMC demonstrated the most efficient cytotoxic effects on triple-negative breast cancer (TNBC) cells. However, nonmalignant MCF-10A cells were unaffected by DMC treatment. The study showed that DMC activated AMPK in TNBC cells. Once activated, AMPK inhibited eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) signaling and mRNA translation via mammalian target of rapamycin (mTOR) and decreased the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). DMC also targeted multiple AMPK downstream pathways. Among these, the dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mTOR inhibition. Moreover, DMC suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation. In addition, DMC also sustained epidermal growth factor receptor (EGFR) activation by suppressing the phosphatases, PP2a and SHP-2. These results suggest that DMC is a potent AMPK activator that acts through a broad spectrum of anti-TNBC activities.

  14. Phosphorylated eIF2α predicts disease-free survival in triple-negative breast cancer patients

    Science.gov (United States)

    Guo, Liang; Chi, Yayun; Xue, Jingyan; Ma, Linxiaoxi; Shao, Zhiming; Wu, Jiong

    2017-01-01

    Phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), which functions as a marker of endoplasmic reticulum stress, has been reported to be associated with patient prognosis in various cancers. However, little is known about the prognostic value of p-eIF2α in breast cancer, particularly in different breast cancer subtypes. An immunohistochemistry screen for p-eIF2α was performed using a tissue microarray containing 233 tumors and paired peritumoral tissues from female patients diagnosed with breast cancer. The staining results were scored semiquantitatively, and the p-eIF2α expression level in breast cancer and its potential prognostic value were investigated. In this retrospective cohort study, we found that p-eIF2α levels were significantly upregulated in breast cancer (P cancer. Our study revealed that p-eIF2α was upregulated in breast cancer and represented a novel predictor of prognosis in patients with triple-negative subtype. PMID:28294178

  15. RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer

    Science.gov (United States)

    Pascual-Vargas, Patricia; Cooper, Samuel; Sero, Julia; Bousgouni, Vicky; Arias-Garcia, Mar; Bakal, Chris

    2017-01-01

    In order to metastasise, triple negative breast cancer (TNBC) must make dynamic changes in cell shape. The shape of all eukaryotic cells is regulated by Rho Guanine Nucleotide Exchange Factors (RhoGEFs), which activate Rho-family GTPases in response to mechanical and informational cues. In contrast, Rho GTPase-activating proteins (RhoGAPs) inhibit Rho GTPases. However, which RhoGEFs and RhoGAPS couple TNBC cell shape to changes in their environment is very poorly understood. Moreover, whether the activity of particular RhoGEFs and RhoGAPs become dysregulated as cells evolve the ability to metastasise is not clear. Towards the ultimate goal of identifying RhoGEFs and RhoGAPs that are essential for TNBC metastasis, we performed an RNAi screen to isolate RhoGEFs and RhoGAPs that contribute to the morphogenesis of the highly metastatic TNBC cell line LM2, and its less-metastatic parental cell line MDA-MB-231. For ~6 million cells from each cell line, we measured 127 different features following the depletion of 142 genes. Using a linear classifier scheme we also describe the morphological heterogeneity of each gene-depleted population. PMID:28248929

  16. Prognostic function of Ki-67 for pathological complete response rate of neoadjuvant chemotherapy in triple-negative breast cancer.

    Science.gov (United States)

    Zhang, Guojing; Xie, Wanqing; Liu, Zhaozhe; Lin, Chao; Piao, Ying; Xu, Long; Guo, Fang; Xie, Xiaodong

    2014-01-01

    Triple-negative breast cancer (TNBC) has fluctuating pathological complete response (pCR) rates to neoadjuvant chemotherapy (NAC) according to published reports. Biomarkers predicting pCR rates of NAC would improve TNBC patients' outcomes. We conducted a meta-analysis to estimate the prognostic function of Ki-67 in relation to pCR rates of NAC in TNBC. Relevant publications in the literature from January 2006 to March 2013 were selected by searching PubMed, SpringerLink, Web of Science, Scopus and the Cochrane Library. The quality of prognostic studies was evaluated according to the standard reported by Hayden et al. Relative risk (RR) and 95% confidence interval (CI) were used to estimate the prognostic function of Ki-67 for pCR rates in TNBC. The fail-safe number was used to detect possible publication bias. Review Manager and MIX software was used to merge extracted data. The pCR rate of TNBC with high Ki-67 expression was 3.36 times that of low Ki-67 expression TNBC. The merged RR was 3.36 (95% CI: 1.61-7.02) and the fail-safe number was 34. No obvious publication bias but heterogeneity of the case series was detected. Ki-67 was a predictor of pCR rates to NAC in TNBC.

  17. Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand.

    Science.gov (United States)

    Amoury, Manal; Bauerschlag, Dirk; Zeppernick, Felix; von Felbert, Verena; Berges, Nina; Di Fiore, Stefano; Mintert, Isabell; Bleilevens, Andreas; Maass, Nicolai; Bräutigam, Karen; Meinhold-Heerlein, Ivo; Stickeler, Elmar; Barth, Stefan; Fischer, Rainer; Hussain, Ahmad Fawzi

    2016-08-23

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62-165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.

  18. Increased sensitivity of BRCA defective triple negative breast tumors to plumbagin through induction of DNA Double Strand Breaks (DSB).

    Science.gov (United States)

    Nair, Rakesh Sathish; Kumar, Jerald Mahesh; Jose, Jedy; Somasundaram, Veena; Hemalatha, Sreelatha K; Sengodan, Satheesh Kumar; Nadhan, Revathy; Anilkumar, Thapasimuthu V; Srinivas, Priya

    2016-05-25

    We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1(Co/Co) and WAP-Cre; BRCA1(Co/Co), at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defective triple negative BRCA1 mutant cell lines and in mouse models occur by inducing ROS mediated DNA DSB. The toxicity profile as compared with CN in transgenic mice provides evidence for PB's safer disposition as a therapeutic lead in breast cancer drug development.

  19. "Triple negative breast cancer": Translational research and the (re)assembling of diseases in post-genomic medicine.

