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Sample records for carcinoma triple negative

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

    International Nuclear Information System (INIS)

    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 (Ktrans), outflow rate constant (kep), leakage space (ve), area under the gadolinium curve (IAUGC60), 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 ve (p = 0.001), shorter MTT (p = 0.007) and higher kep values (p = 0.044) were observed in TNBC. ve was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). ve 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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  3. Triple negative breast carcinoma in a population Uruguayan

    International Nuclear Information System (INIS)

    Full text: Introduction: breast carcinomas that do not express estrogen or progesterone receptors (E R / P R)and are not associated with HER2 overexpression or amplification have been defined as triple-negative breast cancer (T N C M). These account for 15-20% of all breast cancers. They have a poor prognosis because the aggressive phenotypes and partial tumor response to chemotherapy. Currently not available therapeutic targets Clearly stated reason is the focus of intense medical research. Objective: To establish the prevalence and describe the clinico pathological features of the T N C M in a population of Uruguay. Determine disease-free survival (SVLE)and compare these results with the international literature. Methods: We identified all patients with invasive C M diagnosed, histologically confirmed assisted at the Clinical Hospital and Central Hospital of the Armed Forces in Uruguay, in the period 2007-2011. Patients were included in the studies were conducted full statement immunohistochemical negative (E R, P R and HER2). Mean follow-up was 29 months. Results: Of 586 cases of C M, C M identifying T N 49 cases, which gives rise to a prevalence of 8.3%. 57.1% of the patients were between 51-70 years of diagnosis. The most common clinical presentation was palpable tumor in 49%. In the imaging mammary found that 38.7% presented with a mass, corresponding to 32.6% BIRADS 5. As for treatment 85.7% breast surgery was performed, of which 57.2% were conservative surgeries. The ductal histological type was the most frequent (81.6 %). It observed a marked tendency to presentation with high histological grade, corresponding 57.1% to the final histological grade III. Pathologic stage I- II accounted for 63 % of cases with 57.1 % without axillary involvement. As adjuvant therapy, 71 % received chemotherapy and 73% radiotherapy. The 20.1 % relapsed, 77.7 % was systemically. Made a total of 9 dead (18.4 %). SVLE median not yet been reached with the monitoring carried out

  4. Bcl-2 expression and triple negative profile in breast carcinoma.

    Science.gov (United States)

    Kallel-Bayoudh, Imen; Hassen, Hanen Ben; Khabir, Abdelmajid; Boujelbene, Noureddine; Daoud, Jamel; Frikha, Mounir; Sallemi-Boudawara, Tahia; Aifa, Sami; Rebaï, Ahmed

    2011-12-01

    Many biomarkers for breast cancer prognosis have been proposed during the last two decades, among which HER2 and oestrogen receptors are of common use in routine clinical practice. However, in recent years, BCL2 has been recognized as an important prognostic parameter in human breast cancer, although its clinical utility is well established. The aim of this study was to examine the protein expression patterns of BCL2, HER2, oestrogen (ER) and progesterone receptors (PR) and to evaluate their correlation with survival and other prognostic parameters such as tumour size, histological grade and metastasis. We used a retrospective study including 84 Tunisian women with breast cancer. Immunohistochemistry was used to measure protein expression levels of several biomarkers. Association with conventional biopathological factors was analysed by SPSS (version13). The expression rates of BCL2, HER2, ER and PR were, respectively, 69, 62, 58.3 and 51.2%. In univariate analyses, BCL2 was highly correlated with both PR (P < 0.001) and ER (P = 0.006) and also with HER2 expression (P = 0.001). The triple negative profile showed a significant association with SBR (P = 0.016) and BCL2 expression (P = 0.02). In multivariate analyses, a significant association was maintained between BCL2 and both PR and ER (P = 0.02 and P = 0.004, respectively). Survival analysis showed that BCL2 expression was positively correlated with patients survival (P = 0.032). A Bayesian network analysis of all the variables confirmed the high value of BCL2 expression as a predictor of survival. As conclusion, BCL2 expression seems to be a very useful factor that should be in combination with HER2 and ER in breast cancer prognosis. PMID:20890735

  5. 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...

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

    International Nuclear Information System (INIS)

    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. 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. 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. 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

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

    OpenAIRE

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

    2013-01-01

    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 me...

  8. Pure Apocrine Carcinomas Represent a Clinicopathologically Distinct Androgen Receptor-Positive Subset of Triple-Negative Breast Cancers.

    Science.gov (United States)

    Mills, Anne M; E Gottlieb, Chelsea; M Wendroth, Scott; M Brenin, Christiana; Atkins, Kristen A

    2016-08-01

    Apocrine carcinomas comprise ∼1% of all breast cancers and are characterized by large cells bearing abundant eosinophilic granular cytoplasm, round nuclei, and prominent nucleoli. They are typically estrogen receptor/progesterone receptor/HER2 negative, making them unresponsive to typical hormonal or HER2-based chemotherapy. However, this subtype of triple-negative breast cancers expresses androgen receptor (AR), a feature not shared by most nonapocrine triple-negative cancers (NA-TNCs). AR therefore represents a potential diagnostic tool and therapeutic target for apocrine breast carcinoma. All pure apocrine carcinomas diagnosed during a 10-year period were reviewed, and clinicopathologic characteristics were compared with a control group of 26 NA-TNC cases. Twenty apocrine carcinomas were identified (∼0.8% of all breast cancers). The mean age at diagnosis was 69.3 years for apocrine carcinomas and 56.7 years for NA-TNC. All apocrine carcinomas and no NA-TNC were AR positive. The proportions of apocrine carcinoma grades varied, with G1 being seen in 15% of patients, G2 in 55%, and G3 in 30%. In contrast, 100% of NA-TNC cases were G3. The majority of apocrine carcinomas presented at low T stage (T1: 70%; T2: 20%; T3: 10%; T4: 0%), whereas NA-TNC cases more often presented at T2 or higher (T1: 46.2%; T2: 30.8%; T3: 11.5%; T4: 11.5%). Thirty percent of apocrine carcinomas and 30.8% of NA-TNCs had nodal metastases at presentation. Apocrine carcinomas had a favorable clinical prognosis, with 80% of patients showing no evidence of disease-related morbidity or mortality (mean follow-up: 45.2 mo). Pure apocrine carcinomas represent a clinicopathologically distinct subgroup of triple-negative breast cancer characterized by AR positivity. When compared with NA-TNC, apocrine carcinomas more often present in older women with lower grade and T stage, a group in which a more conservative treatment regimen is often desired. PMID:27259012

  9. Molecular Characteristics and Metastasis Predictor Genes of Triple-Negative Breast Cancer: A Clinical Study of Triple-Negative Breast Carcinomas

    OpenAIRE

    Kuo, Wen-Hung; Chang, Yao-Yin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Hsiao, Chuhsing Kate; Chang, King-Jen; Chuang, Eric Y.

    2012-01-01

    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 identif...

  10. Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival.

    Directory of Open Access Journals (Sweden)

    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.

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

    International Nuclear Information System (INIS)

    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. 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. 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. 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

  12. 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.

  13. Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC. We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1). Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022). Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC

  14. GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer

    Science.gov (United States)

    2015-08-17

    Estrogen Receptor Negative Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Triple Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer

  15. p53 alteration in morphologically normal/benign breast tissue in patients with triple-negative high-grade breast carcinomas: breast p53 signature?

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    Wang, Xi; Stolla, Moritz; Ring, Brian Z; Yang, Qi; Laughlin, Todd S; Rothberg, Paul G; Skinner, Kristin; Hicks, David G

    2016-09-01

    p53 alterations have been identified in approximately 23% of breast carcinomas, particularly in hormone receptor-negative high-grade carcinomas. It is considered to be an early event in breast carcinogenesis. Nevertheless, the putative precursor lesion of high-grade breast carcinoma remains elusive. Breast excision specimens from 93 triple-negative high-grade invasive ductal carcinomas, 48 estrogen receptor (ER)-positive/progesterone receptor-positive/Her2-negative non-high-grade invasive ductal carcinomas, and 50 mammoplasty breasts were selected. At least 2 tissue blocks with tumor and adjacent benign tissue were sectioned and subjected to immunohistochemistry staining for p53. TP53 gene sequencing was performed on select tumors. Further immunohistochemistry staining for ER and Ki-67 was performed on consecutive sections of tissue with p53-positive normal/benign cells. Of the 93 high-grade carcinomas, 51 (55%) were positive for p53 alteration, whereas only 3 (6.25%) of the 48 non-high-grade carcinomas were p53 altered. Focal p53 positivity in adjacent normal/benign breast tissue was identified in 19 cases, and 18 of them also had p53 alteration in their carcinomas. Only 1 case had focal p53 staining in normal/benign tissue, but the tumor was negative for p53 alteration. No p53 staining positivity was identified in the mammoplasty specimens. The p53-stained normal/benign cells were ER negative and did not show an increase in the Ki-67 labeling index. These findings indicate that the p53 staining positivity in normal/benign breast tissue is not a random event. It could be considered as the "p53 signature" in breast and serve as an indicator for future potential risk of p53-positive high-grade breast carcinoma. PMID:27246177

  16. HSP90 Inhibitor AT13387 and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

    Science.gov (United States)

    2016-08-08

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

  17. Palbociclib in Treating Patients With Metastatic HER-2 Positive or Triple-Negative Breast Cancer With Brain Metastasis

    Science.gov (United States)

    2016-05-13

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

  18. Association of Notch pathway down-regulation with Triple Negative/Basal-like breast carcinomas and high tumor-infiltrating FOXP3+ Tregs.

    Science.gov (United States)

    Ortiz-Martínez, Fernando; Gutiérrez-Aviñó, Francisco José; Sanmartín, Elena; Pomares-Navarro, Eloy; Villalba-Riquelme, Cristina; García-Martínez, Araceli; Lerma, Enrique; Peiró, Gloria

    2016-06-01

    T regulatory cells (Tregs) are a lineage of lymphocytes involved in immune response suppression that are characterized by the expression of the forkhead box P3 (FOXP3) transcription factor. Notch pathway regulates FOXP3 transcription in Tregs, but its role in breast cancer is unknown. We aimed at studying whether Notch pathway regulates FOXP3 expression and Tregs content in breast cancer, and its association with luminal breast carcinomas. We analyzed by quantitative Real-Time PCR the mRNA levels of FOXP3, Notch pathway genes (Notch1, Notch2, Notch4 and Jagged1) and STAT3 in a series of 152 breast carcinomas including hormone receptor-positive and -negative phenotypes (luminal and Triple Negative/Basal-like). We also studied the protein expression of Notch1, STAT3 and FOXP3 by immunohistochemistry. High FOXP3 mRNA levels correlated with larger tumor size (p=0.010), histological grade 3 (p=0.008) and positive lymph-node status (p=0.031). Also, low levels of Notch pathway genes mRNA correlated with poor prognostic factors such as larger tumor size, positive lymph-node status, tumor phenotype and infiltrating tumor Tregs. A survival analysis for the patients showed that large tumor size, histological grade 3, vascular invasion, infiltrating Tregs and low Notch1 mRNA expression were significantly associated with a decreased patients' overall survival (p≤0.05). On a multivariate analysis, high Tregs content (HR=3.00, 95% CI 1.04-8.90, p=0.042) and low Notch1 mRNA levels (HR=3.33, 95% CI 1.02-10.86, p=0.046) were independent markers for overall survival. Our results support that the Notch pathway up-regulation promotes luminal breast carcinomas, whereas down-regulation correlates with the expression of FOXP3, favors tumor Tregs infiltration and associates with Triple Negative/Basal-like tumors. PMID:27118257

  19. Triple negative breast cancer: an Indian perspective

    Directory of Open Access Journals (Sweden)

    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

  20. Magnetic Resonance Imaging after Completion of Neoadjuvant Chemotherapy Can Accurately Discriminate between No Residual Carcinoma and Residual Ductal Carcinoma In Situ in Patients with Triple-Negative Breast Cancer.

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    Seho Park

    Full Text Available The accurate evaluation of favorable response to neoadjuvant chemotherapy (NCT is critical to determine the extent of surgery. We investigated independent clinicopathological and radiological predictors to discriminate no residual carcinoma (ypT0 from residual ductal carcinoma in situ (ypTis in breast cancer patients who received NCT.Parameters of 117 patients attaining pathological complete response (CR in the breast after NCT between January 2010 and December 2013 were retrospectively evaluated by univariate and multivariate analyses. All patients underwent mammography, ultrasound, and magnetic resonance imaging (MRI before and after NCT.There were 67 (57.3% patients with ypT0. These patients were associated with hormone receptor-negative status, human epidermal growth factor receptor-2 (HER2-negative tumors, and a higher likelihood of breast-conservation surgery. Baseline mammographic and MRI presentation of the main lesion, absence of associated microcalcifications, shape, posterior features, and absence of calcifications on ultrasound were significantly associated with ypT0. CR in mammography, ultrasound, or MRI after NCT was also related to ypT0. By multivariate analysis, independent predictors of ypT0 were the triple-negative subtype [Odds ratio (OR, 4.23; 95% confidence interval (CI, 1.11-16.09] and CR in MRI after NCT (OR, 5.23; 95% CI, 1.53-17.85. Stratified analysis by breast cancer subtype demonstrated that MRI well predicted ypT0 in all subtypes except the HER2-positive subtype. In particular, of 40 triple-negative subtypes, 22 showed CR in MRI and 21 (95.5% were ypT0 after NCT.Among imaging modalities, breast MRI can potentially distinguish between ypT0 and ypTis after NCT, especially in patients with triple-negative breast cancer. This information can help clinicians evaluate tumor response to NCT and plan surgery for breast cancer patients of all subtypes except for those with HER2-enriched tumors after NCT.

  1. Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

    Science.gov (United States)

    2016-05-06

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

  2. Platinum Based Chemotherapy or Observation in Treating Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy

    Science.gov (United States)

    2015-05-14

    Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; 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

  3. Triple Negative Breast Cancer in Pregnancy and Postpartum: Two Case Reports in Hispanic Women

    OpenAIRE

    Ruchi Upadhyay; Qurat-Ul-Ain Butt; Abraham Hamaoui; Cassandra Henderson; Sydney McCalla; Hamid Gilak

    2015-01-01

    Objective. Despite studies suggesting that triple negative breast cancer is more often seen in women of African ancestry, we report here two cases of pregnancy associated triple negative breast cancer in Hispanic women. Cases. Case one is a 37-year-old female para 2-0-0-2, who presented with a left breast mass, at 19 weeks of gestation, the biopsy of which reported an invasive ductal carcinoma, found to be triple receptor negative. The patient underwent chemotherapy during the pregnancy and w...

  4. Glyceollins as novel targeted therapeutic for the treatment of triple-negative breast cancer

    OpenAIRE

    Rhodes, Lyndsay V.; Tilghman, Syreeta L.; Boue, Stephen M.; Wang, Shuchun; KHALILI, HAFEZ; Muir, Shannon E.; Bratton, Melyssa R.; Zhang, Qiang; Wang, Guangdi; BUROW, MATTHEW E.; Collins-Burow, Bridgette M.

    2011-01-01

    The purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple-negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA-MB-231 cells. Triple-negative (ER-, PgR- and Her2/neu-) breast carcinoma cells were used to test the effects of glyceollins on tumorigenesis in vivo. Following this procedure, unbiased microarray analysis of microRNA expression was performed. Additiona...

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

    Science.gov (United States)

    2016-02-12

    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

  6. Comparative study on mammography between triple negative and triple positive breast cancer

    International Nuclear Information System (INIS)

    Objective: To analyze the mammographic findings of triple-negative breast cancer [TNBC, which is estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative] and triple-positive breast cancer (TPBC, which is ER positive, PR positive, and HER2 positive), and to evaluate the relationship of immunohistochemologic receptor status and mammographic findings. Methods: The immunohistochemistry results of 631 cases with breast cancers were reviewed, including 117 cases of TNBC and 44 cases of TPBC. All of the patients took mammography at initial diagnosis. We retrospectively evaluated the visibility, morphology, distribution and size of the lesion (masses and calcifications) and breast density on mammography of TNBC, and compared them with those of TPBC. The age onset and tumor sizes of TNBC and TPBC were compared by using Chi-square test and t test. Results: The visibility rate of TNBC and TPBC on mammography were 88.0%(103/117) and 90.9% (40/44), and the difference between them was insignificant (χ2=0.055, P >0.05). TNBC was more frequently associated with merely a mass (56/103) than TPBC (12/40) (χ2=6.860, P<0.01), and the mean diameter of the mass of TNBC [(2.6 ± 1.4) cm] was larger than that of TPBC [(2.0 ± 0.6) cm] (t=2.087, P<0.05). TNBC were less frequently associated with microcalcifications (37/103) than TPBC (24/40) (χ2=7.423, P<0.01). Mammographic density and lesion visibility were similar between the two different immunophenotypes of breast cancers. The mean age of TNBC (52±9) was more than that of TPBC (48 ±8) (t=2.759, P<0.01). Infiltrating ductal carcinoma was the main pathologic type of both groups. Basal-like breast cancer accounted for 49% (57/117) of TNBC while none happened in TPBC. Conclusions: TNBC shows merely a mass with indistinct margins,lager size and is less associated with microcalcifications. These mammographic features might be useful in diagnosing triple negative

  7. Carboplatin and Eribulin Mesylate in Triple Negative Breast Cancer Patients

    Science.gov (United States)

    2015-06-23

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  8. Molecular characterisation of cell line models for triple-negative breast cancers

    Directory of Open Access Journals (Sweden)

    Grigoriadis Anita

    2012-11-01

    Full Text Available Abstract Background Triple-negative breast cancers (BC represent a heterogeneous subtype of BCs, generally associated with an aggressive clinical course and where targeted therapies are currently limited. Target validation studies for all BC subtypes have largely employed established BC cell lines, which have proven to be effective tools for drug discovery. Results Given the lines of evidence suggesting that BC cell lines are effective tools for drug discovery, we assessed the similarities between triple-negative BCs and cell lines, to identify in vitro representatives, modelling the diversity within this BC subtype. 25 BC cell lines, enriched for those lacking ER, PR and HER2 expression, were subjected to transcriptomic, genomic and epigenomic profiling analyses and comparisons were made to existing knowledge of corresponding perturbations in triple-negative BCs. Transcriptional analysis segregated ER-negative BC cell lines into three groups, displaying distinctive abundances for genes involved in epithelial-mesenchymal transition, apocrine and high-grade carcinomas. DNA copy number aberrations of triple-negative BCs were well represented in cell lines and genes with coordinately altered gene expression showed similar patterns in tumours and cell lines. Methylation events in triple-negative BCs were mostly retained in epigenomes of cell lines. Combined methylation and gene expression analyses revealed a subset of genes characteristic of the Claudin-low BC subtype, exhibiting epigenetic-regulated gene expression in BC cell lines and tumours, suggesting that methylation patterns are likely to underpin subtype-specificity. Conclusion Here, we provide a comprehensive analysis of triple-negative BC features on several molecular levels in BC cell lines, thereby creating an in-depth resource to access the suitability of individual lines as experimental models for studying BC tumour biology, biomarkers and possible therapeutic targets in the context of

  9. The diagnostic utility of the minimal carcinoma triple stain in breast carcinomas.

    Science.gov (United States)

    Ross, Dara S; Liu, Yi-Fang; Pipa, Jennifer; Shin, Sandra J

    2013-01-01

    Pathologists are expected to accurately diagnose increasingly smaller breast carcinomas. Correct classification (ie, lobular vs ductal or in situ vs invasive) directly affects subsequent management, especially when the focus is near a surgical margin or present in a needle core biopsy and is further challenging if the lesion is morphologically ambiguous. We assessed the diagnostic utility of a multiplex, trichromogen immunostain of 3 commonly employed antibodies (CK7, p63, and E-cadherin) developed in our laboratory to evaluate these small lesions. Of the 147 specimens containing minimal (defined as ≤3 mm in size) invasive carcinoma, 81 also contained in situ carcinoma. In each case, the Minimal Carcinoma Triple Stain was prepared with a parallel H&E-stained slide. Observations of staining characteristics in the focus of interest were recorded. The Minimal Carcinoma Triple Stain was diagnostically useful in all but 1 case. In a case of invasive lobular carcinoma in an excisional biopsy, the Minimal Carcinoma Triple Stain stained only the surrounding breast tissue (appropriately) and not the focus of interest. Also, a subset of 29 of 81 excisional biopsies had minimal invasive carcinoma located 2 mm or less from the inked surgical margin, in which in all cases the Minimal Carcinoma Triple Stain was fully interpretable despite morphologic distortion due to concomitant cautery artifact and tissue disruption in some cases. The Minimal Carcinoma Triple Stain offers an accurate and tissue-conserving method to diagnose small, morphologically problematic foci of breast carcinoma while ideally leaving more tissue for additional adjunctive studies. PMID:23270900

  10. Nottingham Prognostic Index in Triple-Negative Breast Cancer: a reliable prognostic tool?

    International Nuclear Information System (INIS)

    A breast cancer prognostic tool should ideally be applicable to all types of invasive breast lesions. A number of studies have shown histopathological grade to be an independent prognostic factor in breast cancer, adding prognostic power to nodal stage and tumour size. The Nottingham Prognostic Index has been shown to accurately predict patient outcome in stratified groups with a follow-up period of 15 years after primary diagnosis of breast cancer. Clinically, breast tumours that lack the expression of Oestrogen Receptor, Progesterone Receptor and Human Epidermal growth factor Receptor 2 (HER2) are identified as presenting a 'triple-negative' phenotype or as triple-negative breast cancers. These poor outcome tumours represent an easily recognisable prognostic group of breast cancer with aggressive behaviour that currently lack the benefit of available systemic therapy. There are conflicting results on the prevalence of lymph node metastasis at the time of diagnosis in triple-negative breast cancer patients but it is currently accepted that triple-negative breast cancer does not metastasize to axillary nodes and bones as frequently as the non-triple-negative carcinomas, favouring instead, a preferentially haematogenous spread. Hypothetically, this particular tumour dissemination pattern would impair the reliability of using Nottingham Prognostic Index as a tool for triple-negative breast cancer prognostication. The present study tested the effectiveness of the Nottingham Prognostic Index in stratifying breast cancer patients of different subtypes with special emphasis in a triple-negative breast cancer patient subset versus non- triple-negative breast cancer. We demonstrated that besides the fact that TNBC disseminate to axillary lymph nodes as frequently as luminal or HER2 tumours, we also showed that TNBC are larger in size compared with other subtypes and almost all grade 3. Additionally, survival curves demonstrated that these prognostic factors are

  11. 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.

  12. Multi-slice CT angiography by triple-phase enhancement in preoperative evaluation of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    XIAO Xi-gang; HAN Xue; SHAN Wei-dong; LI An-yuan

    2005-01-01

    Background Triple-phase enhancement of multi-slice computed tomography (MSCT) has markedly improved the diagnostic accuracy of hepatocellular carcinoma (HCC), and MSCT angiography (MSCTA) has been proved useful in detecting vascular anatomy noninvasively. This study aimed to explore the value of MSCTA by triple-phase enhancement in preoperative evaluation of HCC.Methods Fifty-six consecutive cases of primary HCC scheduled for resection were studied with MSCTA by triple-phase enhancement. The raw data images were processed on a workstation for multiplanar reconstruction (MPR) and three-dimensional (3D) reconstruction. The findings after processing of the data were compared with those after surgery or intraoperative sonography. Results The false positive rate of MSCTA by triple-phase enhancement was 10.1% and its false negative rate was 4.3% in detecting HCC. No significant difference was observed in MSCTA and surgery or intraoperative sonography in detecting vascular anatomy anomalies and pathologic variations, whereas significant difference was found in detecting bile duct invasion with MSCT compared to intraoperative sonography.Conclusions MSCTA by triple-phase enhancement not only improves the detection of HCC, but also provides valuable preoperative information about hepatic vascular architecture and parenchyma. MSCTA by triple-phase enhancement is worthy of application as a non-invasive method in preoperative evaluation of HCC.

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

    OpenAIRE

    Jerusalem, Guy

    2016-01-01

    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 sy...

  14. Results of combination treatment for triple-negative breast cancer

    OpenAIRE

    M. A. Sekundova; V.I. Borisov; A. M. Sdvizhkov

    2014-01-01

    The authors give the results of treatment in 128 patients with operable triple-negative breast cancer (BC). All the patients underwent surgical intervention, the volume of which depended on the stage of the disease. The efficiency of adjuvant and neoadjuvant chemotherapy, as well as pre- and postoperative radiotherapy was evaluated. The side effects of different treatment options were analyzed. Five-year relapse-free and overall survival rates were traced in this patient group. It is conclude...

  15. Prognostic protein markers for triple negative breast cancer

    OpenAIRE

    Umar, Arzu; Liu, Ning Qing; Braakman, René

    2010-01-01

    textabstractBreast cancer is the most commonly diagnosed malignancy in women in the Western world, with 13,000 new patients each year in the Netherlands alone. Extensive research on gene expression profiling has shown that breast cancer is a mixture of biologically different disease entities, referred to as molecular subtypes. Of all molecular subtypes, particularly the triple negative phenotype associates with poor prognosis and poor patient survival. Intriguingly, only a small subgroup of t...

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

    OpenAIRE

    Collignon J; Lousberg L; Schroeder H; Jerusalem G

    2016-01-01

    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 treat...

  17. 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.

    Directory of Open Access Journals (Sweden)

    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.

  18. PD-L1 Expression in Triple Negative Breast Cancer

    OpenAIRE

    Mittendorf, Elizabeth A; Philips, Anne V; Meric-Bernstam, Funda; Qiao, Na; Wu, Yun; Harrington, Susan; Su, Xiaoping; Wang, Ying; Gonzalez-Angulo, Ana M.; Akcakanat, Argun; Chawla, Akhil; Curran, Michael; Hwu, Patrick; Sharma, Padmanee; Litton, Jennifer K.

    2014-01-01

    Early phase trials targeting the T-cell inhibitory molecule PD-L1 have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of the phosphatase and tensin homolog (PTEN) as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n=120) compared to non-TNBC (n=716) (P

  19. 三阴性乳腺癌中E ̄钙黏蛋白的表达及其临床意义%Expression of E ̄cadherin and its prognostic significance in triple negative breast carcinoma

    Institute of Scientific and Technical Information of China (English)

    洪超群; 庄轶轩; 陈继明; 吴晓; 张凡

    2015-01-01

    目的:探讨三阴性乳腺癌组织中的E ̄钙黏蛋白( E ̄cadherin,E ̄cad)的表达及其与临床病理指标和预后的关系。方法2002年1月—2008年10月在汕头大学医学院附属肿瘤医院接受治疗的女性三阴性乳腺癌组织35例,采用免疫组织化学GTvision两步法检测样本中E ̄cad的表达,采用卡方检验分析其与临床病理特征的关系,应用Kaplan ̄Meier法和Cox比例风险回归模型分析E ̄cad表达对预后的影响。结果 E ̄cad主要定位在细胞膜,35例三阴性乳腺癌组织中E ̄cad的低表达率为51�4%(18/35),其表达与临床肿瘤分期( P=0�009)和淋巴结转移有关( P=0�044)。 E ̄cad低表达和高表达患者总体生存曲线差异有统计学意义( Log ̄rank检验,P=0�014)。 Cox比例风险回归模型分析示E ̄cad是三阴性乳腺癌患者独立的预后因素(风险比0�241,95%置信区间0�072~0�814,P=0�022)。结论 E ̄cad低表达或缺失更容易引起三阴性乳腺癌的浸润转移,在三阴性乳腺癌的发展过程中起着重要作用,可以作为三阴性乳腺癌患者预后的一个重要的独立预测因素。%Objective To study the protein expression of E ̄cadherin ( E ̄cad) to understand its relationship with clinicopathological parameters and its influence on the prognosis of human triple negative breast carcinoma ( TNBC) . Methods We collected tumor tissues from 35 female patients with TNBC treated at the Cancer Hospital of Shantou University Medical College from January 2002 to October 2008. Immunohistochemistry was performed to detect the protein expression of E ̄cad in breast tumors,and the chi ̄square test was used to study the relationship between the E ̄cad expre ̄ssion and clinicopathological parameters. The Kaplan ̄Meier method and Cox regression model were conducted to study the influence of E ̄cad on the prognosis of TNBC. Results E ̄cad protein was ex ̄pressed primarily

  20. Tumor Initiating Cells and FZD8 play a major role in drug resistance in Triple-Negative Breast Cancer

    OpenAIRE

    Yin, Shuping; Xu, Liping; Bonfil, R. Daniel; Banerjee, Sanjeev; Sarkar, Fazlul H; Sethi, Seema; Reddy, Kaladhar B.

    2013-01-01

    Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant in...

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are......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...... share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu...