    Science.gov (United States)

    Keating, Peter; Cambrosio, Alberto; Nelson, Nicole C

    2016-10-01

    The paper examines the debate about the nature and status of "Triple-negative breast cancer", a controversial biomedical entity whose existence illustrates a number of features of post-genomic translational research. The emergence of TNBC is intimately linked to the rise of molecular oncology, and, more generally, to the changing configuration of the life sciences at the turn of the new century. An unprecedented degree of integration of biological and clinical practices has led to the proliferation of bio-clinical entities emerging from translational research. These translations take place between platforms rather than between clinical and laboratory settings. The complexity and heterogeneity of TNBC, its epistemic and technical, biological and clinical dualities, result from its multiple instantiations via different platforms, and from the uneven distribution of biological materials, techniques, and objects across clinical research settings. The fact that TNBC comes in multiple forms, some of which seem to be incompatible or, at least, only partially overlapping, appears to be less a threat to the whole endeavor, than an aspect of an ongoing translational research project. Discussions of translational research that rest on a distinction between basic research and its applications fail to capture the dynamics of this new domain of activity, insofar as application is built-in from the very beginning in the bio-clinical entities that emerge from the translational research domain.

  20. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes

    Science.gov (United States)

    Ponente, Manfredi; Campanini, Letizia; Cuttano, Roberto; Piunti, Andrea; Delledonne, Giacomo A.; Coltella, Nadia; Valsecchi, Roberta; Villa, Alessandra

    2017-01-01

    Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients. PMID:28239645

  1. MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Wanqin Wang

    2017-01-01

    Full Text Available AXL receptor tyrosine kinase is overexpressed in a number of solid tumor types including triple-negative breast cancer (TNBC. AXL is considered an important regulator of epithelial-to-mesenchymal transition (EMT and a potential therapeutic target for TNBC. In this work, we used microPET/CT with 64Cu-labeled anti-human AXL antibody (64Cu-anti-hAXL to noninvasively interrogate the degradation of AXL in vivo in response to 17-allylamino-17-demethoxygeldanamycin (17-AAG, a potent inhibitor of HSP90. 17-AAG treatment caused significant decline in AXL expression in orthotopic TNBC MDA-MB-231 tumors, inhibited EMT, and delayed tumor growth in vivo, resulting in significant reduction in tumor uptake of 64Cu-anti-hAXL as clearly visualized by microPET/CT. Our data indicate that 64Cu-anti-hAXL can be useful for monitoring anti-AXL therapies and for assessing inhibition of HSP90 molecular chaperone using AXL as a molecular surrogate.

  2. Down-regulation of hypoxia-inducible factor-1 suppresses malignant biological behavior of triple-negative breast cancer cells.

    Science.gov (United States)

    Wang, Fang; Chang, Miaomiao; Shi, Yonghong; Jiang, Lili; Zhao, Jing; Hai, Ling; Sharen, Gaowa; Du, Hua

    2014-01-01

    This study is to investigate the effect and mechanism of reduced hypoxia-inducible factor (HIF)-1a expression on malignant behavior of MDA-MB-231 cells. HIF-1α expression was interfered by siRNA. Western blot was used to detect protein expression of HIF-1α, active fragments of caspase 3 and vimentin. Cell count, flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and wound scratch assay were performed to measure the ability of cell invasion and migration. After MDA-MB-231 cells were transfected with HIF-1α-targeted siRNA, HIF-1α protein expression was successfully interrupted and cell growth was retarded. Compared with random siRNA group, reduced HIF-1α protein expression in HIF-1α-targeted siRNA group facilitated cell apoptosis but had no effect on cell cycle. In addition, cells treated with HIF-1α-targeted siRNA expressed active fragments of caspase 3 (17 and 12 kD) after serum starvation for 0 to 60 h. Caspase 3 activity assay further confirmed the above finding. Reduced HIF-1α expression impaired the migration and invasiveness with a reduction in the expression of vimentin and CK18 protein. Inhibition of HIF-1α protein synthesis or enhancement of its degradation reversed its malignant phenotypes and could probably be a potential means for the treatment of triple-negative breast cancer.

  3. Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors

    Science.gov (United States)

    Yang, Fang; Cao, Lulu; Sun, Zijia; Jin, Juan; Fang, Hehui; Zhang, Wenwen; Guan, Xiaoxiang

    2016-01-01

    Triple-negative breast cancer (TNBC) is a tumor subtype with aggressive behavior and poor clinical outcome for lacking effective therapies. Breast cancer stem cells (BCSCs) have been suggested to have tumor-initiating properties, but it remains unclear whether their presence contributes to the increased aggressiveness and poor prognosis of TNBC. Also, the breast cancers display frequent inter- and intra-tumor heterogeneity, which adds the complexity in diagnosis and predicting prognosis. Here we investigated the clinical relevance and prognostic value of the BCSC markers, CD44+/CD24-, aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and CD133 in 88 TNBC cases. We found that a few patients displayed spatial heterogeneity of the BCSC markers in expression, which was defined as intratumor stemness heterogeneity (ITSH) below. There was no significant correlation between any BCSC marker alone or ITSH and progression-free survival (PFS). Interestingly, the combined BCSC phenotype by CD44+/CD24- and ALDH1A1 was significantly associated with worse PFS (P = 0.009). Further stratification analysis revealed that this combined BCSC phenotype was an independent prognostic factor for PFS in some subgroups. In conclusion, we demonstrated the existence of ITSH in TNBC and found that the ITSH as well as a single BCSC marker was not significantly associated with survival, whereas combing the analysis of BCSC markers could improve prognostic value. Our findings may lead to an improvement of prognostic indicators in TNBC. PMID:27994520

  4. CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis.

    Science.gov (United States)

    Cerqueira, Otto L D; Truesdell, Peter; Baldassarre, Tomas; Vilella-Arias, Santiago A; Watt, Kathleen; Meens, Jalna; Chander, Harish; Osório, Cynthia A B; Soares, Fernando A; Reis, Eduardo M; Craig, Andrew W B

    2015-04-20

    Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.