  2. 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

  3. Current Issues of Targeted Therapy in Metastatic Triple-Negative Breast Cancer

    OpenAIRE

    Liedtke, Cornelia; Kiesel, Ludwig

    2011-01-01

    Patients with triple-negative breast cancer are characterized by a poor prognosis compared with patients with other breast cancer subtypes. The angiogenesis inhibitor bevacizumab is effective in the palliative treatment of patients with triple-negative breast cancer as well as in other breast cancer subtypes. PARP inhibitors represent the first group of targeted agents to be developed under the particular aspect of treating patients with hereditary and triple-negative breast cancer. In additi...

  4. Identification of Prognostic Genes for Recurrent Risk Prediction in Triple Negative Breast Cancer Patients in Taiwan

    OpenAIRE

    Chen, Lee H.; Kuo, Wen-Hung; Tsai, Mong-Hsun; Chen, Pei-Chun; Hsiao, Chuhsing K.; Chuang, Eric Y.; Chang, Li-Yun; Hsieh, Fon-Jou; Lai, Liang-Chuan; Chang, King-Jen

    2011-01-01

    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 co...

  5. High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients

    OpenAIRE

    Bartholomeusz, Chandra; Gonzalez-Angulo, Ana M.; Liu, Ping; Hayashi, Naoki; Lluch, Ana; Ferrer-Lozano, Jaime; Hortobágyi, Gabriel N.

    2012-01-01

    The clinical significance of extracellular signal–related kinase (ERK) was assessed in patients with triple-negative breast cancer versus patients with non–triple negative breast cancer. High ERK-2 levels were correlated with a lower overall survival rate and high phosphorylated mitogen-activated protein kinase levels were correlated with a higher relapse-free survival rate in triple-negative breast cancer patients.

  6. Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti-cancer activity in human triple negative breast carcinoma cells.

    Science.gov (United States)

    Ahir, Manisha; Bhattacharya, Saurav; Karmakar, Soumendu; Mukhopadhyay, Ayan; Mukherjee, Sudeshna; Ghosh, Swatilekha; Chattopadhyay, Sreya; Patra, Prasun; Adhikary, Arghya

    2016-01-01

    Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug-resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-κB favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent. PMID:26520043

  7. 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.

  8. 7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

    Science.gov (United States)

    2013-09-27

    Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Endometrial Carcinoma; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Triple-negative Breast Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  9. Synchronous unilateral triple breast cancers composed of invasive ductal carcinoma, invasive lobular carcinoma, and Paget's disease.

    Science.gov (United States)

    Onoe, Shunsuke; Tsuda, Hitoshi; Akashi-Tanaka, Sadako; Hasebe, Takahiro; Iwamoto, Eriko; Hojo, Takashi; Kinoshita, Takayuki

    2014-03-01

    We report a case of synchronous unilateral triple breast cancers comprising invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and Paget's disease. A 57-year-old woman with a left breast mass was referred to our hospital. Mammography revealed only an isodense area with foci of microcalcification in the lateral area of the left breast. Ultrasonography revealed 2 hypoechoic masses in the outer lower and inner upper areas, and these 2 lesions were diagnosed by core needle biopsy as ILC and IDC, respectively. Left total mastectomy with sentinel lymph node biopsies was performed. In addition to the ILC and IDC, histological examination also identified Paget's disease. Breast cancer often manifests as multiple unilateral lesions; however, it is sometimes difficult to determine whether these tumors have developed multicentrically or have multifocally invaded from an intraductal carcinoma. This case was clearly diagnosed to have occurred multicentrically because of the absence of continuity among the 3 tumors, the presence of a non-invasive component in all 3 tumors, and different histopathological findings. The synchronous unilateral development of ILCs is well known. Cases of synchronous unilateral triple or more breast cancers were reviewed, and their histopathological characteristics, including the incidence of Paget's disease, is discussed. PMID:21140247

  10. 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

  11. Neoadjuvant Chemotherapy in Triple Negative Breast Cancer: An Observational Study.

    Science.gov (United States)

    Shao, Zhiying; Chaudhri, Shalini; Guo, Meng; Zhang, Longzhen; Rea, Daniel

    2016-01-01

    Triple negative breast cancer (TNBC) is a phenotype of breast cancer with aggressive clinical behavior. Because of the absence of optimal treatment, the prognosis of this disease is poor. The main purpose of this study was to detect the response to neoadjuvant chemotherapy (NACT) in a TNBC cohort and compare the long-term survival between patients with and without pathological complete response (pCR). A total of 53 patients diagnosed with TNBC from 2005 to 2013 who received NACT at the University Hospital Birmingham were enrolled in this study. Overall survival (OS) and progression-free survival (PFS) were compared between the pCR group and non-pCR group. Demographic information and clinical or pathologic parameters were also analyzed to explore potential predictive and prognostic factors. Fourteen patients (26.4%) achieved pCR to NACT. In univariate analysis, patients with pCR had longer PFS time (p = 0.013) and OS time (p = 0.054) compared with their counterparts without pCR. In multivariate analysis, the existence of lymphovascular invasion (LVI) significantly reduced OS (HR = 17.404, 95% CI = 2.923-103.644) and PFS (HR = 7.776, 95% CI = 1.645-36.753). The achievement of pCR to NACT can significantly postpone the incidence of disease progression in patients with TNBC. There is not enough evidence showing its influence on ultimate survival. LVI may be a more potent prognostic factor than pCR in the TNBC cohort. PMID:27131315

  12. Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells

    Science.gov (United States)

    Liu, Tongrui; Yacoub, Rami; Taliaferro-Smith, LaTonia D.; Sun, Shi-Yong; Graham, Tisheeka R.; Dolan, Ryan; Lobo, Christine; Tighiouart, Mourad; Yang, Lily; Adams, Amy; O'Regan, Ruth M.

    2016-01-01

    Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effects were synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. PMID:21690228

  13. Triple cancer: chronic lymphocytic leukemia with bladder and prostate carcinoma.

    Science.gov (United States)

    Gajendra, Smeeta; Sharma, Rashi; Sahoo, Manas Kumar

    2015-08-01

    B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoproliferative disorder with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of second malignancies. We report a case of synchronous bladder transitional cell carcinoma (TCC) and prostatic carcinoma with CLL. A 74-year-old male who underwent transurethral resection of the prostate (TURP) for benign prostatic hyperplasia 2 years before, presented with recurrent urinary tract infection. Peripheral blood smear revealed leukocytosis with absolute lymphocytosis (absolute lymphocyte count: 37870 cells/mm³). Flow cytometric immunophenotyping revealed 75% abnormal lymphoid cells which were positive for CD 19, CD5, CD23, CD22, CD200, CD20 (moderate) with lambda light chain restriction and negative for CD3, CD10, FMC7, CD38, CD138, IgM, CD103, CD123. F Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed increased metabolic activity of the left lateral wall of the urinary bladder extending to the left UV junction, adjacent part of trigone and bladder neck region along with multiple heterogeneous enhancing areas with increased FDG avidity within the prostate. Transurethral resection of the bladder tumour by cystoscopy was performed. Histopathology showed high grade, muscle invasive urothelial carcinoma. Due to presence of uptake in the prostate, transurethral resection of the prostate was done and histopathology revealed adenocarcinoma of prostate (prostate specific antigen- positive), Gleason grade III+III and Gleason score 6. A high index of suspicion is required to detect synchronous and metachronous malignancies. Ancillary studies such as immunohistochemistry, flow cytometry and PET/CT are often essential for detection and an accurate diagnosis. PMID:26277675

  14. 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)

    2016-08-24

    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

  15. Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: Involvement of the RB-microRNA axis

    International Nuclear Information System (INIS)

    The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells. Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines. Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple-negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB-468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in

  16. Molecular basis of the triple negative breast cancer

    OpenAIRE

    Ayse Feyda Nursal

    2015-01-01

    Breast cancer is the most common type of cancer in women and more than 1 million breast cancer cases are diagnosed each year all over the world. Breast cancer is a complex and heterogeneous disease in terms of its molecular structure, mutation type, metastase properties, clinical course and therapeutic response. Breast cancer is divided into subtypes based on expression properties of molecular markers as estrogen receptor, progestron receptor, human epidermal growth factor receptor 2. Triple-...

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

    Directory of Open Access Journals (Sweden)

    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

  18. Site-specific relapse pattern of the triple negative tumors in Chinese breast cancer patients

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    Di Genhong

    2009-09-01

    Full Text Available Abstract Background It has been reported that triple negative phenotype is characterized by aggressive clinical history in Western breast cancer patients, however its pattern of metastatic spread had never been reported in the Chinese population. Considering racial disparities, we sought to analyze the spread pattern for different sites of first recurrence in Chinese triple negative breast cancers. Methods A retrospective study of 1662 patients was carried out from a large database of breast cancer patients undergoing surgery between January 1, 2000 and March 31, 2004 at the Cancer Hospital, Fudan University, Shanghai, China. Survival curves were generated using the Kaplan-Meier method and annual relapse hazards were estimated by the hazard function. Results We found a statistically significant difference in relapse-free survival (RFS for locoregional and visceral recurrence (P = 0.007 and P = 0.025, respectively among the triple negative, ERBB2+ and HR+/ERBB2- subgroups in univariate analysis. In the multivariate Cox proportional hazards regression analysis, RFS for either locoregional or visceral relapse in the triple negative category was inferior to that in HR+/ERBB2- patients (P = 0.027 and P = 0.005, respectively, but comparable to that in ERBB2+ women (both P >0.05. Furthermore, the early relapse peak appeared later in the triple negative group than that in the ERBB2+ counterpart for both locoregional and visceral relapse. On the other hand, when compared with triple negative breast cancers, a significantly lower risk of developing bone relapse was discerned for ERBB2+ women (P = 0.048; HR = 0.384, 95% CI 0.148-0.991, with the borderline significance for HR+/ERBB2- breast cancers (P = 0.058; HR = 0.479, 95% CI 0.224-1.025. In terms of bone metastasis, the hazard rate remained higher for the triple negative category than that for the ERBB2+ subtype. Conclusion Based on the site-specific spread pattern in different subgroups, the triple

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

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    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

  20. 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.

  1. Surgery and radiation therapy of triple-negative breast cancers: From biology to clinics.

    Science.gov (United States)

    Bernier, Jacques; Poortmans, Philip M P

    2016-08-01

    Triple negative breast cancer refers to tumours lacking the expression of the three most used tumour markers, namely oestrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). These cancers are known to carry a more dismal prognosis than the other molecular subtypes. Whether a more aggressive local-regional treatment is warranted or not in patients with triple-negative breast cancer is still a matter of debate. Indeed there remain a number of grey zones with respect to the optimization of the extent and the timing of surgery and radiation therapy (RT) in this patient population, also in consideration of the significant heterogeneity in biological behaviour and response to treatment identified for these tumours. The objective of this review is to provide an insight into the biological and clinical behaviour of triple-negative breast cancers and revisit the most recent advances in their management, focussing on local-regional treatments. PMID:27318170

  2. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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. Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma

    OpenAIRE

    Qian, Chun-Yu; Wang, Kai-Li; Fang, Fan-Fu; Gu, Wei; Huang, Feng; Wang, Fu-Zhe; Li, Bai; Wang, Li-Na

    2015-01-01

    Hepatocellular carcinoma (HCC) is a highly malignant disease, and its outcome of routine therapies is poor. Comprehensive treatment including gene therapy is an important way to improve patients’ prognosis and survival. In this study, we successfully constructed a triple-controlled cancer-selective oncolytic adenovirus, QG511-HA-Melittin, carrying melittin gene, in which the hybrid promoter, hypoxia-response element (HRE)-AFP promoter, was used to control viral E1a expression targeting AFP-po...

  6. 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.)

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

    International Nuclear Information System (INIS)

    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. 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. Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). 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

  8. 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.

  9. Androgen receptor expression as a prognostic and predictive marker in triple-negative breast cancer patients

    OpenAIRE

    Fatma Zakaria; Nehal El-Mashad; Dareen Mohamed

    2016-01-01

    Purpose: It is clear that triple-negative breast cancer (TNBC) tumors are heterogeneous group, but clinically important sub-sets have begun to emerge. We investigate the immunohistochemical expression of androgen receptor (AR) among those hormonal insensitive groups which have only the option of chemotherapy. Exploiting this knowledge for therapy has been challenging. Patients & methods: Seventy seven patients with TNBC subtype, treated from January 2009 until February 2011 were evaluated ...

  10. An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer

    OpenAIRE

    Chindo Hicks; Ranjit Kumar; Antonio Pannuti; Kandis Backus; Alexandra Brown; Jesus Monico; Lucio Miele

    2013-01-01

    Genome-wide association studies (GWAS) have identified genetic variants associated with an increased risk of developing breast cancer. However, the association of genetic variants and their associated genes with the most aggressive subset of breast cancer, the triple-negative breast cancer (TNBC), remains a central puzzle in molecular epidemiology. The objective of this study was to determine whether genes containing single nucleotide polymorphisms (SNPs) associated with an increased risk of ...

  11. Epithelial-mesenchymal transition and its regulators are major targets of triple-negative breast cancer

    OpenAIRE

    Al Moustafa, Ala-Eddin

    2013-01-01

    Triple negative breast cancers (TNBCs) represent a distinct subtype of breast cancers that are associated with early recurrence and an aggressive metastatic progression of the disease and consequently poor outcome. Recently, it was reported that c-Met growth factor receptor is overexpressed in around 52% of TNBCs. On the other hand, it is known that c-Met signaling pathways initiate the epithelial–mesenchymal transition (EMT) phenomenon, which is described as a crucial event during cancer met...

  12. NEW STRATEGIES FOR TRIPLE NEGATIVE BREAST CANCER – DECIPHERING THE HETEROGENEITY

    OpenAIRE

    Mayer, Ingrid A.; Abramson, Vandana G.; Lehmann, Brian D.; Jennifer A Pietenpol

    2014-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression (GE) analyses recently identified six distinct TNBC subtypes, each displaying a unique biology. Exploring novel approaches to treatment of these subtypes is critical, since less than 30% of women with metastatic breast cancer survive five years and virtually all women with metastatic TNBC will ultimately die of their disease despite systemic therapy. To date, not a single targeted therapy has been approved for th...

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

    OpenAIRE

    Collina, Francesca; Di Bonito, Maurizio; Li Bergolis, Valeria; De Laurentiis, Michelino; Vitagliano, Carlo; Cerrone, Margherita; Nuzzo, Francesco; Cantile, Monica; Botti, Gerardo

    2015-01-01

    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...

  14. GATA3 Inhibits Lysyl Oxidase Mediated Metastases of Human Basal Triple-Negative Breast Cancer Cells

    OpenAIRE

    Chu, Isabel M.; Michalowski, Aleksandra M.; Hoenerhoff, Mark; Kornelia M. Szauter; Luger, Dror; Sato, Misako; Flanders, Kathy; Oshima, Akira; Csiszar, Katalin; Green, Jeffrey E

    2011-01-01

    Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative type breast cancers (BTNBC) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that the expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although t...

  15. Clinical efficacy of local targeted chemotherapy for triple-negative breast cancer

    International Nuclear Information System (INIS)

    The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m2]; E: epirubicin [90 mg/m2]; F: 5-fluorouracil [600 mg/m2]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses

  16. Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

    Science.gov (United States)

    Silva, Vera L; Ferreira, Debora; Nobrega, Franklin L; Martins, Ivone M; Kluskens, Leon D; Rodrigues, Ligia R

    2016-01-01

    The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS) were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy. PMID:27548261

  17. Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition.

    Science.gov (United States)

    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. PMID:25792283

  18. 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.

  19. Phototheranostics of CD44-positive cell populations in triple negative breast cancer

    OpenAIRE

    Jiefu Jin; Balaji Krishnamachary; Yelena Mironchik; Hisataka Kobayashi; Bhujwalla, Zaver M.

    2016-01-01

    Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer that has limited treatment options. Its high rates of recurrence and metastasis have been associated, in part, with a subpopulation of breast cancer stem-like cells that are resistant to conventional therapies. A compendium of markers such as CD44high/CD24low, and increased expression of the ABCG2 transporter and increased aldehyde dehydrogenase (ALDH1), have been associated with these cells. We developed...

  20. Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth

    OpenAIRE

    Barbie, Thanh U.; Alexe, Gabriela; Aref, Amir R.; Li, Shunqiang; Zhu, Zehua; Zhang, Xiuli; Imamura, Yu; Thai, Tran C.; Huang, Ying; Bowden, Michaela; Herndon, John; Cohoon, Travis J.; Fleming, Timothy; Tamayo, Pablo; Mesirov, Jill P.

    2014-01-01

    Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase–related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impair...

  1. 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.

  2. Comparison of molecular subtype distribution in triple-negative inflammatory and non-inflammatory breast cancers

    OpenAIRE

    Masuda, Hiroko; Keith A. Baggerly; Ying WANG; Iwamoto, Takayuki; Brewer, Takae; Pusztai, Lajos; Kai, Kazuharu; Kogawa, Takahiro; Finetti, Pascal; Birnbaum, Daniel; Dirix, Luc; Wendy A Woodward; Reuben, James M.; Krishnamurthy, Savitri; Symmans, W Fraser

    2013-01-01

    Introduction Because of its high rate of metastasis, inflammatory breast cancer (IBC) has a poor prognosis compared with non-inflammatory types of breast cancer (non-IBC). In a recent study, Lehmann and colleagues identified seven subtypes of triple-negative breast cancer (TNBC). We hypothesized that the distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. We determined the subtypes and compared clinical outcomes by subtype in TN-IBC and TN-non-IBC patients. Methods We determi...

  3. Triple-Negative Breast Cancer: An Update on Neoadjuvant Clinical Trials

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC

  4. Carboplatin and Paclitaxel Albumin-Stabilized Nanoparticle Formulation Before Surgery in Treating Patients With Locally Advanced or Inflammatory Triple Negative Breast Cancer

    Science.gov (United States)

    2016-07-14

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

  5. Phosphorylated mTOR is associated to androgen receptor expression in early triple-negative breast cancer.

    Science.gov (United States)

    Pistelli, M; Ballatore, Z; Santinelli, A; Biscotti, T; Piva, F; Occhipinti, G; Della Mora, A; Pagliacci, A; Battelli, N; Bastianelli, L; De Lisa, M; Bracci, R; Maccaroni, E; Berardi, R; Cascinu, S

    2016-08-01

    The significance of phosphorylated mTOR (p-mTOR) expression is unknown in triple-negative breast carcinoma (TNBC). The aims of the present study were to assess the expression of p-mTOR in early TNBC and to evaluate possible correlations between androgen receptor (AR) expression, clinicopathological parameters and disease outcome. Between January 2009 and December 2013, all consecutive patients who were diagnosed and completed the treatment of invasive TNBC at our institution were eligible for this analysis. Patients with stage IV disease were excluded. The evaluation of p-mTOR immunohistochemical staining was semi-quantitatively considering both the percentage of positive tumor cells (range, 0-100%) and staining intensity (range, 0-3+). Ninety-eight TNBC patients were included. Approximately 33% of cases were p-mTOR positive and there was no association between positive immunostaining for p-mTOR and DFS (p=0.74) and OS (p=0.81). p-mTOR positivity was associated with small tumor size (p=0.03) and AR expression (p=0.04). High expression of p-mTOR may drive tumor proliferation in almost one third of TNBC. The biological association between mTOR activation and AR pathway suggests that there may exist a subgroup of TNBC in which the combination of both AR antagonism and mTOR inhibition should have a synergistic effect on cell growth and tumor progression. PMID:27350136

  6. Downregulation of microRNA-206 promotes invasion and angiogenesis of triple negative breast cancer.

    Science.gov (United States)

    Liang, Zhongxing; Bian, Xuehai; Shim, Hyunsuk

    2016-08-26

    Triple negative breast tumors don't respond to Tamoxifen and Herceptin, two of the most effective medications for treating breast cancer. Additionally, triple negative breast cancer (TNBC) intrinsically resists or will eventually acquire resistance to chemotherapy. The purpose of this study is to understand better the molecular basis of TNBC as well as develop new therapeutic strategies against it. Here, we analyzed miRNA-206 expression levels in breast cancer cell lines and tissues. In addition, we investigated whether miR-206 mimics inhibited TNBC tumor invasion and angiogenesis. The results showed that miR-206 was downregulated in TNBC compared to non-TNBC cell lines and tissues. Additionally, the decreased levels of miR-206 were inversely consistent with expression levels of VEGF. Furthermore, the forced expression of miR-206 in the mimic-transfected TNBC cells downregulated VEGF, MAPK3, and SOX9 expression levels. The miR-206 mimics inhibited TNBC breast cell invasion and angiogenesis. These findings demonstrate for the first time the involvement of miRNA-206 in TNBC invasion and angiogenesis and suggest that miR-206 may be an efficient agent for therapy of TNBC. PMID:27318091

  7. Outcome for Patients with Triple-Negative Breast Cancer Is Not Dependent on Race/Ethnicity

    Directory of Open Access Journals (Sweden)

    Quyen D. Chu

    2012-01-01

    Full Text Available Introduction. Triple negative breast cancer (TNBC is biologically aggressive and is associated with a worse prognosis. To understand the impact of race/ethnicity on outcome for patients with TNBC, confounding factors such as socioeconomic status (SES need to be controlled. We examined the impact of race/ethnicity on a cohort of patients of low SES who have TNBC. Methods. 786 patients with Stage 0–III breast cancer were evaluated. Of these, 202 patients had TNBC (26%. Primary endpoints were cancer recurrence and death. ZIP code-based income tract and institutional financial data were used to assess SES. Data were analyzed using Kaplan-Meier survival analysis, log-rank tests, Cox Proportional hazard regression, chi square test, and t-tests. A P value ≤0.05 was considered statistically significant. Results. Of the 468 African-Americans (60% in the database, 138 had TNBC; 64 of 318 Caucasians had TNBC. 80% of patients had an annual income of ≤$20,000. The 5-year overall survival was 77% for African-American women versus 72% for Caucasian women (=0.95. On multivariate analysis, race/ethnicity had an impact on disease-free survival (=0.027 but not on overall survival (=0.98. Conclusion. In a predominantly indigent population, race/ethnicity had no impact on overall survival for patients with triple negative breast cancer.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer

    Science.gov (United States)

    Bowie, Michelle; Pilie, Patrick; Wulfkuhle, Julia; Lem, Siya; Hoffman, Abigail; Desai, Shraddha; Petricoin, Emanuel; Carter, Amira; Ambrose, Adrian; Seewaldt, Victoria; Yu, Dihua; Ibarra Drendall, Catherine

    2015-01-01

    AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine (FLX) in representative molecular subtypes of breast cancer. METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative (SUM149PT) and luminal (T47D and Au565) cancer cells and non-transformed MCF10A were investigated. Reverse phase protein microarray (RPPM) was performed with and without 10 μmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins. RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10A. In comparison to the other lines, cell growth reduction in SUM149PT coincided with significant induction of endoplasmic reticulum (ER) stress and autophagy after 24 and 48 h of 10 μmol/L FLX, resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker, cleaved microtubule-associated protein 1 light chain 3, in SUM149PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently, the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis, growth arrest at the G1 phase, autophagy, and caspase-7-mediated cell death. CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy, resulting in death of aggressive triple negative breast cancer SUM149PT. PMID:26677444

  13. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

    Science.gov (United States)

    TUOMELA, JOHANNA; SANDHOLM, JOUKO; KAUPPILA, JOONAS H.; LEHENKARI, PETRI; HARRIS, KEVIN W.; SELANDER, KATRI S.

    2013-01-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  14. Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer

    International Nuclear Information System (INIS)

    Mutational analysis of the KRAS gene has recently been established as a complementary in vitro diagnostic tool for the identification of patients with colorectal cancer who will not benefit from anti-epidermal growth factor receptor (EGFR) therapies. Assessment of the mutation status of KRAS might also be of potential relevance in other EGFR-overexpressing tumors, such as those occurring in breast cancer. Although KRAS is mutated in only a minor fraction of breast tumors (5%), about 60% of the basal-like subtype express EGFR and, therefore could be targeted by EGFR inhibitors. We aimed to study the mutation frequency of KRAS in that subtype of breast tumors to provide a molecular basis for the evaluation of anti-EGFR therapies. Total, genomic DNA was obtained from a group of 35 formalin-fixed paraffin-embedded, triple-negative breast tumor samples. Among these, 77.1% (27/35) were defined as basal-like by immunostaining specific for the established surrogate markers cytokeratin (CK) 5/6 and/or EGFR. KRAS mutational status was determined in the purified DNA samples by Real Time (RT)-PCR using primers specific for the detection of wild-type KRAS or the following seven oncogenic somatic mutations: Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp. We found no evidence of KRAS oncogenic mutations in all analyzed tumors. This study indicates that KRAS mutations are very infrequent in triple-negative breast tumors and that EGFR inhibitors may be of potential benefit in the treatment of basal-like breast tumors, which overexpress EGFR in about 60% of all cases

  15. 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

  16. Differential cytotoxic and radiosensitizing effects of silver nanoparticles on triple-negative breast cancer and non-triple-negative breast cells

    Directory of Open Access Journals (Sweden)

    Swanner J

    2015-06-01

    Full Text Available Jessica Swanner,1 Jade Mims,2 David L Carroll,3,4 Steven A Akman,5 Cristina M Furdui,2 Suzy V Torti,6 Ravi N Singh1,7 1Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 2Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 3Center for Nanoscale and Molecular Materials, Wake Forest University, Winston-Salem, NC, USA; 4Department of Physics, Wake Forest University, Winston-Salem, NC, USA; 5Roper St Francis Cancer Care, Charleston, SC, USA; 6Department of Molecular Biology and Biophysics, University of Connecticut Health Center, CT, USA; 7Comprehensive Cancer Center of Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Identification of differential sensitivity of cancer cells as compared to normal cells has the potential to reveal a therapeutic window for the use of silver nanoparticles (AgNPs as a therapeutic agent for cancer therapy. Exposure to AgNPs is known to cause dose-dependent toxicities, including induction of oxidative stress and DNA damage, which can lead to cell death. Triple-negative breast cancer (TNBC subtypes are more vulnerable to agents that cause oxidative stress and DNA damage than are other breast cancer subtypes. We hypothesized that TNBC may be susceptible to AgNP cytotoxicity, a potential vulnerability that could be exploited for the development of new therapeutic agents. We show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages. AgNPs induced more DNA and oxidative damage in TNBC cells than in other breast cells. In vitro and in vivo studies showed that AgNPs reduce TNBC growth and improve radiation therapy. These studies show that unmodified AgNPs act as a self-therapeutic agent with a combination of selective cytotoxicity and radiation dose-enhancement effects in TNBC

  17. KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer.

    Science.gov (United States)

    Singel, Stina M; Cornelius, Crystal; Zaganjor, Elma; Batten, Kimberly; Sarode, Venetia R; Buckley, Dennis L; Peng, Yan; John, George B; Li, Hsiao C; Sadeghi, Navid; Wright, Woodring E; Lum, Lawrence; Corson, Timothy W; Shay, Jerry W

    2014-03-01

    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. PMID:24784001

  18. Prognostic Value of Triple-Negative Phenotype at the Time of Locally Recurrent, Conservatively Treated Breast Cancer

    International Nuclear Information System (INIS)

    Purpose: To evaluate the prognostic value of triple-negative (TN) ER, PR, Her2/neu basal-like carcinoma of the breast, at the time of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation treatment (RT). Methods and Materials: A tissue microarray was constructed of 47 IBTR specimens of patients who experienced an IBTR after conservative surgery and RT that were processed and stained for ER, PR, and HER2/neu. Results: At a median post-recurrence follow-up of 7.5 years, the 5-year overall survival (OS) and disease metastasis-free survival (DMFS) after IBTR were 91.4% and 83.0%, respectively. Median time to tumor recurrence (TTR) and IBTR was shorter in the TN phenotype (3.88 vs. 5.00 years; p = 0.09). The TN tumors were not associated with size of local recurrence or recurrence elsewhere in the breast. Despite administration of standard chemotherapy at the time of IBTR, the 5-year DMFS and 5-year OS for the TN cohort were 48.6% and 72.7%, respectively. The 5-year DMFS was 48.6% for TN tumors and 90.8% for non-TN tumors (p < 0.01). By univariate analysis, significant factors associated with poor 5-year DMFS and OS after IBTR included: TN phenotype (p < 0.01), TTR 3 years or less (p < 0.01), local recurrence at or near the original tumor site (p = 0.08). In multivariate analysis, TN was a significant independent predictor of poorer 5-year DMFS (relative risk, 5.91; 95% confidence interval, 1.83-19.01; p < 0.01) after IBTR. Conclusions: Although patients experiencing an IBTR have a relatively favorable prognosis, those with IBTR events of the TN phenotype had a rather poor prognosis despite receiving standard chemotherapy. Strategies with novel systemic therapies to improve outcomes in patients experiencing IBTR of the TN phenotype are warranted

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

    Science.gov (United States)

    Liu, Ning Qing; De Marchi, Tommaso; Timmermans, Annemieke; Trapman-Jansen, Anita M. A. C.; Foekens, Renée; Look, Maxime P.; Smid, Marcel; van Deurzen, Carolien H. M.; Span, Paul N.; Sweep, Fred C. G. J.; Brask, Julie Benedicte; Timmermans-Wielenga, Vera; Foekens, John A.; Martens, John W. M.; Umar, Arzu

    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 associated to its expression through gene set enrichment analysis (GSEA). A total of 461 TNBC paraffin-embedded tissues were collected from different academic hospitals in Europe, incorporated into tissue micro-arrays (TMA), and stained for CMPK1 expression. We also collected gene expression data of 60 samples, which were also present in the TMA, for GSEA correlation analysis. CMPK1 IHC staining showed both cytoplasmic and nuclear components. While cytoplasmic CMPK1 did not show any association to metastasis free survival (MFS), nuclear CMPK1 was associated to poor prognosis independently from other prognostic factors in stratified Cox regression analyses. GSEA correlation analysis of the nuclear CMPK1-stratified gene expression dataset showed a significant enrichment of extracellular matrix (ECM; positive correlation) and cell cycle (negative correlation) associated genes. We have shown here that nuclear CMPK1 is indicative of poor prognosis in TNBCs and that its expression may be related to dysregulation of ECM and cell cycle molecules. PMID:27558661

  20. Caffeic Acid Phenethyl Ester and Ethanol Extract of Propolis Induce the Complementary Cytotoxic Effect on Triple-Negative Breast Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Anna Rzepecka-Stojko

    2015-05-01

    Full Text Available Chemotherapy of breast cancer could be improved by bioactive natural substances, which may potentially sensitize the carcinoma cells’ susceptibility to drugs. Numerous phytochemicals, including propolis, have been reported to interfere with the viability of carcinoma cells. We evaluated the in vitro cytotoxic activity of ethanol extract of propolis (EEP and its derivative caffeic acid phenethyl ester (CAPE towards two triple-negative breast cancer (TNBC cell lines, MDA-MB-231 and Hs578T, by implementation of the MTT and lactate dehydrogenase (LDH assays. The morphological changes of breast carcinoma cells were observed following exposure to EEP and CAPE. The IC50 of EEP was 48.35 µg∙mL−1 for MDA-MB-23 cells and 33.68 µg∙mL−1 for Hs578T cells, whereas the CAPE IC50 was 14.08 µM and 8.01 µM for the MDA-MB-231 and Hs578T cell line, respectively. Here, we report that propolis and CAPE inhibited the growth of the MDA-MB-231 and Hs578T lines in a dose-dependent and exposure time-dependent manner. EEP showed less cytotoxic activity against both types of TNBC cells. EEP and, particularly, CAPE may markedly affect the viability of breast cancer cells, suggesting the potential role of bioactive compounds in chemoprevention/chemotherapy by potentiating the action of standard anti-cancer drugs.