  5. BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells.

    Science.gov (United States)

    Khaled, Walid T; Choon Lee, Song; Stingl, John; Chen, Xiongfeng; Raza Ali, H; Rueda, Oscar M; Hadi, Fazal; Wang, Juexuan; Yu, Yong; Chin, Suet-Feung; Stratton, Mike; Futreal, Andy; Jenkins, Nancy A; Aparicio, Sam; Copeland, Neal G; Watson, Christine J; Caldas, Carlos; Liu, Pentao

    2015-01-09

    Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies.

  6. Filamin A (FLNA) modulates chemosensitivity to docetaxel in triple-negative breast cancer through the MAPK/ERK pathway.

    Science.gov (United States)

    Zhao, Pengxin; Ma, Weiyuan; Hu, Zhigang; Zang, Leilei; Tian, Zhisheng; Zhang, Kaili

    2016-04-01

    A previous RNA interference (RNAi) screen identified filamin A (FLNA) as a potential biomarker to predict chemosensitivity in triple-negative breast cancer (TNBC). However, its ability to modulate chemosensitivity and the underlying mechanism has not been investigated. Genetic manipulation of FLNA expression has been performed in an immortalized noncancerous human mammary epithelial cell line and four TNBC cell lines to investigate its effect on chemosensitivity. Western blot analysis was performed to identify the potential signaling pathway involved. Xenograft mouse model was used to examine the in vivo role of FLNA in modulating chemosensitivity. Overexpression of FLNA conferred chemoresistance to docetaxel in noncancerous human mammary epithelial cells. Knockdown of FLNA sensitized four TNBC cell lines, MDA-MB-231, HCC38, Htb126, and HCC1937 to docetaxel which was reversed by reconstituted FLNA expression. Decreased FLNA expression correlated with decreased activation of ERK. Constitutive activation of ERK2 reversed siFLNA-induced chemosensitization. Inhibition of MEK1 recapitulates the effect of FLNA knockdown. MDA-MB-231 xenograft with FLNA knockdown showed enhanced response to docetaxel compared with control xenograft with increased apoptosis. FLNA can function as a modulator of chemosensitivity to docetaxel in TNBC cells through regulation of the MAPK/ERK pathway both in vitro and in vivo. FLNA may serve as a novel therapeutic target for improvement of chemotherapy efficacy in TNBC.

  7. Dual targeted therapy with p53 siRNA and Epigallocatechingallate in a triple negative breast cancer cell model.

    Directory of Open Access Journals (Sweden)

    Cornelia Braicu

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive phenotype that is resistant to standard therapy. Thus, the development of alternative therapeutic strategies for TNBC is essential. The purpose of our in vitro study was to evaluate the impact of p53 gene silencing in conjunction with the administration of a natural compound, epigallocatechingallate (EGCG. RT2Profiler PCR Array technology was used to evaluate the impact of dual treatment on the main genes involved in apoptosis in the Hs578T cell culture model of TNBC. Gene expression analysis revealed 28 genes were significantly altered (16 upregulated and 12 downregulated in response to combined p53 siRNA and EGCG treatment. Further analysis revealed that p53 siRNA and EGCG dual therapy leads to the activation of pro-apoptotic genes and the inhibition of pro-survival genes, autophagy, and cell network formation. These results indicate that this dual therapy targets both the apoptotic and angiogenic pathways, which may improve treatment effectiveness for tumors resistant to conventional treatment.

  8. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance

    Directory of Open Access Journals (Sweden)

    Prema Robinson

    2016-01-01

    Full Text Available Doxorubicin (DOX, an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC, DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP, a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS. Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2 and a TNBC cell line (MDA-MB 231 with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance.

  9. Retroperitoneal Lymph Node Dissection as First-Line Treatment of Node-Positive Seminoma.

    Science.gov (United States)

    Hu, Brian; Shah, Swar; Shojaei, Sepehr; Daneshmand, Siamak

    2015-08-01

    The long-term morbidity associated with treating advanced seminoma can be significant. Retroperitoneal lymph node dissection (RPLND) has established oncologic efficacy in treating germ cell tumors with minimal long-term toxicity. We describe our experience with RPLND as a front-line treatment of lymph node-positive seminoma. We reviewed our institutional review board-approved testicular cancer database to find the patients with pure seminoma and isolated retroperitoneal lymph node disease who had undergone primary RPLND. The clinical and pathologic variables were obtained. The follow-up data were used to determine recurrence and death. Four patients with a mean age of 37 years were identified. All patients had normal tumor markers and retroperitoneal lymphadenopathy measuring 1.1, 1.5, 1.8, and 5.5 cm before RPLND. Of the 4 patients, 3 had had seminoma diagnosed at orchiectomy and 1 (with a 5.5-cm retroperitoneal lymphadenopathy and a burned out primary testicular mass) had had seminoma diagnosed at RPLND after 2 nondiagnostic retroperitoneal biopsies. All patients had undergone nerve-sparing, template, extraperitoneal RPLND and were discharged home after 3 days. An average of 3 positive lymph nodes were found. Of the 4 patients, 3 had pathologic stage IIA and 1 stage IIB disease, with no patient undergoing adjuvant therapy. At a mean follow-up period of 25 months, no patient had experienced disease recurrence, and none had died. All patients maintained antegrade ejaculation, and no long-term complications had developed. Our small series has demonstrated encouraging oncologic efficacy for RPLND as a primary treatment of retroperitoneal lymph node-positive seminoma. A multi-institutional phase II trial of RPLND for stage IIA seminoma is being developed. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. VMAT techniques for lymph node-positive left sided breast cancer

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    Pasler, Marlies; Lutterbach, Johannes; Bjoernsgard, Mari; Reichmann, Ursula; Bartelt, Susanne [Lake Constance Radiation Oncology Center Singen, Friedrichshafen (Germany); Georg, Dietmar [Medical Univ. Vienna/AKH Vienna (Austria). Dept. of Radiooncology; Medical Univ. Vienna (Austria). Christian Doppler Lab. for Medical Radiation Research for Radiation Oncology

    2015-09-01

    To investigate the plan quality of two different volumetric modulated arc therapy (VMAT) techniques for lymph node-positive left-sided breast cancer. Two VMAT plans were generated for 10 lymph node-positive left-sided breast cancer patients: one plan using one single segment of a full rotation, typically an arc segment of 230 (1s-VMAT); and a second plan consisting of 2 small tangential arc segments of about 50 (2s-VMAT). For plan comparison, various dose and dose volume metrics (D{sub mean}, D{sub 98%}, D{sub 2%} for target volumes, D{sub 2%}, D{sub mean} and V{sub x%} for organs at risk (OAR)) were evaluated. Both techniques fulfilled both clinical target dose and OAR goals. 1s-VMAT achieved a slightly better homogeneity and better target coverage (D{sub 2%} = 54.2 ± 0.7 Gy, D{sub 98%} = 30.3 ± 1.8 Gy) compared to 2s-VMAT (D{sub 2%} = 55.0 ± 1.1 Gy, D{sub 98%} = 29.9 ± 1.7 Gy). For geometrical reasons, OAR sparing was noticeable but not significant better using 2s-VMAT, particularly heart and contralateral breast. The heart received a mean dose of 4.4 ± 0.8 Gy using 1s-VMAT and 3.3 ± 1.0 Gy using 2s-VMAT; the contralateral breast received 1.5 ± 0.3 Gy and 0.9 ± 0.3 Gy, respectively. A VMAT technique based on two small tangential arc segments enables improved OAR sparing; the differences between the two techniques in target coverage and homogeneity are minor. Patient age and -anatomy must be considered for each individual case when deciding which technique to be used.

  11. 三阴性乳腺癌的治疗进展%Treatment Advances of Triple Negative Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    何伟(综述); 于凌飞; 段秀庆(审校)

    2015-01-01

    The estrogen receptor, progesterone receptor and human epidermal growth factor receptor of triple negative breast cancer (TNBC) are negative. Compared to other breast cancer subtypes,TNBC has strong invasiveness,high degree of malignancy and poor prognosis,with high recurrence rate after adjuvant therapy. TNBC is more sensitive to chemotherapy,and cytotoxic drugs are the main drugs. In recent years, with the increasing depth study of tumor molecular biology,molecular targeted therapy for breast cancer has become the focus,and here is to make a review of the treatment advances of TNBC.%三阴性乳腺癌( TNBC)是雌激素受体、孕激素受体以及人表皮生长因子受体均为阴性的乳腺癌。相对于其他乳腺癌亚型,其具有侵袭性强、恶性程度高、患者预后差、辅助治疗后复发转移率高等特点。 TNBC对化疗较为敏感,治疗仍以细胞毒性药物为主。近年来,随着肿瘤分子生物学研究的深入,分子靶向治疗成为近几年乳腺癌研究和关注的焦点。该文就TNBC的治疗进展作一综述。

  12. Biological characteristics and clinical outcome of triple negative primary breast cancer in older women - comparison with their younger counterparts.

    Directory of Open Access Journals (Sweden)

    Binafsha M Syed

    Full Text Available Triple negative (ER, PgR and HER2 negative breast cancers (TNBCs are often considered as a poor prognostic phenotype. There is dearth of evidence showing the prevalence and biological behaviour of TNBCs in older women. This study aimed to analyse their biological characteristics in comparison with a well characterised younger series from a single centre with long term clinical follow-up. Over 37 years (1973-2010, 1,758 older (≥70 years women with early operable (<5 cm primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. A total of 127 patients (22.1% had TNBCs and full biological analysis of 15 biomarkers was performed. The results were compared with those of their younger (<70 years counterparts 342 (18.9% from a previously characterised, consecutive series of primary breast cancer treated in the same unit (1986-1998. The 127 older patients with TNBCs showed lower rates of Ki67 and CK 7/8 positivity and high rates of bcl2 and CK18 positivity when compared with their younger counterparts (p<0.05. There was no significant difference in the long term clinical outcome between the two age groups, despite the fact that 47% of the younger patients had adjuvant chemotherapy, while none in the older cohort received such treatment. EGFR, axillary stage and pathological size showed prognostic significance in older women with TNBCs on univariate analysis. Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of whom had chemotherapy. This appears to be related to other biomarkers (in addition to ER/PgR/HER2 eg Ki67, bcl2 and cytokeratins which have different expression patterns influencing prognosis.

  13. Systemic Delivery of Anti-miRNA for Suppression of Triple Negative Breast Cancer Utilizing RNA Nanotechnology.

    Science.gov (United States)

    Shu, Dan; Li, Hui; Shu, Yi; Xiong, Gaofeng; Carson, William E; Haque, Farzin; Xu, Ren; Guo, Peixuan

    2015-10-27

    MicroRNAs play important roles in regulating the gene expression and life cycle of cancer cells. In particular, miR-21, an oncogenic miRNA is a major player involved in tumor initiation, progression, invasion and metastasis in several cancers, including triple negative breast cancer (TNBC). However, delivery of therapeutic miRNA or anti-miRNA specifically into cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miR-21 to block the growth of TNBC in orthotopic mouse models. The 15 nm therapeutic RNA nanoparticles contains the 58-nucleotide (nt) phi29 pRNA-3WJ as a core, a 8-nt sequence complementary to the seed region of miR-21, and a 39-nt epidermal growth factor receptor (EGFR) targeting aptamer for internalizing RNA nanoparticles into cancer cells via receptor mediated endocytosis. The RNase resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection into mice and strongly bound to tumors with little or no accumulation in healthy organs 8 h postinjection, and subsequently repressed tumor growth at low doses. The observed specific cancer targeting and tumor regression is a result of several key attributes of RNA nanoparticles: anionic charge which disallows nonspecific passage across negatively charged cell membrane; "active" targeting using RNA aptamers which increases the homing of RNA nanoparticles to cancer cells; nanoscale size and shape which avoids rapid renal clearance and engulfment by lung macrophages and liver Kupffer cells; favorable biodistribution profiles with little accumulation in healthy organs, which minimizes nonspecific side effects; and favorable pharmacokinetic profiles with extended in vivo half-life. The results demonstrate the clinical potentials of RNA nanotechnology based platform to deliver miRNA based therapeutics for cancer treatment.

  14. Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer.