  1. Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value

    Science.gov (United States)

    Stirzaker, Clare; Zotenko, Elena; Clark, Susan J

    2016-01-01

    abstract Analysis of cancer methylomes has dramatically changed our concept of the potential of diagnostic and prognostic methylation biomarkers in disease stratification. Through whole-genome methylation capture sequencing of triple-negative breast cancers (TNBCs) we recently identified differentially methylated regions with diagnostic and prognostic value that promise to stratify TNBCs for more personalized management. PMID:27308556

  2. High Throughput Screening of Natural Phenolic Compounds Against Migration of Metastatic Triple-Negative Breast Cancer (TNBC) Cells

    OpenAIRE

    Nasrollahi, Samila

    2013-01-01

    In this report, we hypothesize that natural phenolic compounds may present a new class of chemotherapeutics against migration of metastatic triple-negative breast cancers (TNBC). In this project we will screen a small library of phenolic compounds to test this hypothesis, identify compounds that show efficacy against TNBC cell migration, and elucidate underlying molecular mechanisms.

  3. 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.

  4. 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.

  5. Triple angiokinase inhibition, tumour hypoxia and radiation response of FaDu human squamous cell carcinomas

    International Nuclear Information System (INIS)

    Background and purpose: To test the effect of BIBF 1120, a novel small molecule inhibitor of multiple angiogenic receptor tyrosine kinases, on the hypoxia and radiation response of tumours. Materials and methods: Poorly differentiated human squamous cell carcinoma FaDu growing in nude mice was treated with BIBF 1120 and investigated by functional histology. To test the effect of BIBF 1120 on the radiobiological hypoxic fraction (rHF), the number and intrinsic radiation sensitivity of tumour stem cells and the outcome after fractionated irradiation, a series of local tumour control assays were performed. Results: BIBF 1120 significantly reduced the vessel area, vessel area with a perfusion signal and tumour growth rate but did not affect tumour hypoxia or the number and intrinsic radiation sensitivity of tumour stem cells. Concurrent BIBF 1120 had no effect on local tumour control after fractionated irradiation. Conclusion: Triple angiokinase inhibition resulted in a clear-cut decrease of angiogenesis, vessel area with a perfusion signal and tumour growth but did not change tumour hypoxia or radiation response of tumour stem cells. Further experiments into mechanisms of interaction between anti-angiogenic strategies and irradiation appear to be necessary to better define and exploit the potential of this strategy to improve local tumour control after fractionated radiotherapy.

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

    International Nuclear Information System (INIS)

    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 angio genesis. 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

  7. 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.

  8. Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer.

    Science.gov (United States)

    Hamilton, Duane H; Roselli, Mario; Ferroni, Patrizia; Costarelli, Leopoldo; Cavaliere, Francesco; Taffuri, Mariateresa; Palena, Claudia; Guadagni, Fiorella

    2016-10-01

    Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provide rationale for using brachyury-targeting immunotherapy approaches for the treatment of TNBC. PMID:27580659

  9. 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.

  10. Piperlongumine for Enhancing Oral Bioavailability and Cytotoxicity of Docetaxel in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Patel, Ketan; Chowdhury, Nusrat; Doddapaneni, Ravi; Boakye, Cedar H A; Godugu, Chandraiah; Singh, Mandip

    2015-12-01

    Very low oral bioavailability due to extensive pre-systemic metabolism and P-gp efflux has constrained the oral metronomic chemotherapy of docetaxel (DTX). There is tremendous need of compounds facilitating oral delivery of DTX. The research was aimed to investigate the effect of piperlongumine (PPL) on human liver microsomal metabolism, Caco-2 permeability, and cytotoxicity of DTX in triple-negative breast cancer cell lines. Reduction in testosterone and DTX metabolism (twofold increase in half-life) by PPL was comparable to the standard CYP3A4 inhibitor, cyclosporine A. P-gp efflux ratio of DTX across caco-2 monolayer was reduced from 2.37 to 1.52 on co-incubation with PPL. The IC50 value of DTX was reduced three to five times and combination index values in all the cell lines were below 0.6. PPL at non-cytotoxic concentration showed significant enhancement of the antimigration effect of DTX. Expression of tumor markers such as survivin, bcl2, C-myc, and cyclin D1 were downregulated to a great extent with enhanced p53 expression when treated with combination instead of individual drug. Co-treatment with PPL led to 1.68-fold enhancement in DTX bioavailability in SD rats. PPL could be a potential candidate in overcoming the obstacles associated with oral DTX delivery with synergistic anticancer activity. PMID:26372815

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

    Directory of Open Access Journals (Sweden)

    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.

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

    International Nuclear Information System (INIS)

    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.

  13. GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.

    Science.gov (United States)

    Louie, Sharon M; Grossman, Elizabeth A; Crawford, Lisa A; Ding, Lucky; Camarda, Roman; Huffman, Tucker R; Miyamoto, David K; Goga, Andrei; Weerapana, Eranthie; Nomura, Daniel K

    2016-05-19

    Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways. PMID:27185638

  14. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. Microglandular adenosis: a prime suspect in triple-negative breast cancer development.

    Science.gov (United States)

    Tsang, Julia Ys; Tse, Gary Mk

    2016-06-01

    Microglandular adenosis (MGA) and atypical MGA (AMGA) are unusual lesions of the breast. They were once regarded as benign proliferative lesions and innocent bystanders. Several lines of evidence suggested that they could be neoplastic, clonal lesions and a non-obligate precursor for triple-negative breast cancers (TNBC). Recent work published in The Journal of Pathology by Guerini-Rocco and colleagues provided further evidence regarding the precursor-product relationship between MGA/AMGA and TNBC. Using a massively parallel sequencing approach, they demonstrated that MGA/AMGA, particularly those associated with TNBC, could be clonal neoplastic lesions showing clonal non-synonymous mutations, but none in pure MGA. Importantly, those alterations were observed in the associated TNBC. They were also able to identify recurrent alterations in TP53 in those MGA/AMGA cases as well as their associated TNBC. The findings, in conjunction with others, underscore the significance for MGA in clinical diagnosis. The potential of a benign lesion to progress into an aggressive malignant tumour implies that modification of the current management approach may be necessary. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27061094

  18. 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. PMID:27081325

  19. 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.

  20. 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.

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

    International Nuclear Information System (INIS)

    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

  2. Phototheranostics of CD44-positive cell populations in triple negative breast cancer

    Science.gov (United States)

    Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena; Kobayashi, Hisataka; Bhujwalla, Zaver M.

    2016-01-01

    Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer that has limited treatment options. Its high rates of recurrence and metastasis have been associated, in part, with a subpopulation of breast cancer stem-like cells that are resistant to conventional therapies. A compendium of markers such as CD44high/CD24low, and increased expression of the ABCG2 transporter and increased aldehyde dehydrogenase (ALDH1), have been associated with these cells. We developed a CD44-targeted monoclonal antibody photosensitizer conjugate for combined fluorescent detection and photoimmunotherapy (PIT) of CD44 expressing cells in TNBC. The CD44-targeted conjugate demonstrated acute cell killing of breast cancer cells with high CD44 expression. This cell death process was dependent upon CD44-specific cell membrane binding combined with near-infrared irradiation. The conjugate selectively accumulated in CD44-positive tumors and caused dramatic tumor shrinkage and efficient elimination of CD44-positive cell populations following irradiation. This novel phototheranostic strategy provides a promising opportunity for the destruction of CD44-positive populations that include cancer stem-like cells, in locally advanced primary and metastatic TNBC. PMID:27302409

  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. Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth.

    Science.gov (United States)

    Barbie, Thanh U; Alexe, Gabriela; Aref, Amir R; Li, Shunqiang; Zhu, Zehua; Zhang, Xiuli; Imamura, Yu; Thai, Tran C; Huang, Ying; Bowden, Michaela; Herndon, John; Cohoon, Travis J; Fleming, Timothy; Tamayo, Pablo; Mesirov, Jill P; Ogino, Shuji; Wong, Kwok-Kin; Ellis, Matthew J; Hahn, William C; Barbie, David A; Gillanders, William E

    2014-12-01

    Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase-related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds. PMID:25365225

  5. Phototheranostics of CD44-positive cell populations in triple negative breast cancer.

    Science.gov (United States)

    Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena; Kobayashi, Hisataka; Bhujwalla, Zaver M

    2016-01-01

    Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer that has limited treatment options. Its high rates of recurrence and metastasis have been associated, in part, with a subpopulation of breast cancer stem-like cells that are resistant to conventional therapies. A compendium of markers such as CD44(high)/CD24(low), and increased expression of the ABCG2 transporter and increased aldehyde dehydrogenase (ALDH1), have been associated with these cells. We developed a CD44-targeted monoclonal antibody photosensitizer conjugate for combined fluorescent detection and photoimmunotherapy (PIT) of CD44 expressing cells in TNBC. The CD44-targeted conjugate demonstrated acute cell killing of breast cancer cells with high CD44 expression. This cell death process was dependent upon CD44-specific cell membrane binding combined with near-infrared irradiation. The conjugate selectively accumulated in CD44-positive tumors and caused dramatic tumor shrinkage and efficient elimination of CD44-positive cell populations following irradiation. This novel phototheranostic strategy provides a promising opportunity for the destruction of CD44-positive populations that include cancer stem-like cells, in locally advanced primary and metastatic TNBC. PMID:27302409

  6. Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer.

    Science.gov (United States)

    Cuenca-López, María Dolores; Serrano-Heras, Gemma; Montero, Juan Carlos; Corrales-Sánchez, Verónica; Gomez-Juarez, Mónica; Gascón-Escribano, Maria José; Morales, Jorge Carlos; Voisin, Veronique; Núñez, Luz Elena; Morís, Francisco; Bader, Gary D; Pandiella, Atanasio; Ocaña, Alberto

    2015-09-29

    Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy. PMID:26314846

  7. miRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Andrea Mathe

    2015-11-01

    Full Text Available Triple negative breast cancer (TNBC is characterised by the lack of receptors for estrogen (ER, progesterone (PR, and human epidermal growth factor 2 (HER2. Since it cannot be treated by current endocrine therapies which target these receptors and due to its aggressive nature, it has one of the worst prognoses of all breast cancer subtypes. The only treatments remain chemo- and/or radio-therapy and surgery and because of this, novel biomarkers or treatment targets are urgently required to improve disease outcomes. MicroRNAs represent an attractive candidate for targeted therapies against TNBC, due to their natural ability to act as antisense interactors and regulators of entire gene sets involved in malignancy and their superiority over mRNA profiling to accurately classify disease. Here we review the current knowledge regarding miRNAs as biomarkers in TNBC and their potential use as therapeutic targets in this disease. Further, we review other epigenetic changes and interactions of these changes with microRNAs in this breast cancer subtype, which may lead to the discovery of new treatment targets for TNBC.

  8. Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R.

    Science.gov (United States)

    de Lint, Klaas; Poell, Jos B; Soueidan, Hayssam; Jastrzebski, Katarzyna; Vidal Rodriguez, Jordi; Lieftink, Cor; Wessels, Lodewyk F A; Beijersbergen, Roderick L

    2016-07-01

    Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAi-based genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. ©2016 AACR. PMID:27196766

  9. 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.

  10. 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.

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

    International Nuclear Information System (INIS)

    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

  12. A Study Evaluating INIPARIB in Combination With Chemotherapy to Treat Triple Negative Breast Cancer Brain Metastasis

    Science.gov (United States)

    2016-02-17

    Estrogen Receptor Negative (ER-Negative) Breast Cancer; Progesterone Receptor Negative (PR-Negative) Breast Cancer; Human Epidermal Growth Factor Receptor 2 Negative (HER2-Negative) Breast Cancer; Brain Metastases

  13. The diagnostic utility of the triple markers Napsin A, TTF-1, and PAX8 in differentiating between primary and metastatic lung carcinomas.

    Science.gov (United States)

    El-Maqsoud, Nehad M R Abd; Tawfiek, Ehab Rifat; Abdelmeged, Ayman; Rahman, Mohamed Fathy Abdel; Moustafa, Alaa A E

    2016-03-01

    Napsin A and thyroid transcription factor-1 (TTF-1) are useful biomarkers for differentiating lung adenocarcinoma from squamous cell carcinoma and also for differentiating primary lung adenocarcinoma from metastatic lung carcinoma. Pair-boxed 8 (PAX8) can help in distinguishing primary lung carcinoma from metastatic carcinomas and help to determine the primary sites of metastatic carcinomas. Immunohistochemistry for Napsin A, TTF-1, and PAX8 were performed on 193 cases of carcinoma: 50 primary lung carcinoma and 143 carcinomas from other sites. Napsin A and TTF-1 were positive in 54, 52 % of lung carcinomas cases, respectively. While in adenocarcinoma cases, their expressions were 86.7 and 83.3 %, respectively. PAX8 was negative in all lung carcinomas. TTF-1 and PAX8 were positive in 93.3 and 96.7 % of thyroid carcinoma cases and in 87.5 and 93.8 % of papillary carcinoma respectively, and both were positive in 100 % of follicular carcinoma. Napsin A was negative in all thyroid carcinomas. Napsin A and PAX8 were positive in 50 and 93.3 % of renal carcinoma cases and in 81.8 and 100 % of papillary carcinoma, 38.5 and 92.3 % of clear cell carcinoma, and 16.7 and 83.3 % of chromophobe carcinoma respectively. TTF-1 was negative in all renal carcinomas. PAX8 was positive in 80 % of ovarian carcinoma cases; 100 and 60 % of serous mucinous carcinomas, respectively. It was also positive in 100 % of endometrial carcinoma. Napsin A and TTF-1 were negative in both ovarian and endometrial carcinomas. Our data demonstrated that combined use of Napsin A, TTF-1, and PAX8 may help in differentiating between primary lung adenocarcinoma and metastatic lung carcinomas. PMID:26427663

  14. Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.

    Science.gov (United States)

    Thakkar, A; Wang, B; Picon-Ruiz, M; Buchwald, P; Ince, Tan A

    2016-05-01

    Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy. PMID:27120467

  15. Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling

    International Nuclear Information System (INIS)

    The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype. The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression. We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators. Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor. PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways. AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRβ in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR. Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRβ and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways. AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition. Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRβ or Erk1/2 for future development

  16. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities.

    Science.gov (United States)

    Craig, David W; O'Shaughnessy, Joyce A; Kiefer, Jeffrey A; Aldrich, Jessica; Sinari, Shripad; Moses, Tracy M; Wong, Shukmei; Dinh, Jennifer; Christoforides, Alexis; Blum, Joanne L; Aitelli, Cristi L; Osborne, Cynthia R; Izatt, Tyler; Kurdoglu, Ahmet; Baker, Angela; Koeman, Julie; Barbacioru, Catalin; Sakarya, Onur; De La Vega, Francisco M; Siddiqui, Asim; Hoang, Linh; Billings, Paul R; Salhia, Bodour; Tolcher, Anthony W; Trent, Jeffrey M; Mousses, Spyro; Von Hoff, Daniel; Carpten, John D

    2013-01-01

    Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer. PMID:23171949

  17. Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment.

    Science.gov (United States)

    Bodenstine, Thomas M; Chandler, Grace S; Reed, David W; Margaryan, Naira V; Gilgur, Alina; Atkinson, Janis; Ahmed, Nida; Hyser, Matthew; Seftor, Elisabeth A; Strizzi, Luigi; Hendrix, Mary J C

    2016-05-01

    Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/adjuvant chemotherapy. To better understand the growth advantage of TNBC - in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens - by altering signaling pathways critical to cellular survival. PMID:27007464

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

    Science.gov (United States)

    Inoue, Satoshi; Patil, Rameshwar; Portilla-Arias, Jose; Ding, Hui; Konda, Bindu; Espinoza, Andres; Mongayt, Dmitriy; Markman, Janet L; Elramsisy, Adam; Phillips, H Westley; Black, Keith L; Holler, Eggehard; Ljubimova, Julia Y

    2012-01-01

    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; Pnanodrugs for treatment of TNBC. PMID:22355336

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

    Science.gov (United States)

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

    2016-08-01

    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 (4µM) 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

  20. Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells.

    Science.gov (United States)

    Huang, Ou; Zhang, Weili; Zhi, Qiaoming; Xue, Xiaofeng; Liu, Hongchun; Shen, Daoming; Geng, Meiyu; Xie, Zuoquan; Jiang, Min

    2015-04-01

    Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients. PMID:25304315

  1. Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer

    OpenAIRE

    Xinhong Wu; Bo Luo; Shaozhong Wei; Yan Luo; Yaojun Feng; Juan Xu; Wei Wei

    2013-01-01

    Aim: To investigate the treatment efficiency of whole brain irradiation combined with precise radiotherapy on triple-negative (TN) phenotype breast cancer patients with brain metastases and their survival times. Materials and Methods : A total of 112 metastatic breast cancer patients treated with whole brain irradiation and intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT) were analyzed. Thirty-seven patients were of TN phenotype. Objective response rates were co...

  2. Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

    OpenAIRE

    Ljubimova, Julia Y; Portilla-Arias, Jose; Patil, Rameshwar; Ding, Hui; Inoue, Satoshi; Markman, Janet L.; Rekechenetskiy, Arthur; Konda, Bindu; Gangalum, Pallavi R.; Chesnokova, Alexandra; Ljubimov, Alexander V; Black, Keith L.; Holler, Eggehard

    2013-01-01

    Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and ...

  3. Body size and risk of luminal, HER2-overexpressing, and triple-negative breast cancer in postmenopausal women

    OpenAIRE

    Phipps, Amanda I.; Malone, Kathleen E.; Porter, Peggy L.; Daling, Janet R.; Li, Christopher I.

    2008-01-01

    Although the clinical relevance of molecular subtypes of breast cancer has been documented, little is known about risk factors for different tumor subtypes, especially the HER2-overexpressing and triple-negative subtypes which have poor prognoses. Obesity may be differentially related to risk of different subtypes given the various potential mechanisms underlying its association with breast cancer. We pooled two population-based case-control studies of postmenopausal breast cancer for an anal...

  4. Negative predictive value of procalcitonin in medullary thyroid carcinoma.

    Science.gov (United States)

    Lim, Soo Kyung; Guéchot, Jérôme; Vaubourdolle, Michel

    2016-01-01

    Calcitonin (CT), the major biochemical marker in medullary thyroid carcinoma (MTC) is prone to in vitro instability and suffers from scarcity of clinical laboratory platforms. Procalcitonin (PCT), the precursor of CT, free of these shortcomings, has been reported as a potential MTC marker. The aim of this study was to assess the negative predictive value (NPV) of PCT as a first-line marker in MTC. 476 serum samples referred to our laboratory for CT measurements were analyzed for PCT. NPVs of PCT were assessed at 3 cut-offs (0.05, 0.10 and 0.15 ng/mL) and the diagnosis of MTC was based on CT levels. PCT and CT levels were correlated (r=0.7554 for CT levels above 10 pg/mL, n=66). Accepting the CT cut-off based on the upper reference limit the NPV of PCT were 98.1% (0.05 ng/mL), 96.3% (0.10 ng/mL) and 95.4% (0.15 ng/mL) respectively. For a CT cut-off of 100 pg/mL the NPVs of PCT were 100% for all PCT thresholds. Serum PCT has a strong NPV and could be a good candidate for a first-line screening test to exclude MTC in patients with suspicious thyroid nodules or suggestive symptoms. Larger prospective studies are necessary to confirm our results. PMID:26806393

  5. Detection of hepatocelluar carcinoma on triple-phase images of liver using multi-detector row helical CT

    International Nuclear Information System (INIS)

    To determine whether triple-phase multi-detector-row helical CT images of liver improves the detection rate of hepatocellular carcinoma (HCC). Forty-one patients with 103 HCCs underwent triple-detector-row helical CT imaging of the entire liver after contrast administration. Early and late arterial phase images were obtained serially during a single breath-hold, and portal venous-phase images were then obtained. Each image set was independently assessed for the presence of HCC by two radiologists unaware of the possible presence of tumors, and for each phase the detection rate was determined. For each arterial-phase image, lesion conspicuity (attenuation of a tumor compared with that of its parenchyma) was calculated. For reader 1, the detection rates for the early arterial, late arterial, and portal venous phase were 81%, 77%, and 55%, respectively, and for reader 2 were 83%, 81% and 68%, respectively (p>0.05). When triple-phase imaging findings were combined, the detection rate was significantly higher than when only those of the early or late arterial, and portal venous, phase were used (p0.05). Triple-phase imaging of the liver, involving the early arterial, late arterial, and portal venous phase, and using multi-detector-row helical CT, increases the detection rate of HCC

  6. 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)

    2016-03-08

    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

  7. Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer

    OpenAIRE

    Barrett, Michael T.; Anderson, Karen S.; Lenkiewicz, Elizabeth; Andreozzi, Mariacarla; Cunliffe, Heather E.; Klassen, Christine L.; Dueck, Amylou C.; McCullough, Ann E.; Reddy, Srikanth K.; Ramanathan, Ramesh K.; Northfelt, Donald W.; Barbara A Pockaj

    2015-01-01

    We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this ampl...

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  10. Wnt modulates MCL1 to control cell survival in triple negative breast cancer

    International Nuclear Information System (INIS)

    Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells. We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test. WNT5B was elevated both in the tumor and the patients’ serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with

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

    Directory of Open Access Journals (Sweden)

    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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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.

  15. Meta-analysis on the association between pathologic complete response and triple-negative breast cancer after neoadjuvant chemotherapy

    OpenAIRE

    Wu, Kunpeng; Yang, Qiaozhu; Liu, Yi; Wu, Aibing; Yang, Zhixiong

    2014-01-01

    Background Triple-negative breast cancer (TNBC) is a special subtype of breast cancer that is characterized by poor prognosis, strong tumor invasion and a high pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). The pCR rate is a prognostic factor for TNBC. We aimed to evaluate the relationship between pCR and TNBC after NAC and originally tried to identify factors related to achieving pCR for TNBC using a meta-analysis. Methods We systematically searched the literature for ...

  16. Suppression of Spry1 inhibits triple-negative breast cancer malignancy by decreasing EGF/EGFR mediated mesenchymal phenotype

    OpenAIRE

    Qing He; Hongyu Jing; Lucy Liaw; Lindsey Gower; Calvin Vary; Shucheng Hua; Xuehui Yang

    2016-01-01

    Sprouty (Spry) proteins have been implicated in cancer progression, but their role in triple-negative breast cancer (TNBC), a subtype of lethal and aggressive breast cancer, is unknown. Here, we reported that Spry1 is significantly expressed in TNBC specimen and MDA-MB-231 cells. To understand Spry1 regulation of signaling events controlling breast cancer phenotype, we used lentiviral delivery of human Spry1 shRNAs to suppress Spry1 expression in MDA-MB-231, an established TNBC cell line. Spr...

  17. Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells.

    Science.gov (United States)

    Librizzi, Mariangela; Spencer, John; Luparello, Claudio

    2016-01-01

    We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of "aggressive" breast carcinoma. PMID:27483253

  18. Maximiscin Induces DNA Damage, Activates DNA Damage Response Pathways, and Has Selective Cytotoxic Activity against a Subtype of Triple-Negative Breast Cancer.

    Science.gov (United States)

    Robles, Andrew J; Du, Lin; Cichewicz, Robert H; Mooberry, Susan L

    2016-07-22

    Triple-negative breast cancers are highly aggressive, and patients with these types of tumors have poor long-term survival. These breast cancers do not express estrogen or progesterone receptors and do not have gene amplification of human epidermal growth factor receptor 2; therefore, they do not respond to available targeted therapies. The lack of targeted therapies for triple-negative breast cancers stems from their heterogeneous nature and lack of a clear definition of driver defects. Studies have recently identified triple-negative breast cancer molecular subtypes based on gene expression profiling and representative cell lines, allowing for the identification of subtype-specific drug leads and molecular targets. We previously reported the identification of a new fungal metabolite named maximiscin (1) identified through a crowdsourcing program. New results show that 1 has selective cytotoxic efficacy against basal-like 1 MDA-MB-468 cells compared to cell lines modeling other triple-negative breast cancer molecular subtypes. This compound also exhibited antitumor efficacy in a xenograft mouse model. The mechanisms of action of 1 in MDA-MB-468 cells were investigated to identify potential molecular targets and affected pathways. Compound 1 caused accumulation of cells in the G1 phase of the cell cycle, suggesting induction of DNA damage. Indeed, treatment with 1 caused DNA double-strand breaks with concomitant activation of the DNA damage response pathways, indicated by phosphorylation of p53, Chk1, and Chk2. Collectively, these results suggest basal-like triple-negative breast cancer may be inherently sensitive to DNA-damaging agents relative to other triple-negative breast cancer subtypes. These results also demonstrate the potential of our citizen crowdsourcing program to identify new lead molecules for treating the subtypes of triple-negative breast cancer. PMID:27310425

  19. miR-136 suppresses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer

    Science.gov (United States)

    YAN, MEISI; LI, XIAOBO; TONG, DANDAN; HAN, CHANGSONG; ZHAO, RAN; HE, YAN; JIN, XIAOMING

    2016-01-01

    MicroRNAs play an important role in the regulation of cancer migration, invasion and metastasis. Patients with triple-negative breast cancer (TNBC) have a high incidence of early relapse and metastasis; however, the molecular basis for metastasis and recurrence in these individuals remains largely unknown. Herein, we demonstrate that miR-136 is an anti-invasive microRNA in TNBC and suppresses mesenchymal invasion and metastasis. Our results demonstrated that miR-136 was downregulated in TNBC and negative correlated with the WHO grades. However, RASAL2 was identified as a functional target of miR-136, and was overexpressed in TNBC and correlates with pathological grades. Moreover, overexpression of RASAL2 in a breast cancer cell line rescued miR-136-mediated cell migration and invasion. In conclusion, these results indicate that the miR-136/RASAL2/MET axis act as a suppressor of TNBC metastasis. PMID:27108696

  20. 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.