    Science.gov (United States)

    Toy, Kathy A; Valiathan, Rajeshwari R; Núñez, Fernando; Kidwell, Kelley M; Gonzalez, Maria E; Fridman, Rafael; Kleer, Celina G

    2015-02-01

    Receptor kinases Discoidin Domain Receptors (DDRs) 1 and 2 are emerging as new therapeutic targets in breast cancer (BC). However, the expression of DDR proteins during BC progression and their association with BC subtypes remain poorly defined. Herein we report the first comprehensive immunohistochemical analyses of DDR protein expression in a wide range of breast tissues. DDR1 and DDR2 expression was investigated by immunohistochemistry in 218 samples of normal breast (n = 10), ductal carcinoma in situ (DCIS, n = 10), and invasive carcinomas (n = 198), arrayed in tissue microarrays with comprehensive clinical and follow-up information. Staining was evaluated for cell type, subcellular localization, percentage and intensity (scores 1-4), and association with disease subtype and outcome. In normal epithelium and DCIS, DDR1 was highly expressed, while DDR2 was negative in normal epithelium, and in DCIS it localized to cells at the epithelial-stromal interface. Of the 198 invasive carcinomas, DDR1 was high in 87 (44 %) and low in 103 (52 %), and DDR2 was high in 110 (56 %) and low in 87 (44 %). High DDR2 was associated with high tumor grade (P = 0.002), triple-negative subtype (TNBC) (P DDR2(High) profile significantly associated with TNBC, compared to luminal tumors (P = 0.012), and with worse overall survival. In conclusion, DDR2 upregulation occurs in DCIS, before stromal invasion, and may reflect epithelial-stromal cross-talk. A DDR1(Low)/DDR2(High) protein profile is associated with TNBC and may identify invasive carcinomas with worse prognosis.

  15. VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer.

    Science.gov (United States)

    Castilla, María Ángeles; López-García, María Ángeles; Atienza, María Reina; Rosa-Rosa, Juan Manuel; Díaz-Martín, Juan; Pecero, María Luisa; Vieites, Begoña; Romero-Pérez, Laura; Benítez, Javier; Calcabrini, Annarica; Palacios, José

    2014-08-01

    Vestigial-like 1 (VGLL1) is a poorly characterized gene encoding a transcriptional co-activator structurally homologous to TAZ and YAP that modulates the Hippo pathway in Drosophila. In this study, we examined the expression of VGLL1 and its intronic miRNA, miR-934, in breast cancer. VGLL1 and miR-934 expression miRNA profiling was carried out on frozen samples of grade 3 invasive ductal carcinomas. VGLL1 protein was also examined in 433 sporadic and BRCA1-associated breast carcinomas on tissue microarrays. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to confirm differences in VGLL1 and miR-934 expression in different breast cancer subtypes, and to correlate their expression with that of other genes and miRNAs. Of 28 miRNAs differentially expressed in estrogen receptor (ER)-positive and ER-negative grade 3 breast carcinomas, miR-934 was most strongly upregulated in ER-negative carcinomas, and its expression was correlated with that of VGLL1. Nuclear VGLL1 expression was observed in 13% of sporadic breast carcinomas, and while VGLL1 was only occasionally found in luminal A (0.70%) and B (5.60%) carcinomas, it was often expressed in HER2-positive (17%), triple-negative (TN) breast carcinomas (>40%) and BRCA1-associated TN carcinomas (>50%). These findings were confirmed in the TCGA dataset, which revealed positive associations with luminal progenitor genes (GABRP, SLC6A14, FOXC1, PROM1, and BBOX1) and strong negative correlations with ER-associated genes (ESR1, C6ORF211, GATA3, and FOXA1). Moreover, VGLL1 expression was associated with reduced overall survival. In conclusion, VGLL1 and miR-934 are mainly expressed in sporadic and BRCA1-associated TN basal-like breast carcinomas, and their coordinated expression, at least partially mediated by the direct modulation of ESR1, might be involved in the maintenance of a luminal progenitor phenotype.

  16. Genetic Analysis of Microglandular Adenosis and Acinic Cell Carcinomas of the Breast Provides Evidence for the Existence of a Low-grade Triple-Negative Breast Neoplasia Family

    Science.gov (United States)

    Geyer, Felipe C; Berman, Samuel H.; Marchiò, Caterina; Burke, Kathleen A; Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Pareja, Fresia; Wen, Hannah Y; Hodi, Zoltan; Schnitt, Stuart J; Rakha, Emad A; Ellis, Ian O; Norton, Larry; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    Acinic cell carcinoma is an indolent form of invasive breast cancer, whereas microglandular adenosis has been shown to be a neoplastic proliferation. Both entities display a triple-negative phenotype, and may give rise to and display somatic genomic alterations typical of high-grade triple-negative breast cancers. Here we report on a comparison of previously published data on eight carcinoma-associated microglandular adenosis and eight acinic cell carcinomas subjected to targeted massively parallel sequencing targeting all exons of 236 genes recurrently mutated in breast cancer and/or DNA repair-related. Somatic mutations, insertions/deletions and copy number alterations were detected using state-of-the-art bioinformatic algorithms. All cases were of triple-negative phenotype. A median of 4.5 (1–13) and 4.0 (1–7) non-synonymous somatic mutations per carcinoma-associated microglandular adenosis and acinic cell carcinoma were identified, respectively. TP53 was the sole highly recurrently mutated gene (75% in microglandular adenosis versus 88% in acinic cell carcinomas), and TP53 mutations were consistently coupled with loss of heterozygosity of the wild-type allele. Additional somatic mutations shared by both groups included those in BRCA1, PIK3CA and INPP4B. Recurrent (n=2) somatic mutations restricted to microglandular adenosis or acinic cell carcinomas included those affecting PTEN and MED12, or ERBB4, respectively. No significant differences in the repertoire of somatic mutations were detected between microglandular adenosis and acinic cell carcinomas, and between this group of lesions and 77 triple-negative carcinomas from The Cancer Genome Atlas. Microglandular adenosis and acinic cell carcinomas, however, were genetically distinct from estrogen receptor-positive and/or HER2-positive breast cancers from The Cancer Genome Atlas. Our findings support the contention that microglandular adenosis and acinic cell carcinoma are part of the same spectrum of lesions