  1. Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype

    International Nuclear Information System (INIS)

    Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC. Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs. IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis. FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA

  2. 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.

  3. 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.

  4. 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.

  5. Divergent Synthesis of Chondroitin Sulfate Disaccharides and Identification of Sulfate Motifs that Inhibit Triple Negative Breast Cancer

    Science.gov (United States)

    Wei Poh, Zhong; Heng Gan, Chin; Lee, Eric J.; Guo, Suxian; Yip, George W.; Lam, Yulin

    2015-09-01

    Glycosaminoglycans (GAGs) regulate many important physiological processes. A pertinent issue to address is whether GAGs encode important functional information via introduction of position specific sulfate groups in the GAG structure. However, procurement of pure, homogenous GAG motifs to probe the “sulfation code” is a challenging task due to isolation difficulty and structural complexity. To this end, we devised a versatile synthetic strategy to obtain all the 16 theoretically possible sulfation patterns in the chondroitin sulfate (CS) repeating unit; these include rare but potentially important sulfated motifs which have not been isolated earlier. Biological evaluation indicated that CS sulfation patterns had differing effects for different breast cancer cell types, and the greatest inhibitory effect was observed for the most aggressive, triple negative breast cancer cell line MDA-MB-231.

  6. Curcumin and Resveratrol as Promising Natural Remedies with Nanomedicine Approach for the Effective Treatment of Triple Negative Breast Cancer

    Science.gov (United States)

    Shindikar, Amol; Singh, Akshita; Nobre, Malcolm; Kirolikar, Saurabh

    2016-01-01

    Researchers have made considerable progress in last few decades in understanding mechanisms underlying pathogenesis of breast cancer, its phenotypes, its molecular and genetic changes, its physiology, and its prognosis. This has allowed us to identify specific targets and design appropriate chemical entities for effective treatment of most breast cancer phenotypes, resulting in increased patient survivability. Unfortunately, these strategies have been largely ineffective in the treatment of triple negative breast cancer (TNBC). Hormonal receptors lacking render the conventional breast cancer drugs redundant, forcing scientists to identify novel targets for treatment of TNBC. Two natural compounds, curcumin and resveratrol, have been widely reported to have anticancer properties. In vitro and in vivo studies show promising results, though their effectiveness in clinical settings has been less than satisfactory, owing to their feeble pharmacokinetics. Here we discuss these naturally occurring compounds, their mechanism as anticancer agents, their shortcomings in translational research, and possible methodology to improve their pharmacokinetics/pharmacodynamics with advanced drug delivery systems.

  7. 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

    2016-03-01

    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. PMID:26923594

  8. Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines

    International Nuclear Information System (INIS)

    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

  9. Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival.

    Science.gov (United States)

    den Hollander, Petra; Rawls, Kathryn; Tsimelzon, Anna; Shepherd, Jonathan; Mazumdar, Abhijit; Hill, Jamal; Fuqua, Suzanne A W; Chang, Jenny C; Osborne, C Kent; Hilsenbeck, Susan G; Mills, Gordon B; Brown, Powel H

    2016-04-01

    Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR = 0.05) in TNBC compared with ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific siRNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1-S cell-cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients. Cancer Res; 76(7); 1942-53. ©2016 AACR. PMID:26921331

  10. Function of AURKA protein kinase in the formation of vasculogenic mimicry in triple-negative breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Liu Y

    2016-06-01

    Full Text Available Ying Liu,1,2,* Baocun Sun,1–3,* Tieju Liu,1,2,* Xiulan Zhao,1,2 Xudong Wang,3 Yanlei Li,1,2 Jie Meng,2 Qiang Gu,1,2 Fang Liu,1,2 Xueyi Dong,1,2 Peimei Liu,2 Ran Sun,2 Nan Zhao1 1Department of Pathology, General Hospital of Tianjin Medical University, 2Department of Pathology, Tianjin Medical University, 3Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Tumor cell vasculogenic mimicry (VM, a newly defined pattern of tumor blood supply, signifies the functional plasticity of aggressive cancer cells forming vascular networks. VM and cancer stem cells (CSCs have been shown to be associated with tumor growth, local invasion, and distant metastasis. In our previous study, CSCs in triple-negative breast cancer were potential to participate in VM formation. In this study, breast CSCs were isolated from the triple-negative breast cancer cell line MDA-MB-231 by using mammosphere culture. Western blotting and reverse transcription polymerase chain reaction showed that mammosphere cells displayed an increased expression of AURKA protein kinase and stem cell marker c-myc and sox2. The VM formation by mammosphere cells was inhibited by AURKA knockdown or the addition of AURKA inhibitor MLN8237. In the meantime, MLN8237 induced the increased E-cadherin and decreased c-myc, sox2, and β-catenin expressions. The function of AURKA in VM formation was further confirmed using a xenograft-murine model. The results suggested that AURKA protein kinase is involved in VM formation of CSCs and may become a new treatment target in suppressing VM and metastasis of breast cancer. Keywords: AURKA, cancer stem cells, vasculogenic mimicry, breast cancer

  11. Chemogenetic evaluation of the mitotic kinesin CENP-E reveals a critical role in triple-negative breast cancer.

    Science.gov (United States)

    Kung, Pei-Pei; Martinez, Ricardo; Zhu, Zhou; Zager, Michael; Blasina, Alessandra; Rymer, Isha; Hallin, Jill; Xu, Meirong; Carroll, Christopher; Chionis, John; Wells, Peter; Kozminski, Kirk; Fan, Jeffery; Guicherit, Oivin; Huang, Buwen; Cui, Mei; Liu, Chaoting; Huang, Zhongdong; Sistla, Anand; Yang, Jennifer; Murray, Brion W

    2014-08-01

    Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal-like breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E-dependent molecular events (e.g., phosphorylation of histone H3 Ser-10; phospho-HH3-Ser10) to functional outcomes (e.g., chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to premalignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic-pharmacodynamic efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well correlated with increased phospho-HH3-Ser10 levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for patients with triple-negative/basal-a breast cancer. PMID:24928852

  12. Anticancer Properties of Novel Rhenium Pentylcarbanato Compounds against MDA-MB-468(HTB-132) Triple Node Negative Human Breast Cancer Cell Lines

    OpenAIRE

    Parson, Carl; SMITH, VALERIE; Krauss, Christopher; Banerjee, Hirendra N.; Reilly, Christopher; Krause, Jeanette A.; Wachira, James M.; Giri, Dipak; Winstead, Angela; Mandal, Santosh K.

    2015-01-01

    Aim To study the efficacy of novel rhenium compounds to treat triple node negative breast cancer. Place and Duration Six (6) novel rhenium pentycarbanato compounds (PC1-6) were synthesized and triple node negative breast cancer cell lines HTB-132 and Balb/c mouse kidney cell lines were treated with each of them for 48 hours. The results were analyzed by a common trypan blue cell death assay system and statistically analyzed. Place and Duration The compounds were synthesized, analyzed and eval...

  13. 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

    We examined the association between the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of women with primary breast cancer and the risk of axillary lymph node (ALN) involvement at the time of diagnosis. Information on 20,009 women diagnosed with primary breast......-negative 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 < 0.0001). The HR and HER2 statuses are significantly associated with ALN involvement at the time of...... diagnosis. Despite the poor prognosis, TNBC patients have a reduced risk of ALN involvement at the time of diagnosis compared to patients with other subtypes, when adjusting for other risk factors. This may indicate that TNBC tends to spread hematogenously rather than lymphogenously....

  14. Expression patterns of GATA3 and the androgen receptor are strongly correlated in patients with triple-negative breast cancer.

    Science.gov (United States)

    Kim, Sewha; Moon, Byung-In; Lim, Woosung; Park, Sanghui; Cho, Min Sun; Sung, Sun Hee

    2016-09-01

    GATA-binding protein 3 (GATA3) is a diagnostically useful immunohistochemical marker of breast cancer. Because of its strong association with estrogen receptor expression, GATA3 has markedly reduced sensitivity in triple-negative breast cancer (TNBC). We constructed a tissue microarray using a large series of TNBCs and evaluated GATA3 expression by TNBC subtype as defined by surrogate immunohistochemical markers. A total of 205 TNBCs were classified into cancers of the molecular apocrine type (n=23, 11.2%), claudin-low type (n=21, 10.2%), basal-like type (n=91, 44.4%), mixed type (n=62, 30.2%), and null type (n=8, 3.9%). The GATA3 scores (staining intensity × proportion) were categorized as negative (0), focally positive (1-10), or positive (11-300). GATA3 staining was negative in 153 cancers (74.6%), focally positive in 11 (5.4%), and positive in 41 (20.0%). The rate of focal positivity or positivity for GATA3 was significantly higher in the molecular apocrine type (73.9%, 17/23) than in other types of TNBCs (P=.001). The mean GATA3 score of molecular apocrine-type TNBC was significantly higher than that of the other types (P=.001) and differed significantly between androgen receptor (AR)-positive and AR-negative TNBCs (P<.001). In conclusion, GATA3 expression was correlated strongly with AR-positive, molecular apocrine-type TNBCs. Co-expression of AR and GATA3 is a specific feature of molecular apocrine-type TNBC, which may serve as a diagnostic aid for cancer of unknown primary. PMID:27184484

  15. AMPK inhibits MTDH expression via GSK3β and SIRT1 activation: potential role in triple negative breast cancer cell proliferation.

    Science.gov (United States)

    Gollavilli, Paradesi Naidu; Kanugula, Anantha Koteswararao; Koyyada, Rajeswari; Karnewar, Santosh; Neeli, Praveen Kumar; Kotamraju, Srigiridhar

    2015-10-01

    Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti-proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA-MB-231 and BT-549 triple negative breast cancer (TNBC) cells. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, caused growth arrest, inhibition of migration and invasion of TNBC cells. Intriguingly, AICAR or metformin treatment resulted in significant downregulation of MTDH expression via inhibiting c-Myc expression. In contrast, treatment of cells with compound C, an inhibitor of AMPK, increased both c-Myc and MTDH expressions in TNBC cells. Also, AMPK activation caused increased glycogen synthase kinase 3β (GSK3β) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 (SIRT1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK-induced GSK3β and SIRT1 activities were found to be responsible for inhibiting c-Myc-mediated upregulation of MTDH, as LiCl (an inhibitor of GSK3β) and EX-527 (an inhibitor of SIRT1) reversed AICAR-mediated downregulation of c-Myc and MTDH expressions. Similar results were observed with siSIRT1 treatment. Furthermore, AICAR and EX-527 treatments caused increased cell death under MTDH-depleted conditions. Finally, we uncovered a novel regulation of MTDH expression and showed that AMPK activation by inducing GSK3β and SIRT1 downregulates MTDH expression via inhibiting c-Myc in TNBC cells. PMID:26236947

  16. The differences in ultrasound and clinicopathological features between basal-like and normal-like subtypes of triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Ziyao Li

    Full Text Available The aim of this study was to identify the ultrasound features and clinicopathological characteristics of basal-like subtype of triple negative breast cancers (TNBCs.This study was approved by the ethical board of the Second Affiliated Hospital of Harbin Medical University. The patients' clinicopathological information was available. The ultrasound features of 62 tumors from 62 TNBC patients were interpreted. The immunohistochemical results of cytokertain5/6 (CK5/6 and Epidermal Growth Factor Receptor (EGFR were used to classify the tumor into basal-like and normal-like groups. The association of the ultrasound features interpreted by experienced ultrasound doctors with the immunohistochemical classification was studied.Of the 62 TNBC cases, 42 (67.7% exhibited the basal-like phenotype and 20 (32.3% exhibited the normal-like phenotype based on the immunohistochemical CK5/6 and EGFR markers. Of all the tumors, 90.3% were invasive carcinomas. The basal-like tumors were significantly associated with a maximum diameter on ultrasound of more than 20 mm (36, 85.7% (P = 0.0014. The normal-like tumors usually exhibited lateral shadows (15, 75% (P = 0.0115 as well as microlobulated margins (12, 60% (P = 0.0204 compared to the basal-like subtype. Other ultrasound features showed no significant differences between the two groups.Although ultrasound cannot yet be used to differentiate between the basal-like subtype and normal-like subtype of TNBC, ultrasound can be used to provide some useful information to the clinicians.

  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. Locoregional recurrence of triple-negative breast cancer: effect of type of surgery and adjuvant postoperative radiotherapy

    Directory of Open Access Journals (Sweden)

    Bayoumi Y

    2014-09-01

    Full Text Available Yasser Bayoumi,1 Ayman AbdelSamie,2 Ahmed Abdelsaid,3 Aida Radwan4 1Radiation Oncology, 2Medical Oncology, 3Surgical Oncology, 4Medical Physics, National Cancer Institute, Cairo University, Cairo, Egypt Background/purpose: The aim was to evaluate the prognostic significance of postoperative radiotherapy (PORT and surgical type on local recurrence-free survival (LRFS and overall survival (OS in triple-negative breast cancer (TNBC in the Egyptian population. Patients and methods: We evaluated 111 patients with stage I–III TNBC diagnosed at our institute during the period from 2004 to 2009. Patients were stratified according to PORT into two groups: a PORT group and a non-PORT group. The influence of PORT and surgical type on LRFS and OS were evaluated. A cross-matching was done to the non-TNBC group of patients to compare the recurrence and survival rates between them and the studied group of TNBC patients. Results: The mean age of TNBC patients at diagnosis was 63±7 years. The majority of the patients had stage III disease (68.5% and 73% had clinical or pathological positive lymph nodes. Sixty percent (67/111 of patients had modified radical mastectomy and 44/111 (40% patients had breast-conserving treatment. PORT was given for 63% of patients, while systemic treatment was given in 89% of patients. At the time of analysis, 13 patients (11% developed local recurrence: five of 70 (7% in the PORT group and eight of 41 (19.5% in the non-PORT group. Five-year LRFS for the whole group of patients was 88%±6%, which was significantly affected by PORT. The surgical type did not affect local recurrence significantly. Five-year OS for the whole group was 54%±8%. PORT and surgical type did not affect OS significantly (P-value 0.09 and 0.11, respectively. Five-year LRFS was 88%±6% and 90%±11% for TNBC and non-TNBC patients, respectively (P-value 0.8; however, OS for TNBC was significantly lower than for non-TNBC (P-value 0.04. Conclusion: TNBC is an

  19. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    Science.gov (United States)

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-01

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC.Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR

  20. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers.

    Science.gov (United States)

    Paluch-Shimon, Shani; Friedman, Eitan; Berger, Raanan; Papa, Moshe; Dadiani, Maya; Friedman, Neil; Shabtai, Moshe; Zippel, Dov; Gutman, Mordechai; Golan, Talia; Yosepovich, Ady; Catane, Raphael; Modiano, Tami; Kaufman, Bella

    2016-05-01

    The purpose of this study was to assess pathological complete response and whether it serves a surrogate for survival among patients receiving neo-adjuvant doxorubicin-cyclophosphamide followed by paclitaxel for triple-negative breast cancer with respect to BRCA1 mutation status. From a neo-adjuvant systemic therapy database of 588 breast cancer cases, 80 triple-negative cases who had undergone BRCA genotyping were identified. Logistic regression model was fitted to examine the association between BRCA1 status and pathological complete response. Survival outcomes were evaluated using Kaplan-Meier method, differences between study groups calculated by log-rank test. Thirty-four BRCA1 carriers and 43 non-carriers were identified. The BRCA1 carriers had pathological complete response rate of 68 % compared with 37 % among non-carriers, p = 0.01. Yet this did not translate into superior survival for BRCA1 carriers compared with non-carriers. No difference in relapse-free survival were noted among those with or without pathological complete response in BRCA1 carriers regardless of pathological complete response status (Log-rank p = 0.25), whereas in the non-carrier cohort, relapse-free survival was superior for those achieving pathological complete response (Log-rank p < 0.0001). Response to neo-adjuvant systemic therapy differed in BRCA1-associated triple-negative breast cancer compared with triple-negative non-carriers, with a higher rate of pathological complete response. However, compared with non-carrier triple-negative breast cancer, pathological complete response was not a surrogate for superior relapse-free survival in BRCA1 patients. Future studies using specific chemotherapy regimens may provide further improvements in outcomes. PMID:27113739

  1. 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. PMID:27003608

  2. Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers.

    Science.gov (United States)

    Nagano, Kazuya; Maeda, Yuka; Kanasaki, So-Ichiro; Watanabe, Takanobu; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2014-09-10

    Ephrin receptor A10 (EphA10) is a relatively uncharacterized protein which is expressed in many breast cancers but not expressed in normal breast tissues. Here, we examined the potential of EphA10 as a drug target in breast cancer. Immunohistochemical staining of clinical tissue sections revealed that EphA10 was expressed in various breast cancer subtypes, including triple negative breast cancers (TNBCs), with no expression observed in normal tissues apart from testis. Ligand-dependent proliferation was observed in EphA10-transfected MDA-MB-435 cells (MDA-MB-435(EphA10)) and native TNBC cells (MDA-MB-436). However, this phenomenon was not observed in parental MDA-MB-435 cells which express a low level of EphA10. Finally, tumor growth was significantly suppressed by administration of an anti-EphA10 monoclonal antibody in a xenograft mouse model. These results suggest that inhibition of EphA10 signaling may be a novel therapeutic option for management of breast cancer, including TNBCs which are currently not treated with molecularly targeted agents. PMID:24946238

  3. The expression of Dicer and Drosha in matched normal tissues, tumours and lymph node metastases in triple negative breast cancer

    International Nuclear Information System (INIS)

    Breast cancer is the most common malignancy in women world-wide. Triple negative breast cancer (TNBC) is a highly aggressive subtype that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor 2; and is associated with a high propensity for metastatic spread. Several studies have identified critical roles for microRNAs in breast cancer, but the role of two critical enzymes involved in microRNA biogenesis, Dicer and Drosha, is not well understood, particularly with respect to metastatic progression in this subtype. We examined the expression of Dicer and Drosha in a series of invasive 35 TNBCs with matched normal adjacent tissues (n = 18) and lymph node metastases (n = 15) using semi-quantitative real time RT-PCR. The relationship of their expression with clinical features including age at diagnosis, lymph node positivity and tumour size was analysed. We report that Dicer was significantly decreased while Drosha was significantly increased in tumours when compared to normal adjacent tissues. While there was no difference in Drosha expression in lymph node metastases when compared to the primary tumour, Dicer was significantly increased. There was no correlation between the expression of either Dicer or Drosha to age at diagnosis, lymph node positivity and tumour size. In conclusion, Dicer and Drosha are dysregulated in TNBC and matched lymph node metastases however, the clinical relevance of this is still not known. The altered expression of Dicer and Drosha may serve as markers for disrupted miRNA biogenesis in TNBC

  4. Curcumin and Resveratrol as Promising Natural Remedies with Nanomedicine Approach for the Effective Treatment of Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Amol Shindikar

    2016-01-01

    Full Text Available Researchers have made considerable progress in last few decades in understanding mechanisms underlying pathogenesis of breast cancer, its phenotypes, its molecular and genetic changes, its physiology, and its prognosis. This has allowed us to identify specific targets and design appropriate chemical entities for effective treatment of most breast cancer phenotypes, resulting in increased patient survivability. Unfortunately, these strategies have been largely ineffective in the treatment of triple negative breast cancer (TNBC. Hormonal receptors lacking render the conventional breast cancer drugs redundant, forcing scientists to identify novel targets for treatment of TNBC. Two natural compounds, curcumin and resveratrol, have been widely reported to have anticancer properties. In vitro and in vivo studies show promising results, though their effectiveness in clinical settings has been less than satisfactory, owing to their feeble pharmacokinetics. Here we discuss these naturally occurring compounds, their mechanism as anticancer agents, their shortcomings in translational research, and possible methodology to improve their pharmacokinetics/pharmacodynamics with advanced drug delivery systems.

  5. Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression.

    Science.gov (United States)

    Guo, Liwen; Zheng, Jiaping; Zhang, Jing; Wang, Haohao; Shao, Guoliang; Teng, Lisong

    2016-08-01

    Triple-negative breast cancer (TNBC) constitutes ~10-15% of breast cancer patients and represents an aggressive subtype with poor overall prognosis. TNBC is an important clinical challenge because it does not respond well to endocrine therapy and have a higher rate of early recurrence and distant metastasis following chemotherapy. Although it has been reported that the epidermal growth factor receptor (EGFR) was overexpressed in ~80% of TNBC, anti-EGFR therapy showed limited clinical benefit according to phase II studies. In this study, we first observed that knockdown of the transcriptional coactivator with PDZ-binding domain (TAZ) gene can regulate the sensitivity of TNBC cell lines to EGFR inhibitors (EGFRI) in a cell context-depended manner. Furthermore, in certain breast cancer cell lines the YES-associated protein, paralog of TAZ (YAP) expression can be upregulated by TAZ inhibition which leads to EGFRI resistance. These results suggest a specific inhibitor to TAZ/YAP combined with anti-EGFR therapy may prove effective and provide a reason why targeting EGFR showed limited clinical benefit in TNBC treatment. PMID:27373987

  6. γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers

    Science.gov (United States)

    Trošt, Nuša; Peña-Llopis, Samuel; Koirala, Sajjan; Stojan, Jurij; Potts, Patrick Ryan; Tacer, Klementina Fon; Martinez, Elisabeth D.

    2016-01-01

    Over the last decade, breast cancer mortality has declined. However, triple negative breast cancer (TNBC) remains a challenging problem mostly due to early recurrence and lack of molecularly driven treatments. There is a critical need to identify subgroups of TNBC with common molecular features that can be therapeutically targeted. Here we show that in contrast to Klotho and βKlotho, the third member of the Klotho protein family, γKlotho, is overexpressed in more than 60% of TNBCs and correlates with poorer disease progression. Furthermore, we find that γKlotho is expressed in a subset of TNBC cell lines promoting cell growth. Importantly, we demonstrate that in these cells γKlotho is necessary for cell survival and that its depletion leads to constitutive ERK activation, cell cycle arrest and apoptosis. Interestingly, we observe increased oxidative stress in γKlotho-depleted cells suggesting that γKlotho enables cancer cells to cope with an oxidative environment and that cells become dependent on its expression to maintain this survival advantage. These findings indicate that γKlotho might be a potential marker for patients that would benefit from treatments that alter oxidative stress and constitutes a novel drug target for a subset of TN breast cancers. PMID:26556877

  7. 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.

  8. Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment.

    Science.gov (United States)

    Ljubimova, Julia Y; Portilla-Arias, Jose; Patil, Rameshwar; Ding, Hui; Inoue, Satoshi; Markman, Janet L; Rekechenetskiy, Arthur; Konda, Bindu; Gangalum, Pallavi R; Chesnokova, Alexandra; Ljubimov, Alexander V; Black, Keith L; Holler, Eggehard

    2013-12-01

    Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconjugate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future. PMID:24032759

  9. Fate of PLA and PCL-Based Polymeric Nanocarriers in Cellular and Animal Models of Triple-Negative Breast Cancer.

    Science.gov (United States)

    Sitia, Leopoldo; Ferrari, Raffaele; Violatto, Martina B; Talamini, Laura; Dragoni, Luca; Colombo, Claudio; Colombo, Laura; Lupi, Monica; Ubezio, Paolo; D'Incalci, Maurizio; Morbidelli, Massimo; Salmona, Mario; Moscatelli, Davide; Bigini, Paolo

    2016-03-14

    An integrated platform to assess the interaction between nanocarriers and biological matrices has been developed by our group using poly methyl-methacrylate nanoparticles. In this study, we exploited this platform to evaluate the behavior of two biodegradable formulations, poly-ε-caprolactone (PCL3) and poly lactic-acid (PLA8), respectively, in cellular and animal models of triple-negative breast cancer (TNBC). Both NPs shared the main physicochemical parameters (size, shape, ζ-potential) and exclusively differentiated on the material on which they are composed. Our results showed that (1) PLA8 NPs, systemically injected in mice, underwent rapid degradation without penetration into tumors; (2) PLA8 NPs were not internalized in the human TNBC cell line (MDA-MB-231); (3) PCL3 NPs had a longer bioavailability, reached the tumor parenchyma, and efficiently penetrated in MDA-MB-231 cells. Our data highlight the relevance of the material selection to both improve bioavailability and target tropism, and make PCL3 NPs an interesting tool for the development of nanodrugs against TNBC. PMID:26791775

  10. PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation.

    Science.gov (United States)

    Ito, Koichi; Park, Sun Hee; Nayak, Anupma; Byerly, Jessica H; Irie, Hanna Y

    2016-08-01

    Patients with triple-negative breast cancers (TNBC) are at high risk for recurrent or metastatic disease despite standard treatment, underscoring the need for novel therapeutic targets and strategies. Here we report that protein tyrosine kinase 6 (PTK6) is expressed in approximately 70% of TNBCs where it acts to promote survival and metastatic lung colonization. PTK6 downregulation in mesenchymal TNBC cells suppressed migration and three-dimensional culture growth, and enhanced anoikis, resistance to which is considered a prerequisite for metastasis. PTK6 downregulation restored E-cadherin levels via proteasome-dependent degradation of the E-cadherin repressor SNAIL. Beyond being functionally required in TNBC cells, kinase-active PTK6 also suppressed E-cadherin expression, promoted cell migration, and increased levels of mesenchymal markers in nontransformed MCF10A breast epithelial cells, consistent with a role in promoting an epithelial-mesenchymal transition (EMT). SNAIL downregulation and E-cadherin upregulation mediated by PTK6 inhibition induced anoikis, leading to impaired metastatic lung colonization in vivo Finally, effects of PTK6 downregulation were phenocopied by treatment with a recently developed PTK6 kinase inhibitor, further implicating kinase activity in regulation of EMT and metastases. Our findings illustrate the clinical potential for PTK6 inhibition to improve treatment of patients with high-risk TNBC. Cancer Res; 76(15); 4406-17. ©2016 AACR. PMID:27302163

  11. The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

    Directory of Open Access Journals (Sweden)

    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.

  12. Nestin expression associates with poor prognosis and triple negative phenotype in locally advanced (T4 breast cancer

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    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.

  13. Antitumoral activity of the mithralog EC-8042 in triple negative breast cancer linked to cell cycle arrest in G2.

    Science.gov (United States)

    Pandiella, Atanasio; Morís, Francisco; Ocaña, Alberto; Núñez, Luz-Elena; Montero, Juan C

    2015-10-20

    Triple negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often observed in the metastatic setting. Therefore, identification of new therapeutic strategies is required. Here we have investigated the effect of the mithramycin analog EC-8042 (demycarosil-3D-β-D-digitoxosyl mithramycin SK) on TNBC. The drug caused a dose-dependent inhibition of proliferation of a set of TNBC cell lines in vitro, and decreased tumor growth in mice xenografted with TNBC cells. Mechanistically, EC-8042 caused an arrest in the G2 phase of the cell cycle, coincident with an increase in pCDK1 and Wee1 levels in cells treated with the drug. In addition, prolonged treatment with the drug also causes apoptosis, mainly through caspase-independent routes. Importantly, EC-8042 synergized with drugs commonly used in the therapy of TNBC in vitro, and potentiated the antitumoral effect of docetaxel in vivo. Together, these data suggest that the mithralog EC-8042 exerts an antitumoral action on TNBC cells and reinforces the action of standard of care drugs used in the therapy of this disease. These characteristics, together with a better toxicology profile of EC-8042 with respect to mithramycin, open the possibility of its clinical evaluation. PMID:26439989

  14. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.

    Science.gov (United States)

    Camarda, Roman; Zhou, Alicia Y; Kohnz, Rebecca A; Balakrishnan, Sanjeev; Mahieu, Celine; Anderton, Brittany; Eyob, Henok; Kajimura, Shingo; Tward, Aaron; Krings, Gregor; Nomura, Daniel K; Goga, Andrei

    2016-04-01

    Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer. PMID:26950360

  15. miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Adams, Brian D; Wali, Vikram B; Cheng, Christopher J; Inukai, Sachi; Booth, Carmen J; Agarwal, Seema; Rimm, David L; Győrffy, Balázs; Santarpia, Libero; Pusztai, Lajos; Saltzman, W Mark; Slack, Frank J

    2016-02-15

    Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC. PMID:26676753

  16. The Role of Transoral Robotic Surgery in the Management of HPV Negative Oropharyngeal Squamous Cell Carcinoma.

    Science.gov (United States)

    Sload, Ryan; Silver, Natalie; Jawad, Basit Abjul; Gross, Neil D

    2016-09-01

    The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is on the rise. This is largely due to the rapid increase in HPV positive OPSCC, which has been shown to confer a survival advantage. HPV negative OPSCC, however, has a more aggressive tumor biology and is a challenge to treat with standard current therapies. Chemoradiation has demonstrated poor locoregional control in HPV negative OPSCC, and open surgeries are associated with high morbidity. Transoral robotic surgery (TORS) has been proposed as an option to both intensify treatment and decrease surgical morbidity for patients with HPV negative OPSCC. TORS can be utilized as a primary treatment or in persistent, recurrent, or second primary OPSCC. There is emerging data showing improved functional outcomes with TORS versus open surgery or chemoradiation. Unfortunately, there have been no randomized trials comparing TORS to chemoradiation in HPV negative OPSCC. This article will review utility of TORS for HPV negative OPSCC. PMID:27469262

  17. Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer

    International Nuclear Information System (INIS)

    Although diagnosed less often, breast cancer in African American women (AAW) displays different characteristics compared to breast cancer in Caucasian women (CW), including earlier onset, less favorable clinical outcome, and an aggressive tumor phenotype. These disparities may be attributed to differences in socioeconomic factors such as access to health care, lifestyle, including increased frequency of obesity in AAW, and tumor biology, especially the higher frequency of triple negative breast cancer (TNBC) in young AAW. Improved understanding of the etiology and molecular characteristics of TNBC in AAW is critical to determining whether and how TNBC contributes to survival disparities in AAW. Demographic, pathological and survival data from AAW (n = 62) and CW (n = 98) with TNBC were analyzed using chi-square analysis, Student’s t-tests, and log-rank tests. Frozen tumor specimens were available from 57 of the TNBC patients (n = 23 AAW; n = 34 CW); RNA was isolated after laser microdissection of tumor cells and was hybridized to HG U133A 2.0 microarrays. Data were analyzed using ANOVA with FDR <0.05, >2-fold difference defining significance. The frequency of TNBC compared to all BC was significantly higher in AAW (28%) compared to CW (12%), however, significant survival and pathological differences were not detected between populations. Gene expression analysis revealed the tumors were more similar than different at the molecular level, with only CRYBB2P1, a pseudogene, differentially expressed between populations. Among demographic characteristics, AAW consumed significantly lower amounts of caffeine and alcohol, were less likely to breastfeed and more likely to be obese. These data suggest that TNBC in AAW is not a unique disease compared to TNBC in CW. Rather, higher frequency of TNBC in AAW may, in part, be attributable to the effects of lifestyle choices. Because these risk factors are modifiable, they provide new opportunities for the development of risk

  18. Yiqi Formula Enhances the Antitumor Effects of Erlotinib for Treatment of Triple-Negative Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    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.

  19. 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.

  20. Correlation between 18F-FDG uptake on PET/CT and prognostic factors in triple-negative breast cancer

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate whether a correlation exists between 18F-fluorodeoxyglucose (FDG) uptake and prognostic factors in triple-negative breast cancer (TNBC). Between January 2009 and December 2013, 103 patients (mean age, 50.6 years) with primary TNBC (mean, 2.6 cm; range, 1.0-6.5 cm) underwent 18F-FDG PET/CT for initial staging. Correlations between maximum standardized uptake value (SUVmax) on PET/CT and prognostic factors including tumour size, nodal status, histological grade, Ki-67 proliferation index, tumour suppressor p53, and 'basal-like' markers (epidermal growth factor receptor and CK 5/6) were assessed. The mean SUVmax of the 103 tumours was 10.94 ± 5.25 (range: 2-32.8). There was a positive correlation between SUVmax and Ki-67 (Spearman's rho = 0.29, P = 0.003) and tumour size (Spearman's rho = 0.27, P = 0.006), whereas this relationship was not observed in the nodal status, histological grade, p53 status and 'basal-like' phenotypes. In a multivariate regression analysis, Ki-67 (P < 0.001) and tumour size (P = 0.009) were significantly associated with SUVmax in TNBCs. Increased 18F-FDG uptake on PET/CT was correlated with a high Ki-67 proliferation index and larger tumour size in TNBC. These results suggest a potential role of 18F-FDG PET/CT in identifying TNBC with more aggressive behaviour. (orig.)

  1. The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

    Science.gov (United States)

    Dine, Jennifer L; O'Sullivan, Ciara C; Voeller, Donna; Greer, Yoshimi E; Chavez, Kathryn J; Conway, Catherine M; Sinclair, Sarah; Stone, Brandon; Amiri-Kordestani, Laleh; Merchant, Anand S; Hewitt, Stephen M; Steinberg, Seth M; Swain, Sandra M; Lipkowitz, Stanley

    2016-01-01

    Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist. PMID:26759246

  2. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Suba Z

    2014-01-01

    Full Text Available Zsuzsanna Suba National Institute of Oncology, Surgical and Molecular Tumor Pathology Centre, Budapest, Hungary Abstract: Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs may be distinct entities as compared with estrogen receptor (ER+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER- breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers – included TNBCs – is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. Keywords: cancer prevention, infertility, insulin resistance, menopause

  3. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    Science.gov (United States)

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  4. Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.

    Science.gov (United States)

    Brinkman, Ashley M; Chen, Guojun; Wang, Yidan; Hedman, Curtis J; Sherer, Nathan M; Havighurst, Thomas C; Gong, Shaoqin; Xu, Wei

    2016-09-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which there is no available targeted therapy. TNBC cases contribute disproportionately to breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI) investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12 amino acid peptide targeting epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC tumors. These unimolecular micelles possessed excellent stability and preferentially released drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loaded, GE11-conjugated (targeted) unimolecular micelle NPs significantly inhibit orthotopic TNBC tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and tumor level of AF among different treatment groups yet exhibited no increase in plasma aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC. PMID:27267625

  5. miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity.

    Science.gov (United States)

    O'Brien, Keith; Lowry, Michelle C; Corcoran, Claire; Martinez, Vanesa G; Daly, Melissa; Rani, Sweta; Gallagher, William M; Radomski, Marek W; MacLeod, Roderick A F; O'Driscoll, Lorraine

    2015-10-20

    Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer. PMID:26416415

  6. Computational Analysis of mRNA Expression Profiles Identifies the ITG Family and PIK3R3 as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration

    OpenAIRE

    Klahan, Sukhontip; Wu, Mei-Shin; Hsi, Edward; Huang, Chi-Cheng; Hou, Ming-Feng; Chang, Wei-Chiao

    2014-01-01

    Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to det...

  7. Activity Assay of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer Cells Using Peptide-Conjugated Magnetic Beads

    OpenAIRE

    Ghosh, Gargi; Yan, Xiaoliang; Kron, Stephen J.; Palecek, Sean P.

    2013-01-01

    Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options. Epidermal growth factor receptor I (EGFR) has emerged as a promising target in TNBC. Limited success of the EGFR kinase inhibiting small molecules in clinical trials may be attributed in part to inaccuracy in identifying EGFR signatures in patient tumors. In light of the absence of a simple correlation between EGFR expression and its degree of activation, a simple and reliable ...

  8. Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from algeria compared with other types of breast cancer tumors.

    Directory of Open Access Journals (Sweden)

    Marilys Corbex

    Full Text Available The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups.One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology.Viral DNA was found in 22 (17.9% of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type than non-IBC tumors (30% vs. 13%, p<0.04. Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009.Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative. While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings.

  9. Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20–44 years of age

    OpenAIRE

    Li, Christopher I.; Beaber, Elisabeth F.; Tang, Mei-Tzu Chen; Porter, Peggy L.; Daling, Janet R.; Malone, Kathleen E.

    2012-01-01

    Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case–control study of women 20–44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers...

  10. FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells

    OpenAIRE

    Taliaferro-Smith, LaTonia; Oberlick, Elaine; Liu, Tongrui; McGlothen, Tanisha; Alcaide, Tiffanie; Tobin, Rachel; Donnelly, Siobhan; Commander, Rachel; Kline, Erik; Nagaraju, Ganji Purnachandra; Havel, Lauren; Marcus, Adam; Nahta, Rita; O'Regan, Ruth

    2015-01-01

    Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelati...

  11. Targeting triple-negative breast cancer cells with 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles.

    Science.gov (United States)

    Santos, Kathleen; Laranjo, Mafalda; Abrantes, Ana Margarida; Brito, Ana F; Gonçalves, Cristina; Sarmento Ribeiro, Ana Bela; Botelho, M Filomena; Soares, Maria I L; Oliveira, Andreia S R; Pinho e Melo, Teresa M V D

    2014-05-22

    Further studies on 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against breast cancer are reported, allowing to demonstrate the potential of these compounds for the therapy of the triple-negative breast cancer, the most challenging tumors in clinical practice. These compounds were assayed for their in vitro cytotoxicity on several human breast cancer cell lines (MCF7, HCC1954 and HCC1806 cell lines). Particularly interesting were the results obtained for 4-hydroxyphenyl substituted derivative, which proved to be the most promising compound regarding HCC1806 cell line, a triple-negative breast cancer. The effects of the two most active compounds on cell survival, viability, cell cycle, DNA damage and expression of proteins related to cell death pathways were studied. The reported results consolidate the potential of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles for the therapy of breast cancer, particularly the triple-negative. PMID:24747064

  12. Integration of photothermal therapy and synergistic chemotherapy by a porphyrin self-assembled micelle confers chemosensitivity in triple-negative breast cancer.

    Science.gov (United States)

    Su, Shishuai; Ding, Yanping; Li, Yiye; Wu, Yan; Nie, Guangjun

    2016-02-01

    Triple-negative breast cancer is a malignant cancer type with a high risk of early recurrence and distant metastasis. Unlike other breast cancers, triple-negative breast cancer is lack of targetable receptors and, therefore, patients largely receive systemic chemotherapy. However, inevitable adverse effects and acquired drug resistance severely constrain the therapeutic outcome. Here we tailor-designed a porphyrin-based micelle that was self-assembled from a hybrid amphiphilic polymer comprising polyethylene glycol, poly (d, l-lactide-co-glycolide) and porphyrin. The bilayer micelles can be simultaneously loaded with two chemotherapeutic drugs with synergistic cytotoxicity and distinct physiochemical properties, forming a uniform and spherical nanostructure. The drug-loaded micelles showed a tendency to accumulate in the tumor and can be internalized by tumor cells for drug release in acidic organelles. Under near-infrared laser irradiation, high density of self-quenched porphyrins in the hydrophobic layer absorbed light efficiently and converted into an excited state, leading to the release of sufficient heat for photothermal therapy. The integration of localized photothermal effect and synergistic chemotherapy conferred great chemosensitivity to cancer cells and achieved tumor regression using about 1/10 of traditional drug dosage. As a result, chemotherapy-associated adverse effects were successfully avoided. Our present study established a novel porphyrin-based nanoplatform with photothermal activity and expanded drug loading capacity, providing new opportunities for challenging conventional chemotherapy and fighting against stubborn triple-negative breast cancer. PMID:26708642

  13. Frequently increased epidermal growth factor receptor (EGFR) copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative) (TNBC) is a high risk breast cancer that lacks specific therapy targeting these proteins. We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR) gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years. A total of 110 (11.3%) patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers. TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease

  14. Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231.

    Science.gov (United States)

    De Blasio, Anna; Di Fiore, Riccardo; Morreale, Marco; Carlisi, Daniela; Drago-Ferrante, Rosa; Montalbano, Mauro; Scerri, Christian; Tesoriere, Giovanni; Vento, Renza

    2016-06-01

    Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target. PMID

  15. ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Sixiang [University of Wisconsin, Materials Science Program, Madison, WI (United States); Hong, Hao; Orbay, Hakan; Yang, Yunan; Ohman, Jakob D. [University of Wisconsin, Department of Radiology, Madison, WI (United States); Graves, Stephen A.; Nickles, Robert J. [University of Wisconsin, Department of Medical Physics, Madison, WI (United States); Liu, Bai; Wong, Hing C. [Altor BioScience, Miramar, FL (United States); Cai, Weibo [University of Wisconsin, Materials Science Program, Madison, WI (United States); University of Wisconsin, Department of Radiology, Madison, WI (United States); University of Wisconsin, Department of Medical Physics, Madison, WI (United States); University of Wisconsin Carbone Cancer Center, Madison, WI (United States); University of Wisconsin, Departments of Radiology and Medical Physics, Madison, WI (United States)

    2015-07-15

    To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and {sup 64}Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of {sup 64}Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of {sup 64}Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. {sup 64}Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. (orig.)

  16. Lactobacilli Modulate Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway in Triple Negative Breast Cancer Cell Line

    Science.gov (United States)

    Abedin-Do, Atieh; Mirfakhraie, Reza; Shirzad, Mahdieh; Ghafouri-Fard, Soudeh; Motevaseli, Elahe

    2016-01-01

    Objective Hypoxia-Inducible Factor (HIF)-1 plays an essential role in the body’s response to low oxygen concentrations and regulates expression of several genes implicated in homeostasis, vascularization, anaerobic metabolism as well as immunological responses. Increased levels of HIF-1α are associated with increased proliferation and more aggressive breast tumor development. Lactobacilli have been shown to exert anti-cancer effects on several malignancies including breast cancer. However, the exact mechanism of such effect is not clear yet. The aim of this study was to analyze the expression of selected genes from HIF pathway in a triple negative breast cancer cell line (expressing no estrogen and progesterone receptors as well as HER-2/Neu), MDA-MB-231, following treatment with two lactobacilli culture supernatants. Materials and Methods In this experimental study, we analyzed the expression of HIF-1α, SLC2A1, VHL, HSP90, XBP1 and SHARP1 genes from HIF pathway in MDA-MB-231 cells, before and after treatment with Lactobacillus crispatus and Lactobacillus rhamnosus culture supernatants (LCS and LRS, respectively) by means of quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results Both LRS and LCS had cytotoxic effects on MDA-MB-231 cells, while the former type was more cytotoxic. LRS dramatically down-regulated expression levels of the HIF-1α, HSP90 and SLC2A1 in the MDA-MB-231 cells. LCS had similar effect on the expression of HSP90, to what was observed in the LRS treatment. The expression level of tumor suppressor genes VHL and SHARP1 were also decreased in LCS treated cells. Conclusion Although both LCS and LRS had cytotoxic effects on the MDA-MB-231 cells, it is proposed that LRS could be more appropriate for pathway directed treatment modalities, as it did not decrease expression of tumor suppressor genes involved in HIF pathway. Down-regulation of HIF pathway mediated oncogenes by LRS suggests that the cytotoxic effects of this

  17. Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery

    International Nuclear Information System (INIS)

    The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation. A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median Dmax) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %). After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03). Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3. (orig.)

  18. 三阴性乳腺癌患者的临床特征与预后分析%Clinical characteristics and prognosis of triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    Hua Cao; Maosheng Yan; Shubin Wang; Tao Zheng; Rulian Xu; Yixin Chen; Yajie Liu

    2009-01-01

    Objective: We investigated the clinical characteristics, and the prognostic factors of triple-negative breast can-cer. Methods: 130 triple-negative breast cancer patients were reviewed on clinical characteristics and prognosis. All cases were lack of expression of estrogen receptor, progesterone receptor, and HER2/neu determined by immunohistochemistry.Results: 17.1% of all breast cancer patients (774 cases) were triple-negative breast cancer, and 68.9% of triple-negative breast cancer patients (91 cases) were premenopausal. 53.8% of patients (71 cases) had the tumors with T2 size, and 39.4% of them (52 patients) had lymph node metastasis. The rate of relapse in patients with lymph node metastasis was obviously higher than that in patients without lymph node metastasis (P = 0.001). The median time of follow-up was 63 months. 33 cases relapsed and 20 patients died. 23 patients had at least two organs metastasis. The 5-year disease-free and overall survival rates were 73.8% and 85.7%. Conclusion: Triple-negative breast cancer patients commonly have high rate of multiple distant metastasis in 2-3 years after treatment. The status of lymph node is the most important prognostic factor. The triple-negative breast caner patients with lymph node metastasis have poor prognosis.

  19. p53 negativity, CDC25B positivity, and metallothionein negativity are predictors of a response of esophageal squamous cell carcinoma to chemoradiotherapy

    Institute of Scientific and Technical Information of China (English)

    Fumiko Sunada; Masayuki Itabashi; Hisanao Ohkura; Toshiyuki Okumura

    2005-01-01

    AIM: Esophageal squamous cell carcinoma is generally sensitive to chemoradiotherapy (CRT), but some cases are not. Using a retrospective analysis, we aimed to identify the predictors of the response by esophageal squamous cell carcinoma to definitive CRT.METHODS: The intensities of expression of p53, Ki67,Bcl-2, Bax, cyclin D1, VEGF, CDC25B, and metallothionein (MT)were evaluated immunohistochemically in the biopsy specimens obtained before CRT, and the intensities of their expression were tested for correlations with the clinical effects of CRT.RESULTS: The esophageal squamous cell carcinomas with negative p53, positive CDC25B, and negative MT expression were found to be significantly more sensitive to CRT. In addition, p53 positivity and CDC25B positivity respomd well to CRT.CONCLUSION: Esophageal squamous cell carcinomas with negative p53,positive CDC25B, and negative MT expressions respond well to CRT. Even with p53 positivity,if with CDC25B positivity, CRT can be expected.

  20. The role of GATA3 in breast carcinomas: a review.

    Science.gov (United States)

    Asch-Kendrick, Rebecca; Cimino-Mathews, Ashley

    2016-02-01

    GATA3 is a zinc-binding transcription factor that regulates the differentiation of many human tissue types, including the mammary gland. In surgical pathology, immunohistochemistry for GATA3 is largely used to support urothelial or breast origin in a carcinoma of unknown origin. GATA3 is sensitive but not entirely specific in this setting. Although GATA3 labeling is highest in estrogen receptor-positive carcinomas, it also labels estrogen receptor-negative carcinomas and thus has particular diagnostic utility in the setting of triple-negative breast carcinomas, which are typically negative for other mammary-specific markers. PMID:26772397

  1. Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

    International Nuclear Information System (INIS)

    Highlights: • Glycolytic markers are highly expressed in triple negative breast cancers. • Lactate/H+ symporter MCT4 demonstrated the strongest deleterious impact on survival. • MCT4 should serve as a new prognostic factor in node-negative breast cancers. - Abstract: Background: 18Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer. Methods: Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohorts of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively. Results: In the 643 node-negative breast tumor cohort with a median follow-up of 124 months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR = 0.47, P = 0.02) and overall-survival (HR = 0.38, P = 0.002). These results were confirmed in the independent cohort of 127 cancer patients. Conclusion: Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H+ symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors

  2. Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

    Energy Technology Data Exchange (ETDEWEB)

    Doyen, J. [Department of Radiation Oncology, Centre A. Lacassagne, Nice (France); Trastour, C. [Department of Gynecology, Archet II Hospital, 06202 Nice (France); Ettore, F.; Peyrottes, I.; Toussant, N. [Department of Pathology, Centre A. Lacassagne, Nice (France); Gal, J. [Department of Medical Statistics, Centre A. Lacassagne, Nice (France); Ilc, K.; Roux, D. [Institute for Research on Cancer and Aging (IRCAN), University of Nice, Centre A. Lacassagne, 06189 Nice (France); Parks, S.K. [Centre Scientifique de Monaco (CSM) (Monaco); Ferrero, J.M. [Department of Medical Oncology, Centre A. Lacassagne, Nice (France); Pouysségur, J., E-mail: jacques.pouyssegur@unice.fr [Institute for Research on Cancer and Aging (IRCAN), University of Nice, Centre A. Lacassagne, 06189 Nice (France); Centre Scientifique de Monaco (CSM) (Monaco)

    2014-08-15

    Highlights: • Glycolytic markers are highly expressed in triple negative breast cancers. • Lactate/H{sup +} symporter MCT4 demonstrated the strongest deleterious impact on survival. • MCT4 should serve as a new prognostic factor in node-negative breast cancers. - Abstract: Background: {sup 18}Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer. Methods: Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohorts of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively. Results: In the 643 node-negative breast tumor cohort with a median follow-up of 124 months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR = 0.47, P = 0.02) and overall-survival (HR = 0.38, P = 0.002). These results were confirmed in the independent cohort of 127 cancer patients. Conclusion: Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H{sup +} symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors.

  3. Targeting Mutant p53 by a SIRT1 Activator YK-3-237 Inhibits the Proliferation of Triple-Negative Breast Cancer Cells

    OpenAIRE

    Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong; Kong, Yali; Brown, Milton L.; Bae, Insoo

    2013-01-01

    Many types of mutations in tumor suppressor p53 are oncogenic through gain-of-function. Therefore, targeting mutant p53 (mtp53) is a promising therapeutic approach to fight against many types of cancers. We report here a small molecule compound YK-3-237 that reduces acetylation of mtp53 and exhibits anti-proliferative effects toward triple-negative breast cancer (TNBC) cells carrying mtp53. YK-3-237 activates SIRT1 enzyme activities in vitro and deacetylation of both mtp53 and wild type p53 (...

  4. The PIKfyve–ArPIKfyve–Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines

    International Nuclear Information System (INIS)

    Highlights: •We assess PAS complex proteins and phosphoinositide levels in breast cancer cells. •Sac3 and ArPIKfyve are markedly elevated in triple-negative breast cancer cells. •Sac3 silencing inhibits proliferation in triple-negative breast cancer cell lines. •Phosphoinositide profiles are altered in breast cancer cells. •This is the first evidence linking high Sac3 with breast cancer cell proliferation. -- Abstract: The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve–ArPIKfyve–Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P–PtdIns(3,5)P2 synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P–PtdIns(3,5)P2 conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P2 in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the

  5. The PIKfyve–ArPIKfyve–Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Ikonomov, Ognian C., E-mail: oikonomo@med.wayne.edu; Filios, Catherine, E-mail: cfilios@med.wayne.edu; Sbrissa, Diego, E-mail: dsbrissa@med.wayne.edu; Chen, Xuequn, E-mail: xchen@med.wayne.edu; Shisheva, Assia, E-mail: ashishev@med.wayne.edu

    2013-10-18

    Highlights: •We assess PAS complex proteins and phosphoinositide levels in breast cancer cells. •Sac3 and ArPIKfyve are markedly elevated in triple-negative breast cancer cells. •Sac3 silencing inhibits proliferation in triple-negative breast cancer cell lines. •Phosphoinositide profiles are altered in breast cancer cells. •This is the first evidence linking high Sac3 with breast cancer cell proliferation. -- Abstract: The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve–ArPIKfyve–Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P–PtdIns(3,5)P{sub 2} synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P–PtdIns(3,5)P{sub 2} conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P{sub 2} in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or

  6. PARP-1 expression in breast cancer including BRCA1-associated, triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy

    OpenAIRE

    Domagala, Pawel; Huzarski, Tomasz; Lubinski, Jan; Gugala, Karol; Domagala, Wenancjusz

    2011-01-01

    Abstract Despite ongoing trials of PARP inhibitors in the treatment of breast cancer (BC), the extent of poly(ADP-ribose)polymerase-1 (PARP-1) protein expression in BCs, which may influence treatment results, is not known. The purpose of this report is to assess expression of PARP-1 in BC including BRCA1-associated, triple negative (TN), and basal-like tumors. Immunohistochemistry with a PARP-1 antibody on tissue microarrays from 130 BRCA1-associated and 594 BRCA1-non-related BCs w...

  7. Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery

    Energy Technology Data Exchange (ETDEWEB)

    Fastner, Gerd; Zehentmayr, Franz; Kopp, Peter; Fussl, Christoph; Sedlmayer, Felix [Landeskrankenhaus, Paracelsus Medical University, Department of Radiotherapy and Radio-Oncology, Salzburg (Austria); Hauser-Kronberger, Cornelia [Landeskrankenhaus, Paracelsus Medical University, Department of Pathology, Salzburg (Austria); Moder, Angelika [Landeskrankenhaus, Paracelsus Medical University, Institute of Inborn Errors in Metabolism, Salzburg (Austria); Reitsamer, Roland; Fischer, Thorsten [Landeskrankenhaus, Paracelsus Medical University, Department of Special Gynecology, Salzburg (Austria); Landeskrankenhaus, Paracelsus Medical University, Department of Gynecology, Salzburg (Austria); Deutschmann, Heinrich [Landeskrankenhaus, Paracelsus Medical University, Department of Radiotherapy and Radio-Oncology, Salzburg (Austria); Paracelsus Medical University, Institute for Research and Development of Advanced Radiation Technologies (radART), Salzburg (Austria)

    2016-01-15

    The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation. A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median D{sub max}) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %). After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03). Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3. (orig.) [German] Ziel der Studie war es, im Rahmen einer retrospektiven Analyse Ueberlebens- und Lokalkontrollraten bei triple-negativen Mammakarzinomen zu untersuchen. Die Tumoren waren in 5NP(5-Marker-negative)- und CB(core basal)-Subtypen klassifiziert und die Patientinnen hatten nach brusterhaltender Operation und

  8. Combination therapy and evaluation of therapeutic effect in hepatocellular carcinoma cell using triple reporter genes; containing for NIS, HSV1-sr39tk and GFP

    International Nuclear Information System (INIS)

    To identify therapeutic effect after combine Sodium Iodine Symporter (NIS) and Mutant Herpes-simplex virus type 1 sr39tk (HSV1-sr39tk) expression in hepatocellular carcinoma cell, we transfected triple gene and investigated the properties of these gene ability in hepatocellular carcinoma cell line. After making vector with gene encoding a fusion protein comprised of HSV1-sr39tk and green florescence protein (GFP), to make triple reporter genes NIS gene was further fused to the vector using IRES vector. The vector expressing triple reporter gene was transfected to the Huh-7 cell line using liposome. Functions of hNIS and HSV1-sr39tk expression were confirmed by radio iodine uptake with and without perchlorate and [3H]-penciclovir (3-H PCV) uptake, respectively. To evaluate therapeutic effect in vitro, GCV and I-131 was treated in Huh-7/NTG cell and dual therapy performed. An animal imaging acquired using Optix and microPET in vivo. I-125 uptake was increased up to 100-fold compare to that of non-transfected cells. The transfected cell accumulated H-3 PCV up to 53 times higher at 2 hour than that of non-transfected cells. With fluorescence microscopy, green fluorescence was detected in the transfected cell. In cytotoxic studies, the cell viability of Huh-7/NTG cell was decreased to 41 % of control cell at 10ug/ml GCV concentrations. The survival rate of the Huh-7/NTG cell treated with I-131 decreased up to 16%. In I-131 and GCV dual therapy, Huh-7/NTG cell survival rate decreased up to 4%. In animal studies, Huh-7/NTG tumors showed higher uptake of 18F-FHBG and I-124 than Huh-7 tumors. GFP signal is also higher in Huh-7/NTG tumor than control. We successfully constructed a vector with delivery two therapeutic genes and one reporter gene and transfected the vector to a Huh-7 cell. The hepatocellular carcinoma cell transfected with the vector can be treated with GCV and I-131. The effect of dual gene therapy could be easily assessed by the optical reporter gene imaging

  9. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

    Directory of Open Access Journals (Sweden)

    Claudia Tulotta

    2016-02-01

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

  10. Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer.

    Science.gov (United States)

    Barrett, Michael T; Anderson, Karen S; Lenkiewicz, Elizabeth; Andreozzi, Mariacarla; Cunliffe, Heather E; Klassen, Christine L; Dueck, Amylou C; McCullough, Ann E; Reddy, Srikanth K; Ramanathan, Ramesh K; Northfelt, Donald W; Pockaj, Barbara A

    2015-09-22

    We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥ 1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis. PMID:26317899

  11. Utility of a novel triple marker (combination of thyroid transcription factor 1, Napsin A, and P40) in the subclassification of non-small cell lung carcinomas using fine-needle aspiration cases.