  17. Clinical characteristics comparison between triple-negative and non-triple-negative breast cancer%三阴性乳腺癌和非三阴性乳腺癌临床特征的比较

    Institute of Scientific and Technical Information of China (English)

    张慧明; 宣立学; 高纪东; 张保宁; 赵平

    2009-01-01

    Objective To compare the clinical characteristics of triple-negative (TN) breast cancer and non-triple-negative(NTN) breast cancer, enrich the information of TN patients, and provide evidences for individualized combined treatment. Methods The data of 408 cases received operation in the year of 2002 was enrolled in this study. TN patients were confirmed according to the immunohistochemical (IHC) test of estrogen receptor ( ER), progesterone receptor (PR) and HER-2/neu. The clinical characteristics, recurrence, metastasis and survival were compared between the two groups. Results Seventy-seven patients ( 18.9% ) were confirmed TN cases. The median follow-up was 64 months ( range, 3-79 months). Of all the cases, 58 occurred local recurrence or metastasis and 51 died, it was 19 and 12 in TN group. Compared with the NTN group, the TN patient tended to be younger and the tumor mass larger ( P = 0.015 and 0.011 ). However, axillary lymph nodes metastasis occurred more often in NTN patients than in TN patients (P =0.001 ). The rate of local recurrence and metastasis in TN group was significantly higher than in NTN group ( P = 0.005 and 0.025 ), and TN cases were more likely to develop lung metastasis than NTN patients (P <0.01 ). The 3-year and 5-year overall survival rate in TN group were significantly lower than in NTN group (86.4% vs. 93.4% , P =0.0205; 77.7% vs. 87.9%, P=0.0215). The 3-year and 5-year disease-free survival rate in TN group were also significantly lower than in NTN group (78.4% vs. 92.4%, P = 0.0038; 72.8% vs. 85.8%, P =0.0041 ). Tumor size, lymph node status and triple-negative were the most important factors influencing the prognosis on multivariate Cox regression analysis. Conclusions TN breast cancer haa some specific clinical characteristics. The prognosis of TN patients is worse than that of NTN patients. Further study is needed to find individualized treatment for TN breast caner patients.%目的 比较三阴性和非三阴性乳腺癌的临床

  18. MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression

    Science.gov (United States)

    Matamala, Nerea; Vargas, Maria Teresa; González-Cámpora, Ricardo; Arias, Jose Ignacio; Menéndez, Primitiva; Andrés-León, Eduardo; Yanowsky, Kira; Llaneza-Folgueras, Ana; Miñambres, Rebeca; Martínez-Delgado, Beatriz; Benítez, Javier

    2016-01-01

    Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation. PMID:26933805

  19. BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions.

    Science.gov (United States)

    Sinha, Abhilasha; Paul, Bibbin T; Sullivan, Lisa M; Sims, Hillary; El Bastawisy, Ahmed; Yousef, Hend F; Zekri, Abdel-Rahman N; Bahnassy, Abeer A; ElShamy, Wael M

    2017-02-07

    Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.

  20. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

    Science.gov (United States)

    Panayotopoulou, Effrosini G; Müller, Anna-Katharina; Börries, Melanie; Busch, Hauke; Hu, Guohong; Lev, Sima

    2017-02-06

    Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

  1. Treatment Outcomes and Clinicopathologic Characteristics of Triple-Negative Breast Cancer: A Report from Cancer Institute of Iran

    Science.gov (United States)

    Mirzania, Mehrzad; Safaee, Seyed Reza; Shahi, Farhad; Jahanzad, Issa; Zahedi, Ghazal; Mehdizadeh, Reza

    2017-01-01

    Background: Triple-negative breast cancers (TNBC) have a more aggressive course and are associated with poorer prognosis in comparison with other subtypes of breast cancer. One of the most common subtypes of TNBC is basal-like. The aim of this study was to investigate clinicopathological characteristics and clinical course of TNBC in Iranian women and compare them with other studies. Subjects and Methods: Between March 2009 and February 2011, patients with breast cancer in Cancer Institute of Iran were selected and then followed-up for 2 years. Paraffin-embedded tumor block of all TNBC patients were evaluated for CK5/6 and EGFR using IHC method. Results: Among 267 breast cancer patients, 60 cases with TNBC were identified (22.5%), 31 patients (51.7%) had basal-like and 29 patients (48.3%) had non-basal-like tumors. The median age of participants with TNBC was 49.6 years. Among our patients, 70% had positive lymph nodes.93.4% of all patients at the time of diagnosis were stage II or III and tumor size was at least 3 centimeters. No grade 1 TNBC was found in this study. During the follow-up period, there were 26 recurrences and 7 deaths. Conclusion: The percentage of basal-like subtype among Iranian women with TNBC was lower compared to other studies, while bone metastases, clinical stage, lymph node involvement and tumor size were higher. Clinicopathological findings in basal and non-basal-like subgroups were not different, but the probability of lymph node involvement was more common in patients who were EGFR positive. PMID:28286613

  2. Spectrum of EGFR gene copy number changes and KRAS gene mutation status in Korean triple negative breast cancer patients.

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    Yoonjung Kim

    Full Text Available Anti-epidermal growth factor receptor (EGFR therapy has been tried in triple negative breast cancer (TNBC patients without evaluation of molecular and clinical predictors in several randomized clinical studies. Only fewer than 20% of metastatic TNBCs showed response to anti-EGFR therapy. In order to increase the overall response rate, first step would be to classify TNBC into good or poor responders according to oncogenic mutation profiles. This study provides the molecular characteristics of TNBCs including EGFR gene copy number changes and mutation status of EGFR and KRAS gene in Korean TNBC patients. Mutation analysis for EGFR, KRAS, BRAF and TP53 from a total of 105 TNBC tissue samples was performed by direct sequencing, peptide nucleic acid-mediated PCR clamping method and real-time PCR. Copy number changes of EGFR gene were evaluated using multiplex ligation-dependent probe amplification. Out of all 105 TNBCs, 15.2% (16/105 showed EGFR copy number changes. Among them, increased or decreased EGFR copy number was detected in 13 (5 single copy gain, 2 amplification and 4 high-copy number amplification and 3 cases (3 hemizygous deletion, respectively. The mutation frequencies of KRAS, EGFR and TP53 gene were 1.9% (G12V and G12D, 1.0% (exon 19 del and 31.4%, respectively. There was no BRAF V600E mutation found. Future studies are needed to evaluate the clinical outcomes of TNBC patients who undergo anti-EGFR therapy according to the genetic status of EGFR.