    Science.gov (United States)

    Sharma, Rajni; Wang, Yuting; Chen, Li; Gurda, Grzegorz T; Geddes, Susan; Gabrielson, Edward; Askin, Frederic; Li, Qing Kay

    2016-08-01

    Personalized treatment of lung cancer requires an accurate subclassification of non-small cell lung carcinoma (NSCLC) into adenocarcinoma (ADC), squamous cell carcinoma (SqCC), and other subtypes. In poorly differentiated tumors especially on small fine-needle aspirate specimens, the subclassification could be difficult in certain cases. Our previous study using resected tumor tissue has shown that the combination of commonly used individual markers (thyroid transcription factor 1 [TTF-1], P40, and Napsin A) into a novel triple marker has high sensitivity and specificity in subclassification of NSCLC and also the advantage of using minimal tumor tissue. In this study, we further evaluated the utility of this novel triple marker using fine-needle aspirate cases. We included primary NSCLC, consisting of 37 SqCCs (primary, 35; metastasis, 2) and 50 ADCs (primary, 29; metastasis, 21), 12 metastatic ADCs of nonpulmonary primary, and 10 small cell lung carcinomas. The immunohistochemical patterns were semiquantitatively scored. In lung SqCCs and ADCs, the sensitivity and specificity of the triple marker were 100% and 97.1% and 86.0% and 100%, respectively. The triple marker showed no immunoreactivity in 12 metastatic nonpulmonary ADCs. In 10 small cell lung carcinomas, TTF-1 had focal positivity in 40% of cases. The limitations of the triple marker include staining of alveolar macrophages (by TTF-1 and Napsin A), basal layer of bronchial epithelial cells (by P40), and nonspecific cytoplasmic staining of TTF-1. Our study not only supports our previous finding using resected tumor specimens but also provides evidence that the triple marker can be used for cytological material and preserving tumor tissue for molecular testing. PMID:27045515

  12. Significant difference in p53 and p21 protein immunoreactivity in HPV 16 positive and HPV negative breast carcinomas

    International Nuclear Information System (INIS)

    Human papillomavirus (HPV) 16 has previously been found in 19/41 breast carcinomas (46%) in women with a history of HPV 16 positive CIN III lesions. There was no significant difference in distribution of histological subtypes, mean or median tumour diameter or number of regional lymph node metastases in the HPV positive and HPV negative breast carcinoma groups. P53, p21 and c-erbB-2 proteins were analyzed by immunohistochemistry in the HPV 16 positive and HPV negative breast carcinomas. There was a significant difference in p53 and p21 protein immunoreactivity between HPV 16 positive and HPV negative breast carcinomas (p=0.0091 and p=0.0040), with a significant less detectable p53 and p21 protein immunoreactivity in the HPV 16 positive cases. There was also a significant difference in the coexpression of p53/p21 between the HPV 16 positive and HPV 16 negative breast carcinomas (p=0.002). No significant difference in immunostaining for c-erbB-2 protein in the two groups was found (p=0.15), or for the coexpression of p53/c-erbB-2 (p=0.19). The significantly lower expression of p53 and p21 proteins in HPV 16 positive than in HPV 16 negative breast carcinomas supports the hypothesis of inactivation and degradation of wild-type p53 proteins by HPV 16 E6 and that p53 mutation is not necessary for transformation in the HPV 16 positive cases. (orig.)

  13. Response and Long-Term Effect of Patients with Triple-Negative Breast Cancer Receiving Neo-Adjuvant Anthracycline-Based

    Institute of Scientific and Technical Information of China (English)

    Zhengkui Sun; Xingtian Ma; Yudong Wu; Fan Fan; Xianghua Wan; Airong Fu

    2009-01-01

    OBJECTIVE The breast cancer lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) is defined as the Triple-negative breast cancer (TNBC). Our purpose is to compare the response and long-term effect of the TNBC and non-TNBC patients receiving neo-adjuvant anthracycline-based chemotherapy, and to investigate the mechanisms of TNBC affecting the survivals. METHODS Data of long-term follow-up (median, 5.4 years) of 326 patients who received neo-adjuvant chemotherapy with anthracycline-based regimen, during a period from 2000 to 2003, were analyzed. Expressions of ER, PR, HER-2, P53, Ki-67 and E-cadherin were determined using immunohistochemical staining method. A multivariate Cox regression analysis was used to analyze independent prognostic factors affecting the relapse-free survival (RFS) and overall survival (OS) rates. Clinical effects of the neo-adjuvant anthracycline-based chemotherapeutic regimen and the RFS and OS rates were compared between the patients with TNBC and non-TNBC, and the correlations among the triple- negative phenotype (TNP), tumor grading and the expressions of P53, Ki-67 and E-cadherins were analyzed. RESULTS TNP, TNM staging, histological grades, clinical response of the neo-adjuvant chemotherapy and pathological complete remission (pCR) rate were the independent prognostic factors affecting the survival rates. Furthermore, 70 (21.5%) of the 326 patients suffered TNBC. Compared with the subjects in non- TNBC group, the patients with TNBC had a significantly higher pCR rate (P=0.046) and clinical response rate (P=0.037), but also decreased 5-year RFS (P=0.001) and OS (P=0.004) rates. The RFS and OS rates were not improved in the TNBC patients who achieved a clinical remission after the neo-adjuvant chemotherapy. The triple-negative phenotype was positively correlated with the level of P53, Ki-67 expression (P=0.007, P=0.028), but negatively correlated with level of

  14. Estrogen receptor-negative breast ductal carcinoma: clinicopathological features and MIB-1 (Ki-67 proliferative index association.

    Directory of Open Access Journals (Sweden)

    Noorasmaliza Mdpaiman

    Full Text Available Breast cancer estrogen receptor (ER status is one of the strong additional factors in predicting response of patients towards hormonal treatment. The main aim of this study was to assess the morphological characteristics and proliferative activity using MIB-1(Ki-67 of estrogen receptor negative invasive breast ductal carcinoma (NOS type as well as to correlate these features with clinicopathological data. We also aim to study the expression of c-erbB2 in ER negative breast tumors. High proliferative rate (MIB-1 above 20% was observed in 63 (63.6% of 99 ER negative tumors and that these tumors were associated with high expression of c-erbB2 (57.6%. We observed that MIB-1 is a reliable independent prognostic indicator for ER negative infiltrating ductal carcinoma in this study.

  15. Estrogen Receptor-Negative Breast Ductal Carcinoma: Clinicopathological Features and Mib-1 (Ki-67) Proliferative Index Association

    OpenAIRE

    Noorasmaliza Mdpaiman; Siti Aishah Md Ali; Reena Mdzin; Meor Zamari Meor Kamal; Wan Anna Md Amin; Mohan Nallusamy; Pavitratha Puspanathan; Rohaizak Muhammad; Sharifa Ezat Wan Puteh; Srijit Das

    2014-01-01

    Breast cancer estrogen receptor (ER) status is one of the strong additional factors in predicting response of patients towards hormonal treatment. The main aim of this study was to assess the morphological characteristics and proliferative activity using MIB-1(Ki-67) of estrogen receptor negative invasive breast ductal carcinoma (NOS type) as well as to correlate these features with clinicopathological data. We also aim to study the expression of c-erbB2 in ER negative breast tumors. High pro...

  16. The Comparative Study on Ultrastructure and Immunohistochemistry in AFP Negative and Positive Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    郑美蓉; 阮幼冰; 杨木兰; 官阳; 武忠弼

    2004-01-01

    To comparatively investigate ultrastructural characteristics and expressions of AFP(alpha-fetoprotein) and Tn (Thomsen-Friedenreich-related antigen) protein in AFP negative (AFP-)and AFP positive (AFP+) primary hepatocellular carcinoma. Fourty-three cases of AFP- and AFP+ hepatocellular carcinoma (HCC) tissues and five cases of normal liver tissues were divided into three groups: control group (normal liver tissue, n=5); AFP+ HCC group (the serum AFP level was higher than 10 ng/ml, n = 22); AFP- HCC group (the serum AFP level was lower than 10 ng/ml, n=21). The ultrastructural morphology was studied by transmission electron microscopy, the expressions of AFP and Tn protein were detected by immunohistochemistry and cell image analysis. 1. The immunohistochemical study showed that (1) the expression intensity and positive rate of Tn protein in AFP- HCC group were markedly higher than that in AFP+ HCC group (P<0.01); (2) The expression intensity of AFP in AFP- HCC group was lower than that in AFP+ HCC group (P<0.01 ). 2. The transmission electron microscopy demonstrated that some AFP- HCC cells linked closely with each other, others dispersed loosely just as cultured cells, the remarkable morphologic features in AFP- HCC cells were simple organelles, But they were abundant in the free polyribosomes. In AFP+ HCC group, all the HCC cells linked closely together and were rich organelles in their cytoplasm, especially the rough endoplasmic reticula. In addition, mitochondria and Golgi complex were obviously observed. (1) The AFP and Tn protein had discrepancy distribution in AFP- and AFP+ HCC tissues, Tn protein may be one of the early diagnostic indicators in AFP- HCC; (2) The synthetic locations of the AFP and Tn protein were different in hepatocarcinoma cells by ultrastructural observation.

  17. Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials

    DEFF Research Database (Denmark)

    Juul, Nicolai Stefan; Szallasi, Zoltan Imre; Eklund, Aron Charles;

    2010-01-01

    )/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes......Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER...... involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple...

  18. Sentinel lymph node biopsy in node-negative squamous cell carcinoma of the oral cavity and oropharynx.

    LENUS (Irish Health Repository)

    Burns, P

    2012-02-01

    OBJECTIVES: Considerable controversy exists regarding the merits of elective neck dissection in patients with early stage oral cavity and oropharyngeal squamous cell carcinoma. It is highly desirable to have a method of identifying those patients who would benefit from further treatment of the neck when they are clinically node-negative. The purpose of the present study was to examine the use of sentinel lymph node biopsy in identifying occult neck disease in a cohort of patients with node-negative oral cavity and oropharyngeal squamous cell carcinoma. DESIGN: We evaluated a total of 13 patients with oral cavity and oropharyngeal cancer who were clinically and radiologically node-negative. RESULTS: A sentinel lymph node was found in all 13 patients, revealing metastatic disease in five patients, four of whom had one or more positive sentinel lymph nodes. There was one false negative result, in which the sentinel lymph node was negative for tumour whereas histological examination of the neck dissection specimen showed occult disease. CONCLUSION: In view of these findings, we would recommend the use of sentinel lymph node biopsy in cases of oral cavity and oropharyngeal squamous cell carcinoma, in order to aid the differentiation of those patients whose necks are harbouring occult disease and who require further treatment.

  19. Computational Analysis of mRNA Expression Profiles Identifies the ITG Family and PIK3R3 as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration

    Directory of Open Access Journals (Sweden)

    Sukhontip Klahan

    2014-01-01

    Full Text Available Triple-negative breast cancer (TNBC is an aggressive type of breast cancer that does not express estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor (Her2/neu. TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926 and non-Asian populations (GSE46581 to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes, PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy.

  20. A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer

    Science.gov (United States)

    Kaur, Sukhbir; Elkahloun, Abdel G.; Singh, Satya P.; Chen, Qing-Rong; Meerzaman, Daoud M.; Song, Timothy; Manu, Nidhi; Wu, Weiwei; Mannan, Poonam; Garfield, Susan H.; Roberts, David D.

    2016-01-01

    CD47 is a signaling receptor for thrombospondin-1 and the counter-receptor for signal-regulatory protein-α (SIRPα). By inducing inhibitory SIRPα signaling, elevated CD47 expression by some cancers prevents macrophage phagocytosis. The anti-human CD47 antibody B6H12 inhibits tumor growth in several xenograft models, presumably by preventing SIRPα engagement. However, CD47 signaling in nontransformed and some malignant cells regulates self-renewal, suggesting that CD47 antibodies may therapeutically target cancer stem cells (CSCs). Treatment of MDA-MB-231 breast CSCs with B6H12 decreased proliferation and asymmetric cell division. Similar effects were observed in T47D CSCs but not in MCF7 breast carcinoma or MCF10A breast epithelial cells. Gene expression analysis in breast CSCs treated with B6H12 showed decreased expression of epidermal growth factor receptor (EGFR) and the stem cell transcription factor KLF4. EGFR and KLF4 mRNAs are known targets of microRNA-7, and B6H12 treatment correspondingly enhanced microRNA-7 expression in breast CSCs. B6H12 treatment also acutely inhibited EGF-induced EGFR tyrosine phosphorylation. Expression of B6H12-responsive genes correlated with CD47 mRNA expression in human breast cancers, suggesting that the CD47 signaling pathways identified in breast CSCs are functional in vivo. These data reveal a novel SIRPα-independent mechanism by which therapeutic CD47 antibodies could control tumor growth by autonomously forcing differentiation of CSC. PMID:26840086

  1. Visualising dual downregulation of insulin-like growth factor receptor-1 and vascular endothelial growth factor-A by heat shock protein 90 inhibition effect in triple negative breast cancer

    NARCIS (Netherlands)

    Terwisscha Van Scheltinga, Anton G. T.; Berghuis, Paul; Nienhuis, Hilde H.; Timmer-Bosscha, Hetty; Pot, Linda; Gaykema, Sietske B. M.; Lub-de Hooge, Marjolijn N.; Kosterink, Jos G. W.; de Vries, Elisabeth G. E.; Schroder, Carolien P.

    2014-01-01

    Purpose: Triple negative breast cancer (TNBC) is biologically characterised by heterogeneous presence of molecular pathways underlying it. Insulin-like growth factor receptor-1 (IGF-1R) expression and vascular endothelial growth factor-A (VEGF-A) have been identified as key factors in these pathways

  2. 三阴性乳腺癌66例临床分析%Clinical analysis about 66 cases of the triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    钟巨辉; 刘晓安

    2015-01-01

    目的:研究三阴性乳腺癌患者的临床特点,并分析影响其预后的因素。方法采用病案调查法,收集我院2011年9月~2013年10月就诊的66例三阴性乳腺癌患者,将其分为三阴性乳腺癌组(TNBC组,16例)和非三阴性乳腺癌组(non-TNBC组,50例)。用χ2检验及精确概率 Fisher检验对患者的生存情况、临床病理学特征等临床资料以及年龄、肿瘤大小、腋窝淋巴结数目、病理类型、局部及远处转移等因素进行统计学分析。结果三阴性乳腺癌组与非三阴性乳腺癌组的临床病理学特点、发病时月经状态差异无统计学意义(P>0.05);病理检查肿瘤大小、腋窝淋巴结数目、病理类型、局部及远处转移等显示两组有统计学差异(P0.05);pathologic examination,tumor size,axillary lymph node number,pathological type,such as local and distant metastasis showed in the two groups was statistically difference (P<0.05); the recurrence metastasis rate of two groups had a differences with statistically sig-nificant (P<0.05). Conclusion The triple-negative was a high risk of breast cancer, breast cancer in premenopausal women. The association between tumor size and axillary lymph node status was not big; tumor diameter of the head,high recurrence rate, distant metastasis occurred early; should promote targeted drugs appeared for triple-negative breast cancer patients.

  3. The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells.

    Science.gov (United States)

    Chen, Ming; He, Mengye; Song, Yinjing; Chen, Luoquan; Xiao, Peng; Wan, Xiaopeng; Dai, Feng; Shen, Peng

    2014-07-01

    Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor‑negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug-induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple‑negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB‑231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for

  4. PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.

    Science.gov (United States)

    Gari, Hamid H; DeGala, Gregory D; Ray, Rahul; Lucia, M Scott; Lambert, James R

    2016-10-01

    Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells. PMID:27452906

  5. Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer

    International Nuclear Information System (INIS)

    Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment 18F-FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. Initial staging with 18F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. 18F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P 18F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation. (orig.)

  6. Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides.

    Directory of Open Access Journals (Sweden)

    Yung-Luen Yu

    Full Text Available Tyrosine 211 (Y211 phosphorylation of proliferation cell nuclear antigen (PCNA coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR tyrosine kinase inhibitor (TKI-resistant cells, both nuclear EGFR (nEGFR expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC. Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA in vivo; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP, which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.

  7. The relationship between nuclear factor (NF)-κB family gene expression and prognosis in triple-negative breast cancer (TNBC) patients receiving adjuvant doxorubicin treatment.

    Science.gov (United States)

    Kim, Ji-Yeon; Jung, Hae Hyun; Ahn, Soomin; Bae, SooYoun; Lee, Se Kyung; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    We investigated gene expression profiles of the NF-κB pathway in patients with triple-negative breast cancer (TNBC) receiving adjuvant chemotherapy to determine the prognostic value of NF-κB pathway genes according to chemotherapeutic regimen. We used the nCounter expression assay to measure expression of 11 genes (NFKB1, NFKB2, RELA, RELB, REL, TP53, FOXC1, TBP, SP1, STAT3 and IRF1 genes) belonging to the NF-κB pathway using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Of the 203 patients, 116 were treated with a chemotherapeutic regimen containing doxorubicin. As revealed by the expression profiles of the 11 genes, increased expression of SP1 was associated with poor prognosis in TNBC patients treated with adjuvant doxorubicin chemotherapy (5-year distant recurrence-free survival [5Y DRFS], low vs. high expression [cut-off: median]: 92.3% vs. 71.6%, P = 0.001). In a multivariate Cox regression model, SP1 expression was a useful marker for predicting long-term prognosis in TNBC patients receiving doxorubicin treatment, and we thus suggest that SP1 expression could serve as a prognostic marker in these patients. PMID:27545642

  8. Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells.

    Science.gov (United States)

    Fang, Yi; Zhang, Qian; Wang, Xin; Yang, Xue; Wang, Xiangyu; Huang, Zhen; Jiao, Yuchen; Wang, Jing

    2016-03-01

    Around one sixth of breast cancer cases are classified as triple-negative breast cancer (TNBC), named after the absence of the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2); however, patients with TNBC suffer from poor clinical outcome and shortage of targeted therapy. Genistein, an estrogenic soy isoflavone, shows anticancer effects in TNBC cells such as inducing G2/M cell cycle arrest and apoptosis. However, the underlying mechanism of its anticancer effects is poorly understood and its elucidation can help the development of novel therapeutic strategies for TNBC. In this study, by combining isobaric tag-based TMT labeling with titanium dioxide-based phosphopeptide enrichment, we quantitated 5,445 phosphorylation sites on 2,008 phosphoproteins in the TNBC cell line MDA-MB-231, upon genistein treatment. Our analysis revealed 332 genistein-regulated phosphorylation sites on 226 proteins. Our data show that genistein can regulate several biological processes during the cell cycle, including DNA replication, cohesin complex cleavage, and kinetochore formation. Furthermore, genistein can also activate DNA damage response, including activation of ATR and BRCA1 complex. Overall, our study presents evidence at a phosphoproteomic level that genistein is able to inhibit TNBC cell growth by regulating the cell cycle and DNA damage response in a more complex manner. Our findings help elucidate the mechanisms through which genistein exerts its anticancer effects in TNBC cells. PMID:26783066

  9. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair.

    Science.gov (United States)

    Liang, Diana H; Choi, Dong Soon; Ensor, Joe E; Kaipparettu, Benny A; Bass, Barbara L; Chang, Jenny C

    2016-07-01

    Triple negative breast cancer (TNBC), characterized by an abundance of treatment-resistant breast cancer stem cells (CSCs), has a poorer prognosis than other types of breast cancers. Despite its aggressiveness, no effective targeted therapy exists for TNBC. Here, we demonstrate that CQ effectively targets CSCs via autophagy inhibition, mitochondrial structural damage, and impairment of double-stranded DNA break repair. Electron microscopy demonstrates CQ-induced mitochondrial cristae damage, which leads to mitochondrial membrane depolarization with a significant reduction in the activity of cytochrome c oxidase and accumulation of superoxide and double-stranded DNA breaks. CQ effectively diminishes the TNBC cells' ability to metastasize in vitro and in a TNBC xenograft model. When administered in combination with carboplatin, CQ effectively inhibits carboplatin-induced autophagy. This combination treatment significantly diminishes the expression of DNA repair proteins in CSC subpopulations, resulting in tumor growth reduction in carboplatin-resistant BRCA1 wild-type TNBC orthotopic xenografts. As TNBC's high treatment failure rate has been attributed to enrichment of CSCs, CQ, an autophagy inhibitor with anti-CSC effects, may be an effective adjunct to current TNBC chemotherapy regimens with carboplatin. PMID:27060208

  10. Multi-agent System for Obtaining Relevant Genes in Expression Analysis between Young and Older Women with Triple Negative Breast Cancer.

    Science.gov (United States)

    González-Briones, Alfonso; Ramos, Juan; De Paz, Juan Francisco; Corchado, Juan Manuel

    2015-01-01

    Triple negative breast cancer is an aggressive form of breast cancer. Despite treatment with chemotherapy, relapses are frequent and response to these treatments is not the same in younger women as in older women. Therefore, the identification of genes that cause this difference is required. The identification of therapeutic targets is one of the sought after goals to develop new drugs. Within the range of different hybridization techniques, the developed system uses expression array analysis to measure the expression of the signal levels of thousands of genes in a given sample. Probesets of Gene 1.0 ST GeneChip arrays provide categorical genome transcript coverage, providing a measurement of the expression level of the sample. This paper proposes a multi-agent system to manage information of expression arrays, with the goal of providing an intuitive system that is also extensible to analyze and interpret the results. The roles of agent integrate different types of techniques, statistical and data mining methods that select a set of genes, searching techniques that find pathways in which such genes participate, and an information extraction procedure that applies a CBR system to check if these genes are involved in the disease. PMID:26673929

  11. The relationship between nuclear factor (NF)-κB family gene expression and prognosis in triple-negative breast cancer (TNBC) patients receiving adjuvant doxorubicin treatment

    Science.gov (United States)

    Kim, Ji-Yeon; Jung, Hae Hyun; Ahn, Soomin; Bae, SooYoun; Lee, Se Kyung; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    We investigated gene expression profiles of the NF-κB pathway in patients with triple-negative breast cancer (TNBC) receiving adjuvant chemotherapy to determine the prognostic value of NF-κB pathway genes according to chemotherapeutic regimen. We used the nCounter expression assay to measure expression of 11 genes (NFKB1, NFKB2, RELA, RELB, REL, TP53, FOXC1, TBP, SP1, STAT3 and IRF1 genes) belonging to the NF-κB pathway using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Of the 203 patients, 116 were treated with a chemotherapeutic regimen containing doxorubicin. As revealed by the expression profiles of the 11 genes, increased expression of SP1 was associated with poor prognosis in TNBC patients treated with adjuvant doxorubicin chemotherapy (5-year distant recurrence-free survival [5Y DRFS], low vs. high expression [cut-off: median]: 92.3% vs. 71.6%, P = 0.001). In a multivariate Cox regression model, SP1 expression was a useful marker for predicting long-term prognosis in TNBC patients receiving doxorubicin treatment, and we thus suggest that SP1 expression could serve as a prognostic marker in these patients. PMID:27545642

  12. Novel cell-penetrating peptide-loaded nanobubbles synergized with ultrasound irradiation enhance EGFR siRNA delivery for triple negative Breast cancer therapy.

    Science.gov (United States)

    Jing, Hui; Cheng, Wen; Li, Shouqiang; Wu, Bolin; Leng, Xiaoping; Xu, Shouping; Tian, Jiawei

    2016-10-01

    The lack of safe and effective gene delivery strategies remains a bottleneck for cancer gene therapy. Here, we describe the synthesis, characterization, and application of cell-penetrating peptide (CPP)-loaded nanobubbles (NBs), which are characterized by their safety, strong penetrating power and high gene loading capability for gene delivery. An epidermal growth factor receptor (EGFR)-targeted small interfering RNA (siEGFR) was transfected into triple negative breast cancer (TNBC) cells via prepared CPP-NBs synergized with ultrasound-targeted microbubble destruction (UTMD) technology. Fluorescence microscopy showed that siEGFR and CPP were loaded on the shells of the NBs. The transfection efficiency and cell proliferation levels were evaluated by FACS and MTT assays, respectively. In addition, in vivo experiments showed that the expression of EGFR mRNA and protein could be efficiently downregulated and that the growth of a xenograft tumor derived from TNBC cells could be inhibited. Our results indicate that CPP-NBs carrying siEGFR could potentially be used as a promising non-viral gene vector that can be synergized with UTMD technology for efficient TNBC therapy. PMID:27388967

  13. FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells.

    Science.gov (United States)

    Taliaferro-Smith, LaTonia; Oberlick, Elaine; Liu, Tongrui; McGlothen, Tanisha; Alcaide, Tiffanie; Tobin, Rachel; Donnelly, Siobhan; Commander, Rachel; Kline, Erik; Nagaraju, Ganji Purnachandra; Havel, Lauren; Marcus, Adam; Nahta, Rita; O'Regan, Ruth

    2015-03-10

    Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelationship between IGF1R and FAK signaling in regulating the malignant properties of TNBC cells. Using small hairpin RNA (shRNA)-mediated IGF1R silencing methods, we showed that IGF1R is essential for sustaining mesenchymal morphologies of TNBC cells and modulates the expression of EMT-related markers. We further showed that IGF1R overexpression promotes migratory and invasive behaviors of TNBC cell lines. Most importantly, IGF1R-driven migration and invasion is predominantly mediated by FAK activation and can be suppressed using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs. PMID:25749031

  14. 多西他赛联合卡培他滨方案在新辅助化疗三阴乳腺癌与非三阴乳腺癌中的近期疗效观察%Short-term Curative Effects of Docetaxel Combined with Capecitabine in Neoadjuvant Chemotherapy of Triple-negative Breast Cancer and Non Triple-negative Brest Cancer

    Institute of Scientific and Technical Information of China (English)

    张淼; 宋敏; 屈淑贤; 章国晶; 郭放; 韩雅玲; 谢晓冬

    2015-01-01

    目的:探讨三阴乳腺癌( triple-negative breast cancer, TNBC)与非三阴乳腺癌患者应用多西他赛联合卡培他滨( DX)方案行新辅助化疗的临床疗效及不良反应。方法选择2008年7月—2013年8月收治的102例乳腺癌患者,其中TNBC 27例,非TNBC75例,均应用DX方案新辅助化疗。观察临床疗效和毒副反应发生情况。结果TNBC患者总有效率与非TNBC患者比较差异无统计学意义( P>0.05)。 TNBC患者病理完全缓解率、临床完全缓解率高于非TNBC患者(P0.05)。结论 TNBC患者较非TNBC患者对DX方案新辅助化疗更敏感,且未增加毒副反应发生率。%Objective To compare the curative effect and adverse reactions of Docetaxel combined with Capecit-abine (DX) in neoadjuvant chemotherapy of patients with triple-negative breast cancer (TNBC) or non triple-negative breast cancer. Methods A total of 102 patients with breast cancer during July 2008 and August 2013 underwent DX neoadjuvant chemotherapy, including 27 patients and 75 non-TNBC patients. The curative effect and adverse reactions were observed. Results There was no significant difference in the overall response ( OR) between TNBC patients and non-TNBC patients (P>0. 05). The pathological complete response and clinical complete remission rates of TNBC pa-tients were significantly higher than those of non-TNBC patients (P0. 05). Conclusion The neoadjuvant chemotherapy using Docetaxel combined with Capecitabine shows a higher sensi-tivity in TNBC patients, compared with that in non-TNBC patients without an increase of incidence rate of adverse reac-tions.

  15. miR-125b inhibited epithelialal–mesenchymal transition of triple-negative breast cancer by targeting MAP2K7

    Directory of Open Access Journals (Sweden)

    Hong LQ

    2016-05-01

    Full Text Available Liquan Hong,1 Feng Pan,1 Huifen Jiang,2 Lahong Zhang,1 Yuhua Liu,1 Chengsong Cai,1 Chunzhen Hua,3 Xian Luo,1 Jinhua Sun,4 Zhaojun Chen1 1Department of Clinical Laboratory, Affiliated Hospital of Hangzhou Normal University, 2Zhejiang Provincial Tumor Hospital, 3Zhejiang Provincial Children’s Hospital, 4Technology Department, Hangzhou Joingenome Diagnostics, Hangzhou, Zhejiang Province, People’s Republic of China Abstract: MicroRNAs (miRNAs play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. Among the differentially expressed miRNAs in breast cancer, miR-125b was revealed to be deregulated and associated with poor prognosis and chemoresistance in triple-negative breast cancer (TNBC, but the mechanism is still unknown. In our study, we showed downregulated expression of miR-125b in TNBC tissues and decreased migration and invasion in miR-125b-expressing Hs578T cells. MAP2K7 was then detected to be a novel target of miR-125b, and downregulation of MAP2K7 by miR-125b was similar to transient knockdown of MAP2K7 which hindered epithelial–­mesenchymal transition (EMT of Hs578T cells. Upregulation of MAP2K7 in miR-125b-overexpressing Hs578T cells partly rescued the migration and invasion suppression of miR-125b. Furthermore, MAP2K7 was overexpressed in TNBC samples compared with normal tissues and negatively correlated with miR-125b expression. In light of these findings, miR-125b emerged as a tumor suppressor in TNBC by targeting MAP2K7 to inhibit EMT. Keywords: miR-125b, MAP2K7, TNBC, Hs578T, EMT

  16. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems. To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis. We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A). Taken together, we have developed a TNBC-TICs model system

  17. E-cadherin-negative acinar cell carcinoma of the pancreas: report of a case showing a solid pseudopapillary growth pattern.