  3. ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.

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    Clément Chevalier

    Full Text Available The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.

  4. EGFR expression is associated with cytoplasmic staining of CXCR4 and predicts poor prognosis in triple-negative breast carcinomas.

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    Li, Rong-Hui; Huang, Wen-He; Wu, Jun-Dong; Du, Cai-Wen; Zhang, Guo-Jun

    2017-02-01

    The purpose of the present study was to investigate the significance of C-X-C motif chemokine receptor type 4 (CXCR4) and epidermal growth factor receptors (EGFRs) in triple-negative breast cancer (TNBC). CXCR4 and EGFR expression levels were immunohistochemically determined in 207 primary breast cancer specimens. The associations between receptor expression and clinicopathological characteristics were analyzed, and receptor expression was also assessed as a prognostic factor. In the human MDA-MB-231 TNBC cell line, CXCR4 or EGFR was stably knocked down by short hairpin RNA, and the biological behavior of the cells, including migration, invasion and tumorigenesis, was investigated. The results revealed that TNBC was associated with younger age, higher histological grade and an aggressive phenotype. CXCR4 and EGFR were highly expressed in patients with TNBC, and those with high CXCR4 or EGFR expression exhibited an unfavorable prognosis in terms of disease-free survival and overall survival. In MDA-MB-231 cells, the expression of CXCR4 protein was decreased following EGFR silencing, while CXCR4 knockdown also caused a decrease in EGFR protein levels. The migratory and invasive capabilities of MDA-MB-231 cells were decreased following the knockdown of CXCR4 or EGFR expression. A strong correlation between CXCR4 and EGFR expression was identified in patients with TNBC. The results suggest that elevated expression levels of these two receptors may serve as predictive factors for poor prognosis in patients with TNBC. In addition, tumor proliferation, migration, invasion and tumorigenesis are weakened in MDA-MB-231 cells following suppression of CXCR4 or EGFR expression. Therefore, EGFR and CXCR4 may be potential therapeutic targets for TNBC.

  5. Phase III study of TAC and TP regimens as neoadjuvant chemotherapy in patients with triple-negative breast cancer

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    Hanguang Ruan; Juan Xiong; Meng Wu

    2014-01-01

    This study aimed to compare the eficacy and safety of neoadjuvant chemotherapy with TAC and TP regimens of triple negative breast cancer (TNBC).Methods: A total of 102 patients with TNBC were confirmed by histopathol-ogy. They were divided into TAC group (52 cases) and TP group (50 cases). Group TAC: Docetaxel 75 mg/m2 or paclitaxel (taxol liposome) 135 mg/m2 on d1, pirarubicin 40 mg/m2 or epirubicin 75 mg/m2 on d2, cyclophosphamide 600 mg/m2 on d1;Group TP: Docetaxel 75 mg/m2 or paclitaxel (taxol liposome) 135 mg/m2 on d1, cisplatin 30 mg/m2on d2-d4, with 21 days as a cycle. Al patients underwent operation after 2-4 cycles of chemotherapy. The short-term efects and toxic and adverse efects were evaluated. Results: In TAC group, 5 cases (9.6%) had pathological complete release (pCR), 35 cases (67.3%) partial release (PR), 9 cases (17.3%) stable disease (SD), and the response rate (RR) was 76.9%. In TP group, 4 cases (8%) had pCR, 32 cases (64%) PR, 5 cases (10%) SD, and RR was 72%. In 102 patients, 12 patients with tumor progression after 2 cycles of chemotherapy, included 3 cases in TAC group, 9 cases in TP group. In TAC group, 2 cases occurred atrial premature contraction; while 3 cases developed grade 2 renal injury in TP group. In TAC group, grade 3-4 hematologic toxicity and alo-pecia was significantly higher than that in TP group, but grade 3-4 gastrointestinal reaction rate in TP group was significantly higher than TAC group.Conclusion:TAC and TP regimens al had certain eficacy in the neoadjuvant chemotherapy for TNBC, and the toxicity reactions can be tolerated.

  6. Comparison of Radiologic Features of Triple-Negative and Estrogen Receptor/Progesteron Receptor Positive Breast Cancer

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    Kim, Young Joong; Kim, Keum Won; Kim, Dae Ho; Cho, Yong Jun; Hwang, Cheol Mog; Seo, Jae Young; Kim, Jin Suk; Yoon, Dae Sung [Dept. of Konyang University College of Medicine, Konyang University Hospital, Daejeon (Korea, Republic of); Kim, Gyu Soon [Dept. of Radiology, Eulji University College of Medicine, Eulji University Hospital, Daejeon (Korea, Republic of)

    2013-06-15

    To retrospectively investigate the imaging [mammographic, ultrasonographic (US), magnetic resonance (MR) imaging] features and standardized uptake values (SUV) in positron emission tomography (PET)/computed tomography (CT) of triple-negative breast cancers (TNBC) and to compare them with breast cancers that are either estrogen receptor (ER) positive or progesteron receptor (PR) positive. 155 breast cancers cases were identified in 134 women (mean age, 51 years; range, 31-86 years). Surgically confirmed TNBC (n = 27) and ER-positive/PR-positive breast cancers (n = 81) were included among them. Cancers were investigated with mammography (n = 81), US (n = 106), MR imaging (n = 34) and PET-CT (n = 59). Mammographic findings are identified by detection of characteristic masses and microcalcifications. US findings included tumor size, margin, tumor shape, calcification and posterior shadowing. MR findings included tumor size, shape, margin, internal enhancement, intratumoral signal intensity and kinetics. Peak SUVs (p-SUV) of breast cancers were evaluated in PET/CT. These findings were compared with TNBC and ER/PR positive groups. Mammographic findings had no significant association with the TNBC. High pathological grade (p < 0.05), larger than 2 cm in size, well-marginal mass, and round or oval-shaped (p < 0.05) is US were significantly associated with TNBC. In MR imaging, round mass shape (p < 0.05), well-circumscribed mass margin (p < 0.05), rim enhancement (p < 0.05), were significantly associated with TNBC. The peak SUV of TNBC tend to be higher than that of ER-positive/PR-positive breast cancer (7.95 {+-} 5.50 vs. 4.91 {+-} 3.00, p < 0.05). TNBC tend to have high pathological grade, are of a large, round and smooth mass with rim enhancement on MR and US. In addition to above features, PET-CT with SUV estimation can improve the accuracy of test through the evaluation of TNBC.