    Science.gov (United States)

    Tajima, Shogo; Waki, Michihiko; Azuma, Masaki; Koda, Kenji; Ohata, Akihiko

    2016-09-01

    E-cadherin expression patterns in acinar cell carcinomas (ACCs) of the pancreas have not been well documented. Herein, we present a hitherto undescribed case of E-cadherin-negative ACC with a solid pseudopapillary growth pattern in a 65-year-old man. We used an antibody against the extracellular domain of E-cadherin. As a further unusual status in ACC, faint β-catenin expression was observed in the cytoplasm of carcinoma cells. Morphological distinction from a solid pseudopapillary neoplasm (SPN) of the pancreas might be problematic in such a case, because of their similarities concerned with the growth pattern and E-cadherin negativity. Without nuclear accumulation of β-catenin, a diagnosis of SPN was almost excluded. Immunoreactivity for trypsin and BCL10 made an accurate diagnosis of ACC to this case. The tumor recurred 10 months post-surgery as rapidly enlarging masses in the liver, presumably indicating the aggressiveness of the E-cadherin-negative phenotype among ACCs. PMID:25600280

  18. Limited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers.

    Science.gov (United States)

    Zugazagoitia, Jon; Pérez-Segura, Pedro; Manzano, Arancha; Blanco, Ignacio; Vega, Ana; Custodio, Ana; Teulé, Alex; Fachal, Laura; Martínez, Beatriz; González-Sarmiento, Rogelio; Cruz-Hernández, Juan Jesús; Chirivella, Isabel; Garcés, Vicente; Garre, Pilar; Romero, Atocha; Caldés, Trinidad; Díaz-Rubio, Eduardo; de la Hoya, Miguel

    2014-11-01

    Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 (BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients (N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher's exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14%, whereas it dropped to 3% in non-TNBCs with adequate family history (OR 5.31, 95% CI 1.38-23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing. PMID:25342642

  19. Effect of dendritic cell/cytokine-induced killer cell immunobiological cancer therapy combined with adjuvant chemotherapy in patients with triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    Ranran Zhang; Dongchu Ma; Xiaodong Xie; Wanqing Xie Co-first author; Tao Han; Yongye Liu; Zhaozhe Liu; Fang Guo; Yaling Han; Zhenyu Ding; Yinghui Sun

    2015-01-01

    Objective The aim of the present study was to investigate the ef ect of dendritic cel (DC)/cytokine-in-duced kil er cel (CIK) immunobiological cancer therapy in patients with triple-negative breast cancer (TNBC) who underwent adjuvant chemotherapy. Methods From January 2010 to October 2013, 120 patients with postoperative TNBC were recruited and included in the study. Patients were enrol ed in one of two groups according to whether they accepted DC/CIK immunobiological cancer therapy during adjuvant chemotherapy; the patients in the DC/CIK group underwent adjuvant chemotherapy combined with DC/CIK immunobiological cancer therapy, and the control group underwent adjuvant chemotherapy alone. When six cycles of adjuvant chemotherapy and six cycles of DC/CIK immunobiological cancer therapy had been completed, dif erences between the two groups with regard to quality of life (QoL), immunological indicators (CD3, CD4, CD8, and NK cel levels), disease-free survival (DFS), and side ef ects of chemotherapy and DC/CIK treatment were evaluated. Results In the DC/CIK group, the proportion of NK cel s and CD3+ and CD4+ T-cel subgroups significantly increased, and the proportion of CD8+ cel s decreased when they were compared before and after DC/CIK therapy (P Conclusion The DC/CIK treatment had potential benefits for patients with TNBC compared with the con-trol group, and was not associated with any obvious side ef ects. Therefore, DC/CIK therapy is a safe and ef ective method for the treatment of TNBC.

  20. Correlation between {sup 18}F-FDG uptake on PET/CT and prognostic factors in triple-negative breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Hye Ryoung [Seoul National University College of Medicine, Department of Radiology, 28 Yongon-dong, Chongno-gu, Seoul (Korea, Republic of); Hanyang University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, Jeong Seon [Hanyang University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Han, Wonshik [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of); Park, In Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Moon, Woo Kyung [Seoul National University College of Medicine, Department of Radiology, 28 Yongon-dong, Chongno-gu, Seoul (Korea, Republic of)

    2015-11-15

    The purpose of this study was to investigate whether a correlation exists between {sup 18}F-fluorodeoxyglucose (FDG) uptake and prognostic factors in triple-negative breast cancer (TNBC). Between January 2009 and December 2013, 103 patients (mean age, 50.6 years) with primary TNBC (mean, 2.6 cm; range, 1.0-6.5 cm) underwent {sup 18}F-FDG PET/CT for initial staging. Correlations between maximum standardized uptake value (SUV{sub max}) on PET/CT and prognostic factors including tumour size, nodal status, histological grade, Ki-67 proliferation index, tumour suppressor p53, and 'basal-like' markers (epidermal growth factor receptor and CK 5/6) were assessed. The mean SUV{sub max} of the 103 tumours was 10.94 ± 5.25 (range: 2-32.8). There was a positive correlation between SUV{sub max} and Ki-67 (Spearman's rho = 0.29, P = 0.003) and tumour size (Spearman's rho = 0.27, P = 0.006), whereas this relationship was not observed in the nodal status, histological grade, p53 status and 'basal-like' phenotypes. In a multivariate regression analysis, Ki-67 (P < 0.001) and tumour size (P = 0.009) were significantly associated with SUV{sub max} in TNBCs. Increased {sup 18}F-FDG uptake on PET/CT was correlated with a high Ki-67 proliferation index and larger tumour size in TNBC. These results suggest a potential role of {sup 18}F-FDG PET/CT in identifying TNBC with more aggressive behaviour. (orig.)

  1. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers.

    Science.gov (United States)

    Gari, Hamid H; Gearheart, Christy M; Fosmire, Susan; DeGala, Gregory D; Fan, Zeying; Torkko, Kathleen C; Edgerton, Susan M; Lucia, M Scott; Ray, Rahul; Thor, Ann D; Porter, Christopher C; Lambert, James R

    2016-03-29

    Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells. PMID:26909599

  2. Role of Ultrasonography of Regional Nodal Basins in Staging Triple-Negative Breast Cancer and Implications For Local-Regional Treatment

    International Nuclear Information System (INIS)

    Purpose: We sought to determine the rate at which regional nodal ultrasonography would increase the nodal disease stage in patients with triple-negative breast cancer (TNBC) beyond the clinical stage determined by physical examination and mammography alone, and significantly affect the treatments delivered to these patients. Methods and Materials: We retrospectively reviewed the charts of women with stages I to III TNBC who underwent physical examination, mammography, breast and regional nodal ultrasonography with needle biopsy of abnormal nodes, and definitive local-regional treatment at our institution between 2004 and 2011. The stages of these patients' disease with and without ultrasonography of the regional nodal basins were compared using the Pearson χ2 test. Definitive treatments of patients whose nodal disease was upstaged on the basis of ultrasonographic findings were compared to those of patients whose disease stage remained the same. Results: A total of 572 women met the study requirements. In 111 (19.4%) of these patients, regional nodal ultrasonography with needle biopsy resulted in an increase in disease stage from the original stage by physical examination and mammography alone. Significantly higher percentages of patients whose nodal disease was upstaged by ultrasonographic findings compared to that in patients whose disease was not upstaged underwent neoadjuvant systemic therapy (91.9% and 51.2%, respectively; P<.0001), axillary lymph node dissection (99.1% and 34.5%, respectively; P<.0001), and radiation to the regional nodal basins (88.2% and 29.1%, respectively; P<.0001). Conclusions: Regional nodal ultrasonography in TNBC frequently changes the initial clinical stage and plays an important role in treatment planning

  3. Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator.

    Science.gov (United States)

    Lee, Kuen-Haur; Hsu, En-Chi; Guh, Jih-Hwa; Yang, Hsiao-Ching; Wang, Dasheng; Kulp, Samuel K; Shapiro, Charles L; Chen, Ching-Shih

    2011-11-11

    The antitumor activities of the novel adenosine monophosphate-activated protein kinase (AMPK) activator, OSU-53, were assessed in in vitro and in vivo models of triple-negative breast cancer. OSU-53 directly stimulated recombinant AMPK kinase activity (EC(50), 0.3 μM) and inhibited the viability and clonogenic growth of MDA-MB-231 and MDA-MB-468 cells with equal potency (IC(50), 5 and 2 μM, respectively) despite lack of LKB1 expression in MDA-MB-231 cells. Nonmalignant MCF-10A cells, however, were unaffected. Beyond AMPK-mediated effects on mammalian target of rapamycin signaling and lipogenesis, OSU-53 also targeted multiple AMPK downstream pathways. Among these, the protein phosphatase 2A-dependent dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mammalian target of rapamycin inhibition. OSU-53 also modulated energy homeostasis by suppressing fatty acid biosynthesis and shifting the metabolism to oxidation by up-regulating the expression of key regulators of mitochondrial biogenesis, such as a peroxisome proliferator-activated receptor γ coactivator 1α and the transcription factor nuclear respiratory factor 1. Moreover, OSU-53 suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation, and inhibited hypoxia-induced epithelial-mesenchymal transition in association with the silencing of hypoxia-inducible factor 1a and the E-cadherin repressor Snail. In MDA-MB-231 tumor-bearing mice, daily oral administration of OSU-53 (50 and 100 mg/kg) suppressed tumor growth by 47-49% and modulated relevant intratumoral biomarkers of drug activity. However, OSU-53 also induced protective autophagy that attenuated its antiproliferative potency. Accordingly, cotreatment with the autophagy inhibitor chloroquine increased the in vivo tumor-suppressive activity of OSU-53. OSU-53 is a potent, orally bioavailable AMPK activator that acts through a broad spectrum of antitumor activities. PMID

  4. Role of Ultrasonography of Regional Nodal Basins in Staging Triple-Negative Breast Cancer and Implications For Local-Regional Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Shaitelman, Simona F., E-mail: sfshaitelman@mdanderson.org [Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tereffe, Welela [Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dogan, Basak E. [Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hess, Kenneth R. [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Caudle, Abigail S. [Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Valero, Vicente [Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Stauder, Michael C. [Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Krishnamurthy, Savitri [Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Candelaria, Rosalind P. [Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Strom, Eric A.; Woodward, Wendy A. [Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hunt, Kelly K. [Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Buchholz, Thomas A. [Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Whitman, Gary J. [Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2015-09-01

    Purpose: We sought to determine the rate at which regional nodal ultrasonography would increase the nodal disease stage in patients with triple-negative breast cancer (TNBC) beyond the clinical stage determined by physical examination and mammography alone, and significantly affect the treatments delivered to these patients. Methods and Materials: We retrospectively reviewed the charts of women with stages I to III TNBC who underwent physical examination, mammography, breast and regional nodal ultrasonography with needle biopsy of abnormal nodes, and definitive local-regional treatment at our institution between 2004 and 2011. The stages of these patients' disease with and without ultrasonography of the regional nodal basins were compared using the Pearson χ{sup 2} test. Definitive treatments of patients whose nodal disease was upstaged on the basis of ultrasonographic findings were compared to those of patients whose disease stage remained the same. Results: A total of 572 women met the study requirements. In 111 (19.4%) of these patients, regional nodal ultrasonography with needle biopsy resulted in an increase in disease stage from the original stage by physical examination and mammography alone. Significantly higher percentages of patients whose nodal disease was upstaged by ultrasonographic findings compared to that in patients whose disease was not upstaged underwent neoadjuvant systemic therapy (91.9% and 51.2%, respectively; P<.0001), axillary lymph node dissection (99.1% and 34.5%, respectively; P<.0001), and radiation to the regional nodal basins (88.2% and 29.1%, respectively; P<.0001). Conclusions: Regional nodal ultrasonography in TNBC frequently changes the initial clinical stage and plays an important role in treatment planning.

  5. A novel approach for targeted elimination of CSPG4-positive triple-negative breast cancer cells using a MAP tau-based fusion protein.

    Science.gov (United States)

    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

    2016-08-15

    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 factor receptor 2. TNBC is particularly prevalent among young premenopausal women. No suitable targeted therapies are currently available and therefore, novel agents for the targeted elimination of TNBC are urgently needed. Here, we present a novel cytolytic fusion protein (CFP), designated αCSPG4(scFv)-MAP, that consists of a high affinity CSPG4-specific single-chain antibody fragment (scFv) genetically fused to a functionally enhanced form of the human microtubule-associated protein (MAP) tau. Our data indicate that αCSPG4(scFv)-MAP efficiently targets CSPG4(+) TNBC-derived cell lines MDA-MB-231 and Hs 578T and potently inhibits their growth with IC50 values of ∼200 nM. Treatment with αCSPG(scFv)-MAP resulted in induction of the mitochondrial stress pathway by activation of caspase-9 as well as endonuclease G translocation to the nucleus, while induction of the caspase-3 apoptosis pathway was not detectable. Importantly, in vivo studies in mice bearing human breast cancer xenografts revealed efficient targeting to and accumulation of αCSPG4(scFv)-MAP at tumor sites resulting in prominent tumor regression. Taken together, this preclinical proof of concept study confirms the potential clinical value of αCSPG4(scFv)-MAP as a novel targeted approach for the elimination of CSPG4-positive TNBC. PMID:27037627

  6. ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

    Energy Technology Data Exchange (ETDEWEB)

    Heravi, Mitra [Department of Human Genetics, McGill University, Montreal (Canada); Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Kumala, Slawomir [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Rachid, Zakaria; Jean-Claude, Bertrand J. [Cancer Drug Research Laboratory, McGill University Health Center, Montreal (Canada); Radzioch, Danuta [Department of Human Genetics, McGill University, Montreal (Canada); Muanza, Thierry M., E-mail: tmuanza@yahoo.com [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada)

    2015-06-01

    Purpose: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. Methods and Materials: The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Results: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. Conclusions: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings.

  7. A novel EGR-1 dependent mechanism for YB-1 modulation of paclitaxel response in a triple negative breast cancer cell line.

    Science.gov (United States)

    Lasham, Annette; Mehta, Sunali Y; Fitzgerald, Sandra J; Woolley, Adele G; Hearn, James I; Hurley, Daniel G; Ruza, Igor; Algie, Michael; Shelling, Andrew N; Braithwaite, Antony W; Print, Cristin G

    2016-09-01

    Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required. One protein shown to be involved in drug resistance is Y-box binding protein 1 (YB-1). High levels of YB-1 have previously been associated with resistance to PTX in TNBCs. In this study, we aimed to determine mechanisms by which YB-1 confers PTX resistance. We generated isogenic TNBC cell lines that differed by YB-1 levels and treated these with PTX. Using microarray analysis, we identified EGR1 as a potential target of YB-1. We found that low EGR1 mRNA levels are associated with poor breast cancer patient prognosis, and that EGR1 and YBX1 mRNA expression was inversely correlated in a TNBC line and in a proportion of TNBC tumours. Reducing the levels of EGR1 caused TNBC cells to become more resistant to PTX. Given that PTX targets cycling cells, we propose a model whereby high YB-1 levels in some TNBC cells can lead to reduced levels of EGR1, which in turn promotes slow cell cycling and resistance to PTX. Therefore YB-1 and EGR1 levels are biologically linked and may provide a biomarker for TNBC response to PTX. PMID:27072400

  8. Inhibition of SK4 Potassium Channels Suppresses Cell Proliferation, Migration and the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Panshi Zhang

    Full Text Available Treatments for triple-negative breast cancer (TNBC are limited; intermediate-conductance calcium-activated potassium (SK4 channels are closely involved in tumor progression, but little is known about these channels in TNBC. We aimed to investigate whether SK4 channels affect TNBC. First, by immunohistochemistry (IHC and western blotting (WB, increased SK4 protein expression in breast tumor tissues was detected relative to that in non-tumor breast tissues, but there was no apparent expression difference between various subtypes of breast cancer (p>0.05. Next, functional SK4 channels were detected in the TNBC cell line MDA-MB-231 using WB, real-time PCR, immunofluorescence and patch-clamp recording. By employing SK4 specific siRNAs and blockers, including TRAM-34 and clotrimazole, in combination with an MTT assay, a colony-formation assay, flow cytometry and a cell motility assay, we found that the suppression of SK4 channels significantly inhibited cell proliferation and migration and promoted apoptosis in MDA-MB-231 cells (p<0.05. Further investigation revealed that treatment with epidermal growth factor (EGF/basic fibroblast growth factor (bFGF caused MDA-MB-231 cells to undergo the epithelial-mesenchymal transition (EMT and to show increased SK4 mRNA expression. In addition, the down-regulation of SK4 expression inhibited the EMT markers Vimentin and Snail1. Collectively, our findings suggest that SK4 channels are expressed in TNBC and are involved in the proliferation, apoptosis, migration and EMT processes of TNBC cells.

  9. The Dietary Flavonoid Fisetin Causes Cell Cycle Arrest, Caspase-Dependent Apoptosis, and Enhanced Cytotoxicity of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.

    Science.gov (United States)

    Smith, Matthew L; Murphy, Kaylee; Doucette, Carolyn D; Greenshields, Anna L; Hoskin, David W

    2016-08-01

    Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid found in a number of fruits and vegetables, has diverse biological activities, including cytotoxic effects on cancer cells. In this study, we investigated the effect of fisetin on triple-negative breast cancer (TNBC) cells. TNBC has a poorer prognosis than other types of breast cancer and treatment options for this disease are limited. Fisetin inhibited the growth of MDA-MB-468 and MDA-MB-231 TNBC cells, as well as their ability to form colonies, without substantially affecting the growth of non-malignant cells. In addition, fisetin inhibited the growth of estrogen receptor-bearing MCF-7 breast cancer cells and human epidermal growth factor receptor 2-overexpressing SK-BR-3 breast cancer cells. Fisetin inhibited TNBC cell division and induced apoptosis, which was associated with mitochondrial membrane permeabilization and the activation of caspase-9 and caspase-8, as well as the cleavage of poly(ADP-ribose) polymerase-1. Induction of caspase-dependent apoptosis by fisetin was confirmed by reduced killing of TNBC cells in the presence of the pan-caspase inhibitors Z-VAD-FMK and BOC-D-FMK. Decreased phosphorylation of histone H3 at serine 10 in fisetin-treated TNBC cells at G2/M phase of the cell cycle suggested that fisetin-induced apoptosis was the result of Aurora B kinase inhibition. Interestingly, the cytotoxic effect of cisplatin, 5-fluorouracil, and 4-hydroxycyclophosphamide metabolite of cyclophosphamide on TNBC cells was increased in the presence of fisetin. These findings suggest that further investigation of fisetin is warranted for possible use in the management of TNBC. J. Cell. Biochem. 117: 1913-1925, 2016. © 2016 Wiley Periodicals, Inc. PMID:26755433

  10. Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade.

    Science.gov (United States)

    Choy, Cecilia; Raytis, John L; Smith, David D; Duenas, Matthew; Neman, Josh; Jandial, Rahul; Lew, Michael W

    2016-06-01

    In response to recent studies, we investigated an association between perioperative β-blockade and breast cancer metastases. First, a retrospective study examining perioperative β-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to β2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative β-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased β2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to β2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased β2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding β2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative β-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases. PMID:27035124

  11. ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

    International Nuclear Information System (INIS)

    Purpose: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. Methods and Materials: The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Results: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. Conclusions: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings

  12. Piperlongumine, an alkaloid causes inhibition of PI3 K/Akt/mTOR signaling axis to induce caspase-dependent apoptosis in human triple-negative breast cancer cells.

    Science.gov (United States)

    Shrivastava, Shweta; Kulkarni, Prasad; Thummuri, Dinesh; Jeengar, Manish Kumar; Naidu, V G M; Alvala, Mallika; Redddy, G Bhanuprakash; Ramakrishna, Sistla

    2014-07-01

    The phosphatidylinositol 3-kinase (PI3 K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth and survival under physiological conditions. However, aberrant PI3 K/Akt/mTOR signaling has been implicated in many human cancers, including human triple negative breast cancer. Therefore, dual inhibitors of PI3 K/Akt and mTOR signaling could be valuable agents for treating breast cancer. The objective of this study was to investigate the effect of piperlongumine (PPLGM), a natural alkaloid on PI3 K/Akt/mTOR signaling, Akt mediated regulation of NF-kB and apoptosis evasion in human breast cancer cells. Using molecular docking studies, we found that PPLGM physically interacts with the conserved domain of PI3 K and mTOR kinases and the results were comparable with standard dual inhibitor PF04691502. Our results demonstrated that treatment of different human triple-negative breast cancer cells with PPLGM resulted in concentration- and time-dependent growth inhibition. The inhibition of cancer cell growth was associated with G1-phase cell cycle arrest and down-regulation of the NF-kB pathway leads to activation of the mitochondrial apoptotic pathway. It was also found that PPLGM significantly decreased the expression of p-Akt, p70S6K1, 4E-BP1, cyclin D1, Bcl-2, p53 and increased expression of Bax, cytochrome c in human triple-negative breast cancer cells. Although insulin treatment increased the phosphorylation of Akt (Ser473), p70S6K1, 4E-BP1, PPLGM abolished the insulin mediated phosphorylation, it clearly indicates that PPLGM acts through PI3 k/Akt/mTOR axis. Our results suggest that PPLGM may be an effective therapeutic agent for the treatment of human triple negative breast cancer. PMID:24729100

  13. Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC)

    OpenAIRE

    Jay Overholser; Kristen Henkins Ambegaokar; Eze, Siobhan M.; Eduardo Sanabria-Figueroa; Rita Nahta; Tanios Bekaii-Saab; Kaumaya, Pravin T. P.

    2015-01-01

    Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, pot...

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

    Science.gov (United States)

    Ma, Fang-Jing; Liu, Zhe-Bin; Qu, Li; Hao, Shuang; Liu, Guang-Yu; Wu, Jiong; Shao, Zhi-Ming

    2014-01-01

    Background Type 2 diabetes mellitus (T2DM) is one of the most common chronic metabolic diseases. Increased cause-specific mortality and decreased disease-free survival (DFS) have been reported among cancer patients with T2DM compared with patients without T2DM, even after adjustments of other comorbidities. However, less is known about the impact of T2DM and other comorbidities on DFS in Chinese patients with early stage triple-negative breast cancer (TNBC). Patients and methods We assessed patients who were newly diagnosed with early stage primary TNBC at the Department of Breast Surgery, Fudan University, from 2003 to 2011. Of the 1,100 TNBC patients, 865 female patients had invasive and early stage TNBC. The association of the variables in the T2DM and non-T2DM groups was compared using the Pearson’s chi-square and independent t-tests. DFS was estimated using the Kaplan–Meier method. The effects of T2DM and other possible risk factors on DFS were assessed by Cox proportional hazards regression using univariate or multivariate analysis. Results A total of 865 early stage primary TNBC cases were studied, including 104 (12.02%) subjects with T2DM. Metastatic or recurrent disease was detected in 24 (23.08%) patients in the T2DM group and 35 (4.60%) patients in the non-T2DM group. Patients with T2DM exhibited a significantly lower DFS than patients without T2DM (log-rank P50 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

  15. 具有基底细胞样免疫表型的三阴性乳腺癌临床病理分析%Clinicopathological Analysis of Triple-negative Breast Cancer with Basal Cell-like Phenotype

    Institute of Scientific and Technical Information of China (English)

    张升瑞; 王星; 孙洁; 宦大为; 王翠芳

    2012-01-01

    Objective To detect the expression of triple-negative breast cancels (TNBCs) with the basal cell-like phenotype, to explore whether TNBCs have the basal cell-like phenotype, and to study the clinicopathological features and Ki67,p53 expressions differences between basal cell-like and non-basal cell-like TNBCs. Methods Immunohistochemical staining was used to detect the protein expressions of CK5/6,CK14,EGFR,Ki67 and P53 in 42 cases of triple-negative breast invasive carcinoma. We studied the relationship among the expression of basal cell-like phenotvpe.clinieopathological features and the expressions of Ki67 and P53. Results Twenty four cases expressed one or several basal cell-like phenotype markers (CK5/6,CK14,EGFR),accounting for 57.1% of the 42 triple negative breast patients,while CK14 was not solely expressed. Eighteen cases (42.9%) did not express CK5/6.CK14 or EGFR. Twenty four TNBCs with basal cell-like phenotype had similar morphological characteristic and nuclear levels,including grade III (22 cases) and grade II (2 cases). And Ki67 was expressed in 22 out of 24 cases. The breast cancer cells nuclear levels of 18 non-basal cell-like cases snowed grade III (3 cases) and grade I (15 cases).grade II (15 cases),and Ki67 was expressed in 8 out of 18 cases. The difference in nuclear level and Ki67 expression between basal-like and non-basal-like TNBCs was statistically significant (P < 0.01). Conclusion Basal cell-like phenotype of TNBCs is a breast cancer with a unique phenotype and morphological characteristics. Characteristic morphological changes and clinical use of CK5/6, EGFR and Ki67 marked by immunohistochemical staining had practical significance in the diagnosis and prognosis of such lesions.%目的 分析三阴性乳腺癌中基底细胞样免疫表型的表达情况,探讨具有或不具有基底细胞样免疫表型的三阴性乳腺癌在临床病理特征和Ki67、P53表达等方面的差异.方法 用免疫组化方法观察42例

  16. Overcoming Triple Segregation

    Science.gov (United States)

    Gandara, Patricia

    2010-01-01

    Latinos are, after whites, the most segregated student group in the United States, and their segregation is closely tied to poor academic outcomes. Latinos experience a triple segregation: by race/ethnicity, poverty, and language. Racial segregation perpetuates negative stereotypes, reduces the likelihood of a strong teaching staff, and is often…

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

    Directory of Open Access Journals (Sweden)

    Ma FJ

    2014-11-01

    Full Text Available Fang-Jing Ma,1–3,* Zhe-Bin Liu,1,2,* Li Qu,4,* Shuang Hao,1,2 Guang-Yu Liu,1,2 Jiong Wu,1,2 Zhi-Ming Shao1,2 1Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Breast Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China; 4Department of General Surgery, Zhejiang Hospital, Hangzhou, People’s Republic of China  *These authors have contributed equally to this workBackground: Type 2 diabetes mellitus (T2DM is one of the most common chronic metabolic diseases. Increased cause-specific mortality and decreased disease-free survival (DFS have been reported among cancer patients with T2DM compared with patients without T2DM, even after adjustments of other comorbidities. However, less is known about the impact of T2DM and other comorbidities on DFS in Chinese patients with early stage triple-negative breast cancer (TNBC.Patients and methods: We assessed patients who were newly diagnosed with early stage primary TNBC at the Department of Breast Surgery, Fudan University, from 2003 to 2011. Of the 1,100 TNBC patients, 865 female patients had invasive and early stage TNBC. The association of the variables in the T2DM and non-T2DM groups was compared using the Pearson's chi-square and independent t-tests. DFS was estimated using the Kaplan–Meier method. The effects of T2DM and other possible risk factors on DFS were assessed by Cox proportional hazards regression using univariate or multivariate analysis.Results: A total of 865 early stage primary TNBC cases were studied, including 104 (12.02% subjects with T2DM. Metastatic or recurrent disease was detected in 24 (23.08% patients in the T2DM group and 35 (4.60% patients in the non-T2DM group. Patients with T2DM exhibited a

  18. Research development of triple-negative breast cancer chemotherapy%三阴乳腺癌化疗的研究进展

    Institute of Scientific and Technical Information of China (English)

    章国晶; 谢晓冬

    2012-01-01

    三阴乳腺癌(TNBC)因浸润性较强是乳腺癌中预后不佳的一种亚型,其治疗已受到广泛关注,但尚无明确的标准.TNBC在新辅助化疗中可获得12%~48%的病理完全反应率(pCR),高于其他类型乳腺癌,但其pCR在文献报道中波动幅度较大.辅助化疗在早期TNBC中的应用仍存在争议,有学者主张使用不含蒽环类药物的化疗方案.紫杉类、蒽环类等细胞毒性药物仍是目前TNBC解救化疗的主力药物,临床试验显示,联合应用吉西他滨或卡培他滨可延长患者生存期.ADP-核糖聚合酶(PARP)成为TNBC靶向治疗新的研究靶点,对其抑制剂如BSI-201和Olaparib的深入研究有望为临床治疗提供更多有效的选择.%Triple-negative breast cancer ( TNBC ) is a subtype of breast cancer,and it is characterized by an aggressive clinical course with a poor prognosis.Treatment for TNBC has attracted much attention in recent years,however,there is no standard treatment for TNBC in clinical setting.The pCR rates of neoadjuvant chemotherapy in TNBC ranges from 12% to 48% in the current published data,and it is higher than that in other types of breast cancer,however,the fluctuating range of the TNBC ’s pCR is large in literature.Although the administration of adjuvant chemotherapy for early TNBC is controversial,the regimen without anthracyclines is reported to be suitable for early TNBC patients.Standard cytotoxic agents including taxanes and anthracyclines are still the main choices for TNBC salvage treatment,and the combination with gemcitabine or capecitabine may improve the overall survival.Poly (ADP-ribose) polymerase (PARP) is a new molecular target for TNBC in ongoing studies.Further research on the target-inhibitors such as BSI-201and Olaparib will provide more effective choices to clinical treatment.

  19. Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer.