  7. Yiqi Formula Enhances the Antitumor Effects of Erlotinib for Treatment of Triple-Negative Breast Cancer Xenografts

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    Ming-juan Liao

    2014-01-01

    Full Text Available Yiqi formula (YF, a traditional herbal prescription, has long been used to treat triple-negative breast cancer (TNBC patients. The present study aims to investigate the effects and the related mechanism of YF for treatment of TNBC xenografts. MDA-MB-231 (human TNBC cells were subcutaneously injected into the second mammary fat pad of 40 female nude mice, which were divided into four groups: control, erlotinib (an epidermal growth factor receptor (EGFR tyrosine kinase inhibitor, YF, and combination (YF plus erlotinib. All treatments were administered orally for 30 days. Inhibition rate of tumor weight by erlotinib, YF, and the combination was 26.47%, 17.24%, and 39.15%, respectively. Western blotting showed that YF, erlotinib, and the combination downregulated p-EGFR (P<0.01 and p-Akt1 (pT308 (P<0.05 and upregulated PTEN compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. Similar results were detected by immunohistochemistry. Real-time quantitative PCR showed that YF, erlotinib, and the combination increased PTEN mRNA (P<0.05, P<0.01 compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. In conclusion, YF can regulate the main components of the PI3K/Akt pathway in TNBC xenografts. When YF was used in combination with erlotinib, it enhanced the antitumor effects of erlotinib on TNBC xenografts. These findings suggest that YF is suitable to use for the treatment of TNBC patients.

  8. Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer.

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    Julie L Boerner

    Full Text Available Patients with metastatic triple-negative breast cancer (TNBC have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose polymerase (PARP, a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.

  9. Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.

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    Noori, Mahboubeh S; O'Brien, John D; Champa, Zachary J; Deosarkar, Sudhir P; Lanier, Olivia L; Qi, Chunyan; Burdick, Monica M; Schwartz, Frank L; Bergmeier, Stephen C; McCall, Kelly D; Goetz, Douglas J

    2017-03-23

    Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.

  10. Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK.

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    Zhao, Ming; Howard, Erin W; Parris, Amanda B; Guo, Zhiying; Zhao, Qingxia; Yang, Xiaohe

    2017-03-01

    Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however, the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis. Understanding the molecular mechanisms of TNBC etiology remains a significant challenge. In this study, we investigated cellular responses to alcohol in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Our results showed that alcohol at low concentrations (0.025-0.1% v/v) induced cell proliferation, migration, and invasion in 1% FBS-containing medium. Molecular analysis indicated that these phenotypic changes were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation. Likewise, p38 or JNK inhibition attenuated alcohol-induced cell migration and invasion. We revealed that alcohol treatment activated/phosphorylated NF-κB regulators and increased transcription of NF-κB-targeted genes. While examining the role of acetaldehyde, the major alcohol metabolite, in alcohol-associated responses in TNBC cells, we saw that acetaldehyde induced cell migration, invasion, and increased phospho-p38, phospho-JNK, and phospho-IκBα in a pattern similar to alcohol treatment. Taken together, we established that alcohol promotes TNBC cell proliferation, migration, and invasion in vitro. The underlying mechanisms involve the induction of oxidative stress and the activation of NF-κB signaling. In particular, the activation of p38 and JNK plays a pivotal role in alcohol-induced cellular responses. These results will advance our understanding of alcohol-mediated development and promotion of TNBC. © 2016 Wiley Periodicals, Inc.

  11. Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients.

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    Ring, Brian Z; Hout, David R; Morris, Stephan W; Lawrence, Kasey; Schweitzer, Brock L; Bailey, Daniel B; Lehmann, Brian D; Pietenpol, Jennifer A; Seitz, Robert S

    2016-02-23

    Recently, a gene expression algorithm, TNBCtype, was developed that can divide triple-negative breast cancer (TNBC) into molecularly-defined subtypes. The algorithm has potential to provide predictive value for TNBC subtype-specific response to various treatments. TNBCtype used in a retrospective analysis of neoadjuvant clinical trial data of TNBC patients demonstrated that TNBC subtype and pathological complete response to neoadjuvant chemotherapy were significantly associated. Herein we describe an expression algorithm reduced to 101 genes with the power to subtype TNBC tumors similar to the original 2188-gene expression algorithm and predict patient outcomes. The new classification model was built using the same expression data sets used for the original TNBCtype algorithm. Gene set enrichment followed by shrunken centroid analysis were used for feature reduction, then elastic-net regularized linear modeling was used to identify genes for a centroid model classifying all subtypes, comprised of 101 genes. The predictive capability of both this new "lean" algorithm and the original 2188-gene model were applied to an independent clinical trial cohort of 139 TNBC patients treated initially with neoadjuvant doxorubicin/cyclophosphamide and then randomized to receive either paclitaxel or ixabepilone to determine association of pathologic complete response within the subtypes. The new 101-gene expression model reproduced the classification provided by the 2188-gene algorithm and was highly concordant in the same set of seven TNBC cohorts used to generate the TNBCtype algorithm (87%), as well as in the independent clinical trial cohort (88%), when cases with significant correlations to multiple subtypes were excluded. Clinical responses to both neoadjuvant treatment arms, found BL2 to be significantly associated with poor response (Odds Ratio (OR) =0.12, p=0.03 for the 2188-gene model; OR = 0.23, p sets can recapitulate the TNBC subtypes identified by the original 2188

  12. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer.

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    Rangel, Maria Cristina; Bertolette, Daniel; Castro, Nadia P; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David S

    2016-04-01

    Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo thr