    Science.gov (United States)

    Matsumoto, Hirofumi; Thike, Aye Aye; Li, Huihua; Yeong, Joe; Koo, Si-Lin; Dent, Rebecca Alexandra; Tan, Puay Hoon; Iqbal, Jabed

    2016-04-01

    Tumour-infiltrating lymphocytes (TILs) signify immune response to tumour in a variety of cancers including breast cancer. However, earlier studies examining the clinical significance of TILs in breast cancers have generated mixed results. There are only a few that address the relationship between TILs and clinical outcomes in triple-negative breast cancers (TNBC). The aim of this study is to evaluate the clinical significance of TILs that express CD4 + and CD8 + , in TNBC. Immunohistochemical staining of CD4 and CD8 was performed on tissue microarrays of 164 cases of TNBC. TILs were counted separately as intratumoral when within the cancer cell nests (iTILs) and as stromal when within cancer stroma (sTILs). High CD8 + iTILs and sTILs, and CD4 + iTILs correlated with histologic grade. On Kaplan-Meier analysis, a significantly better survival rate was observed in high CD8 + iTIL (disease-free survival, DFS: P = 0.004, overall survival, OS: P = 0.02) and both high CD4 + iTILs (DFS: P = 0.025, OS: P = 0.023) and sTILs (DFS: P = 0.01, OS: P = 0.002). In multivariate analysis, CD8 + iTILs (DFS: P = 0.0095), CD4 + sTILs (DFS: P = 0.0084; OS: P = 0.0118), and CD4 (high) CD8 (high) CD8 iTILs (DFS: P = 0.0121; OS: P = 0.0329) and sTILs (DFS: P = 0.0295) showed significantly better survival outcomes. These results suggest that high levels of both CD8 + iTILs and CD4 + sTILs as well as CD4 (high) CD8 (high) iTILs and sTILs are independent prognostic factors in TNBC. PMID:26960711

  20. The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer.

    Science.gov (United States)

    Şakalar, Çağrı; İzgi, Kenan; İskender, Banu; Sezen, Sedat; Aksu, Huriye; Çakır, Mustafa; Kurt, Büşra; Turan, Ali; Canatan, Halit

    2016-04-01

    Thymoquinone (TQ) is the active ingredient of Nigella sativa which has a therapeutic potential in cancer therapy and prevention. In this study, TQ has been shown to induce specific cytotoxicity and apoptosis and to inhibit wound healing in triple-negative breast cancer cell line. TQ also inhibited cancer growth in a mouse tumor model. Moreover, TQ and paclitaxel (Pac) combination inhibited cancer growth in cell culture and in mice. Genes involved in TQ and TQ-Pac-mediated cytotoxicity were studied using focused real-time PCR arrays. After bioinformatic analysis, genes in apoptosis, cytokine, and p53 signaling categories were found to be modulated with a high significance in TQ-treated cells (p < 10(-28), p < 10(-8), and p < 10(-6), respectively). Important to note, TQ has been found to regulate the genes involved in the induction of apoptosis through death receptors (p = 5.5 × 10(-5)). Additionally, tumor suppressor genes such as p21, Brca1, and Hic1 were highly upregulated by TQ and TQ-Pac combination. Interestingly, when cells were treated with high dose TQ, several growth factors such as Vegf and Egf were upregulated and several pro-apoptotic factors such as caspases were downregulated possibly pointing out key pathways manipulated by cancer cells to resist against TQ. In cells treated with the combination of TQ and Pac, genes in apoptosis cascade (p < 10(-12)), p53 signaling (p = 10(-5)), and JAK-STAT signaling (p < 10(-3)) were differentially expressed. TQ has also been shown to induce protein levels of cleaved Caspase-3, Caspase-7, and Caspase-12 and PARP and to reduce phosphorylated p65 and Akt1. The in vivo therapeutic potential of TQ-Pac combination and the genetic network involved in this synergy have been shown for the first time to the best of our knowledge. PMID:26500095

  1. Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge.

    Science.gov (United States)

    Singh, Balraj; Kinne, Hannah E; Milligan, Ryan D; Washburn, Laura J; Olsen, Mark; Lucci, Anthony

    2016-01-01

    We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells were no longer affected by MO-I-500 even in Gln-free medium. We conclude that panresistant MA cells contain interconnected molecular networks that govern developmental status and

  2. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

    Science.gov (United States)

    Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

  3. Prognostic impact of {sup 18}F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Groheux, D.; Merlet, P. [Saint-Louis Hospital, Department of Nuclear Medicine, Paris Cedex 10 (France); University of Paris VII, B2T Doctoral School, Institut Universitaire d' Hematologie, Paris (France); Giacchetti, S.; Hamy, A.S.; Espie, M. [Saint-Louis Hospital, Breast Diseases Unit, Department of Medical Oncology, Paris (France); Delord, M. [Institut Universitaire d' Hematologie, Department of Biostatistics and Bioinformatics, Paris (France); Roquancourt, A. de [Saint-Louis Hospital, Department of Pathology, Paris (France); Hindie, E. [University of Bordeaux, Department of Nuclear Medicine, Haut-Leveque Hospital, CHU Bordeaux, Bordeaux (France)

    2014-11-29

    Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment {sup 18}F-FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. Initial staging with {sup 18}F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. {sup 18}F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P <.001): among patients with occult metastases on baseline PET/CT, 2-year DSS was 18.2 %, and among patients without initial metastases on PET/CT, 5-year DSS was 61.3 % in patients without pCR after NAC and 95.2 % in those with pCR. Of the 51 patients who did not achieve pCR, 21 relapsed (17 developed distant metastases). The sites of distant recurrence were: lung/pleura (nine patients), brain (eight patients), liver (six patients), distant lymph nodes (six patients) and bone (five patients). In patients with clinical stage II/III TNBC, {sup 18}F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation. (orig.)

  4. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner.

    Directory of Open Access Journals (Sweden)

    Nandini Dey

    Full Text Available Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012. Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP, including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54. The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25% and High Rd (74% in clinical stage T3 pathologic response in contrast to the high pCR (40% and low residual disease (RD (60% of the low MMP7 group.

  5. Treatment of clinically negative neck of squamous cell carcinoma in floor of mouth

    International Nuclear Information System (INIS)

    To determine how surgical treatment of the neck for N0 cases of squamous cell carcinoma in the floor of the mouth should be done, the pattern of occult cervical lymph node metastases was evaluated. The number of N0 cases without local failure from 1970 to 1999 was 53 (48 males and 5 females, average age 60.3 years old). T classification was as follows: T1: 14 patients, T2: 35 patients, T3: 4 patients. Initial treatment consisted of surgery only (29 patients), radiation therapy only (7 patients), surgery and radiation therapy (14 patients), surgery and chemotherapy (3 patients). Elective neck dissection (ENT) was performed in 16 patients. Histological cervical lymph node metastasis was detected in 18.9%, 2 of 16 patients who underwent ENT and 8 of 37 patients who underwent therapeutic neck dissection (TND). Frequency of secondary cervical lymph node metastasis by initial treatment and T classification distinction was not different. The sites of metastasis were level III except one case. The 5-year survival rate was 73.1% in the ENT group and 66.9% in the TND group. The results suggest that surgical treatment of the neck is not necessary for initial treatment for N0 cases of squamous cell carcinoma in the floor of the mouth. (author)

  6. Calcitonin-negative neuroendocrine tumor of thyroid gland mimicking anaplastic carcinoma: an unusual entity

    Science.gov (United States)

    Arpaci, Rabia Bozdogan; Berkesoglu, Mustafa; Dag, Ahmet; Sezer, Emel; Bal, Kemal Koray; Vayısoğlu, Yusuf

    2015-01-01

    Medullary thyroid cancer is the neuroendocrine tumor (NET) of thyroid with mostly both secreting calcitonin and immunohistochemically showing calcitonin positivity. Occasionally; NETs of thyroid may have little or no calcitonin expression. We present a case of serum calcitonin negative and immunohistochemically calcitonin-negative staining tumor with positive reaction to neuroendocrine markers synaptophysin and chromogranin-A. The patient’s right vocal cord was paralytic and thyroid mass was huge with descending to thorax till hilar region. We discussed diagnostic difficulties and way of treatment about NETs of thyroid with the light of current literature with this case. PMID:26312221

  7. MHC class I expression in HPV positive and negative tonsillar squamous cell carcinoma in correlation to clinical outcome.

    Science.gov (United States)

    Näsman, Anders; Andersson, Emilia; Nordfors, Cecilia; Grün, Nathalie; Johansson, Hemming; Munck-Wikland, Eva; Massucci, Giuseppe; Dalianis, Tina; Ramqvist, Torbjörn

    2013-01-01

    Human papillomavirus (HPV) is an important factor for the development of tonsillar squamous cell carcinoma (TSCC). In addition, patients with HPV-positive TSCC have a better clinical outcome than patients with HPV-negative TSCC. Although, HPV is an important prognostic marker, additional biomarkers are needed to better predict clinical outcome to individualize treatment. Hence, we examined if classical HLA HLA-A,B,C and nonclassical HLA-E,G could serve as such marker. Formalin-fixed paraffin-embedded TSCC from 150 patients diagnosed 2000-2006, earlier analyzed for HPV DNA and p16(INK4a), and treated with intention to cure were evaluated for the expression of HLA-A,B,C and HLA-E,G by immunohistochemistry. For HPV-positive TSCC a low expression of HLA-A,B,C, whereas for HPV-negative TSCC, a normal expression of HLA-A,B,C was significantly correlated to a favorable clinical outcome. These correlations were more pronounced for membrane staining of HLA-A,B,C when compared with cytoplasmatic staining. No significant correlation was found between HLA-E,G and HPV status or clinical outcome. The unexpected contrasting correlation between HLA-A,B,C expression, and clinical outcome depending on HPV, indicates essential differences between HPV-positive and HPV-negative TSCC. Furthermore, our data demonstrate that for both HPV-positive and HPV-negative TSCC, the expression of HLA-A,B,C together with HPV may serve as a useful biomarker for predicting clinical outcome. PMID:22592660

  8. MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

    International Nuclear Information System (INIS)

    MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCC cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC. - Highlights: • Navigator-3 (NAV-3) suppresses proliferation, migration and tumorigenesis of HCC cells. • NAV-3 was a novel target of miR-21. • MiR-21 negatively regulates NAV-3 in HCC

  9. MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhipeng, E-mail: dr_zpwang@163.com [The Digestive and Vascural Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region (China); Yang, Huan [The Department of Liver and Biliary Pancreatic Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region (China); Ren, Lei [The Department of General Surgery, Branching Hospital of the First People' s Hospital of Urumqi, 830000, Xinjiang Uygur Autonomous Region (China)

    2015-09-04

    MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCC cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC. - Highlights: • Navigator-3 (NAV-3) suppresses proliferation, migration and tumorigenesis of HCC cells. • NAV-3 was a novel target of miR-21. • MiR-21 negatively regulates NAV-3 in HCC.

  10. Targeted Cancer Therapy: Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity (Adv. Healthcare Mater. 11/2016).

    Science.gov (United States)

    Othman, Basmah A; Greenwood, Christina; Abuelela, Ayman F; Bharath, Anil A; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen S; Porter, Alexandra E

    2016-06-01

    On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho. PMID:27275627

  11. Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity

  12. Locoregional recurrence in patients suffering from a triple-negative breast cancer: interest of a systematic adjuvant ganglionary irradiation; Recidives locoregionales chez les patientes atteintes d'un cancer du sein triple-negatif: interet d'une irradiation ganglionnaire adjuvante systematique?

    Energy Technology Data Exchange (ETDEWEB)

    Clerc, J.; Sunyach, M.P.; Duruisseaux, M.; Mignotte, H.; Bajard, A.; Tredan, O.; Carrie, C.; Arnaud, A. [Centre Leon-Berard, Lyon (France)

    2011-10-15

    The authors report the assessment of locoregional recurrence percentage within women suffering from a triple-negative breast cancer without ganglionary attack, in order to examine the interest of a systematic adjuvant ganglionary irradiation. Nearly 250 women have been treated for a breast cancer between 1999 and 2009 in the Leon-Berard Centre in Lyons. All had surgery followed or not by a chemotherapy and/or a radiotherapy. The locoregional recurrence rate is not very high, but the authors cannot yet be sure to systematically propose this treatment. Short communication

  13. 137例术后三阴性乳腺癌的临床特征及预后分析%Clinical characteristics and prognosis of 137 postoperative triple- negative breast cancer patients

    Institute of Scientific and Technical Information of China (English)

    赵真; 段卫明; 陶敏

    2012-01-01

    Objective:To study the clinical features and prognosis of patients with triple-negative breast cancer (TNBC) who received postoperative adjuvant therapies. Methods; Between May 2003 and December 2008, a total of 137 TNBC patients who received surgical procedure were included in this study. The clinical features, long-term survival and treatment outcomes were retrospectively evaluated. Results: The median age of the 137 patients varying from clinical stage I to Ⅲ was 50 years old. Among the 137 patients, 95.6% had invasive ductal carcinomas ,7.5% was classified over T3, and 51.1% was with positive lymph nodes. The median follow-up period was 63 months (34-100 months), and the 5-year disease-free survival ( DFS) was 59. 1 %. The 5-year DFS of patients treated with anthracycline-based regimens was higher than those treated with the regimens containing cyclophosphamide, methotrexate, and fluorouracil (P = 0.038). The tumor size, lymph nodes status, the number of the adjuvant chemotherapy cycles, and chemotherapy regimens were correlated with DFS by univariate analysis. Furthermore, lymph nodes status was demonstrated to be an independent prognostic factor by multivariate Cox regression analysis. Conclusion; TNBC has distinctive clinicopathological features.%目的:分析三阴性乳腺癌(TNBC)病例资料,探讨术后辅助治疗的三阴性乳腺癌的临床特点及预后.方法:收集2003年5月至2008年12月在苏州大学附属第一医院的137例术后TNBC的临床资料,进行回顾分析,研究其临床特征、生存情况、治疗效果.结果:137例患者确诊为三阴性乳腺癌时中位年龄50岁,为术后Ⅰ至Ⅲ期病人,浸润性导管癌131例(95.6%);肿瘤直径≥5cm者24例(17.5%);区域淋巴结阳性者70例(51.1%).中位随访时间63个月(34-100个月).5年无病生存率(DFS)为59.1%.以蒽环类为基础的辅助化疗方案5年无病生存率(63.6%)高于CMF方案(37.5%)(P=0.038).单因素预后分析显示肿块大小

  14. THE PROGNOSIS SIGNIFICANCE OF CATHEPSIN-D EXPRESSION IN THE DIFFERENT LOCATIONS IN AXILLARY NODES NEGATIVE CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: The aim of this study was to investigate Cathepsin-D (Cath-D) expression in different location and its relationship with prognosis in the axillary lymph nodes negative (ANN) breast cancer patients. Methods: Cath-D expression in 192 cases of breast carcinoma were examined by immunohistochemistry. Depending on different parts of expression, three evaluating methods were used, compared and analysed. Results: The positive rate of Cath-D expression in ANN breast cancer with poor prognosis group and axillary nodes positive (ANP) group were significantly higher than that in ANN breast cancer with good prognosis group (x2=23.20, P0.05). Cath-D expression in stromal cells had no statistical difference among the three groups (x2=1.56, P>0.05). When the Cath-D expression in cancer and stromal cells were counted into the positive rate, it was near the same (u1=0.47, u2=1.41, P>0.05). Conclusion: These results suggest that Cath-D expression is one of the powerful prognostic markers in ANN breast cancer. It's a reliable, practical, and convenient method to observe and evaluate Cath-D expression in cancer cells.

  15. BAG-1/SODD, HSP70, and HSP90 are potential prognostic markers of poor survival in node-negative breast carcinoma.

    Science.gov (United States)

    Davidson, Ben; Valborg Reinertsen, Kristin; Trinh, Don; Reed, Wenche; Bøhler, Per Johannes

    2016-08-01

    The objective of this study was to analyze the expression and clinical role of 13 signaling molecules in a large cohort of breast carcinoma patients with long follow-up period. Breast carcinomas (n=410) were analyzed for protein expression of phosphorylated mitogen-activated protein kinases (p-ERK, p-JNK, p-p38) and phosphoinositide 3-kinase signaling pathway proteins (p-AKT, p-mTOR, p-p70S6K); the BAG family proteins BAG-1 and BAG-4/SODD; the antiapoptotic protein Bcl-2; the inhibitor of apoptosis family member Survivin; and the heat shock protein family members HSP27, HSP70, and HSP90. Protein expression was studied for association with clinicopathological parameters and survival. Significantly higher expression of p-AKT (Pmarkers in node-negative breast carcinoma that merit further research. PMID:27038683

  16. Upgrading Subgroup Triple Product Property Triples

    CERN Document Server

    Hedtke, Ivo

    2011-01-01

    In 2003 COHN and UMANS introduced a group-theoretic approach to fast matrix multiplication. This involves finding large subsets of a group $G$ satisfying the Triple Product Property (TPP) as a means to bound the exponent $\\omega$ of matrix multiplication. Recently, Hedtke and Murthy discussed several methods to find TPP triples. Because the search space for subset triples is too large, it is only possible to focus on subgroup triples. We present methods to upgrade a given TPP triple to a bigger TPP triple. If no upgrade is possible we use reduction methods (based on random experiments and heuristics) to create a smaller TPP triple that can be used as input for the upgrade methods. If we apply the upgrade process for subset triples after one step with the upgrade method for subgroup triples we achieve an enlargement of the triple size of 100 % in the best case.

  17. Upgrading Subgroup Triple Product Property Triples

    OpenAIRE

    Hedtke, Ivo

    2011-01-01

    In 2003 COHN and UMANS introduced a group-theoretic approach to fast matrix multiplication. This involves finding large subsets of a group $G$ satisfying the Triple Product Property (TPP) as a means to bound the exponent $\\omega$ of matrix multiplication. Recently, Hedtke and Murthy discussed several methods to find TPP triples. Because the search space for subset triples is too large, it is only possible to focus on subgroup triples. We present methods to upgrade a given TPP triple to a bigg...

  18. THE PROGNOSIS SIGNIFICANCE OF CATHEPSIN-D EXPRESSION IN THE DIFFERENT LOCATIONS IN AXILLARY NODES NEGATIVE CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    NIU; Yun

    2001-01-01

    [1]Garcia M, Platet N, Liaudet Estradiol, et al. Biological and clinical significance of cathepsin D in breast cancer metastasis [J]. Stem Cells 1996; 14:642.[2]Johnson MD, Torri JA, Lippman ME, et al. The role of cathepsin D in the invasiveness of human breast cancer cells [J]. Cancer Res 1993; 53: 873.[3]Duffy MJ. Proteases as prognostic markers in cancer [J]. Clin Cancer Res 1996; 2:613.[4]Westley BR, May FE. Cathepsin D and breast cancer [J]. Eur J Cancer 1996; 32A:7.[5]Riley LB, Lange MK, Browne RJ, et al. Analysis of cathepsin D in human breast cancer: usefulness of the processed 31 kDa active form of the enzyme as a prognostic indicator in node-negative and node-positive patients [J]. Breast Cancer Res Treat 2000; 60:173.[6]Fu XL. Histopathologic diagnosis. Chinese Common Malignant Tumor Diagnosis and Treatment Rule. Breast Carcinoma Volume [M]. 2nd ed. Beijing: Beijing Medical University and Chinese Xiehe Medical University Union Publisher, 1999; 23.[7]Yang SQ. Health Statistics [M]. 3rd ed. Beijing: People Health Publisher, 1998; 131.[8]Bittl A, Nap M, Jager W, et al. Immuno-histochemical detection of P-glycoprotein on frozen and paraffin-embedded tissue sections of normal and malignant tissues [J]. Anticancer Res 1995; 15:1007.[9]Isola J, Weitz S, Visakorpi T, et al. Cathepsin D expression detected by immunohistochemistry has independent prognostic value in axillary node-negative breast cancer [J]. J Clin Oncol 1993; 11:36.[10]Castiglioni T, Merino MJ, Elsner B, et al. Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer [J]. Hum Pathol 1994; 25:857.[11]Montcourrier P, Mangeat PH, Valembois C, et al. Characterization of very acidic phagosomes in breast cancer cells and their association with invasion [J]. J Cell Sci 1994; 107:238l.[12]Foekens JA, Look MP, Bolt de Vries J, et al. Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients [J]. Br J Cancer 1999

  19. 吉西他滨联合卡培他滨治疗转移性三阴性乳腺癌的临床观察%Clinical Outcomes of Gemcitabine Combined Capecitabine with Metastatic Triple-negative Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    李景; 高俊峰

    2013-01-01

    Objective:To observe the ef ect and side reaction of Gemcitabine combined capecitabine inmetastatic triple-negative breast cancer. Method:28 patients with metastatic triple-negative breast cancer were enrol ed. Capecitabine was oral dose with 2000mg/m2 per day though day 1 to day 14 and Gemcitabine injected with 1000mg/m2 at day 1 and day 8. Every 2 weeks repeated. Results:The outcomes in 28 patients included completed response (n=2,7.14%),partial response (n=10,35.7%) , stable disease (n=10,35.7%),progressive disease (n=6,21.4%) Total ef ective rate was 42.9%. Conclusion: Gemcitabine combined capecitabine was ef ective plan with with metastatic triple-negative breast cancer after the patients were failed with anthracycline and/or taxanes.%目的观察吉西他滨联合卡培他滨治疗蒽环及紫杉类药物耐药的转移性三阴性乳腺癌的疗效及不良反应。方法28例转移性三阴性乳腺癌患者,卡培他滨2000mg/m2·d,第1~14d,早晚饭后30min,2次/d口服;吉西他滨1000mg/m2,第1、8d,3周天为1周期。结果28例患者中,CR2例(7.14%),PR 10例(35.7%),SD 10例(35.7%),PD6例(21.4%),总有效率(CR+PR)为42.9%。结论卡培他滨联合吉西他滨治疗蒽环类和(或)紫杉类耐药转移性三阴性乳腺癌患者疗效较好,不良反应可以耐受.可以作为蒽环类和(或)紫杉类耐药的晚期三阴性乳腺癌患者的一个有效解救方案。

  20. miR141 expression is downregulated and negatively correlated with STAT5 expression in esophageal squamous cell carcinoma

    Science.gov (United States)

    TAN, HONGWU; ZHU, YUNFENG; ZHANG, JILING; PENG, LIJUN; JI, TAO

    2016-01-01

    The aim of the present study was to investigate the association between microRNA-141 (miR141) and signal transducer and activator of transcription 5 (STAT5) expression levels in human esophageal squamous cell carcinoma (ESCC) and to investigate the effects of miR141 on ESCC cells. A total of 45 consecutive patients with ESCC were enrolled in the study. The expression of miR141 in ESCC tissue samples was detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The expression of STAT5 in the ESCC tissues was detected using immunohistochemical staining and western blotting. In addition, Eca109 cells were transfected with miR141 mimic, and the levels of STAT5 were detected using western blotting. The effects of miR141 on the proliferation, invasion and migration of the cells were also detected using MTT, scratch and Transwell invasion assays, respectively. The miR141 expression level in the ESCC tissue samples was significantly decreased compared with that in the adjacent normal tissues (Pgender, age, tumor size, lesion location, differentiation and invasion (P>0.05). The results suggest that the miR141 mimic significantly inhibited the proliferation, migration and invasion of Eca109 cells in vitro. miR141 and STAT5 expression levels exhibited a negative association in the ESCC tissues, and were both closely associated with the progression of ESCC. Therefore, it appears that miR141 plays an important role in the development, invasion and metastasis of ESCC by regulating the expression of STAT5.

  1. The Cytoplasmic Domain of proEGF Negatively Regulates Motility and Elastinolytic Activity in Thyroid Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Aleksandra Glogowska

    2008-10-01

    Full Text Available The intracellular domains of the membrane-anchoring regions of some precursors of epidermal growth factor (EGF family members have intrinsic biologic activities. We have determined the role of the human proEGF cytoplasmic domain (proEGFcyt as part of the proEGF transmembrane-anchored region (proEGFctF in the regulation of motility and elastinolytic invasion in human thyroid cancer cells. We found proEGFctF to act as a negative regulator of motility and elastin matrix penetration and the presence of proEGFcyt or proEGF22.23 resulted in a similar reduction in motility and elastinolytic migration. This activity was counteracted by EGF-induced activation of EGF receptor signaling. Decreased elastinolytic migratory activity in the presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with decreased secretion of elastinolytic procathepsin L. The presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with the specific transcriptional up-regulation of t-SNARE member SNAP25. Treatment with siRNA-SNAP25 resulted in motility and elastin migration being restored to normal levels. Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor-mediated proteasomal degradation of SNAP25. These data provide first evidence for an important function of the cytoplasmic domain of the human proEGF transmembrane region as a novel suppressor of motility and cathepsin L-mediated elastinolytic invasion in human thyroid carcinoma cells and suggest important clinical implications for EGF-expressing tumors.

  2. Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes

    Directory of Open Access Journals (Sweden)

    Zhang W

    2015-07-01

    Full Text Available Wendian Zhang,1 Fangqi Peng,1 Taotao Zhou,1 Yifei Huang,2 Li Zhang,3 Peng Ye,4 Miao Lu,1 Guang Yang,5 Yongkang Gai,1 Tan Yang,1 Xiang Ma,1 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, 2Department of Pharmacy, 3Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 4Department of Pharmacy, Wuhan University, Renmin Hospital, 5School of Medicine, Jianghan University, Wuhan, People’s Republic of China Abstract: Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221 to the transferrin (Tf receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of -15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4°C. Anti-miR-221-encapsulated Tf-targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27kip1, and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor-bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3-anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27kip1, and TIMP3. Our results demonstrate that the Tf-targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC. Keywords: transferrin, gene, HCC, target delivery system, anionic liposome 

  3. VX-970, Cisplatin, and Radiation Therapy in Treating Patients With Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma

    Science.gov (United States)

    2016-04-05

    Head and Neck Squamous Cell Carcinoma; Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma

  4. Carbonic anhydrase IX expression in clear cell renal cell carcinomas negatively correlates with the proportion of the granular cell component

    Czech Academy of Sciences Publication Activity Database

    Skapa, P.; Hyršl, L.; Závada, Jan; Soukup, J.; Zámečník, J.

    2008-01-01

    Roč. 26, č. 22 (2008), s. 3811-3812. ISSN 0732-183X Institutional research plan: CEZ:AV0Z40550506 Keywords : carbonic anhydrase IX * CAIX * renal carcinoma Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 17.157, year: 2008

  5. Expression of toll-like receptors in HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma--an in vivo and in vitro study.

    Science.gov (United States)

    Jouhi, Lauri; Datta, Neeta; Renkonen, Suvi; Atula, Timo; Mäkitie, Antti; Haglund, Caj; Ahmed, Abdirisak; Syrjänen, Stina; Grénman, Reidar; Auvinen, Eeva; Lehtonen, Sanna; Hagström, Jaana

    2015-09-01

    The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past decades in many western countries. This trend is mainly attributed to the human papillomavirus (HPV). Cancer-related actions of immunological defense systems are being intensively researched. Human toll-like receptors (TLRs) are a family of pattern recognition receptors that participate in the immunological defense against pathogens, but their actions are also linked to cancer. The expression of TLRs in cervical epithelium alters both during the clearance of HPV infection and the HPV-induced neoplasia, but the expression of TLRs has not been studied in OPSCC. Thirty-five paraffin-embedded, formalin-fixed, squamous cell carcinoma tissue specimens were analyzed for TLRs 2, 3, 4, 5, 7, and 9 and HPV and p16 statuses. The TLR 9 expression was lower in HPV-positive tumors compared with HPV-negative tumors. TLR 7 was expressed in all cancer specimens, but elevated expression was evident in HPV and/or p16-positive tumors. The majority of p16-positive tumors did not express TLR 5, whereas its expression was stronger in p16-negative tumors. The results of in vitro analysis of five human OPSCC cell lines and one human oral tongue squamous cell carcinoma cell line agree with the in vivo trends: low levels of TLR 5 and high levels of TLR 7 in p16-positive OPSCC. Overall, TLR 7 and 9 expression patterns are demonstrated here to relate to the HPV status in vivo and TLR 5 and 7 expression patterns to the p16 status in vivo and in vitro. PMID:25941114

  6. Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC

    Directory of Open Access Journals (Sweden)

    Jay Overholser

    2015-07-01

    Full Text Available Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC and triple-negative breast cancer (TNBC. Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.

  7. Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple-Negative Breast Cancer (TNBC via Suppressing MMP2/9 by Blocking NF-κB and ERK/MAPK Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Yuping Liu

    Full Text Available Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS, a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated.MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK.DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.

  8. The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells.

    Science.gov (United States)

    Montani, Maura; Pazmay, Gretta V Badillo; Hysi, Albana; Lupidi, Giulio; Pettinari, Riccardo; Gambini, Valentina; Tilio, Martina; Marchetti, Fabio; Pettinari, Claudio; Ferraro, Stefano; Iezzi, Manuela; Marchini, Cristina; Amici, Augusto

    2016-05-01

    Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC. PMID:27038531

  9. Basal cytokeratin as a potential marker of low risk of invasion in ductal carcinoma in situ

    Directory of Open Access Journals (Sweden)

    Fernando N. Aguiar

    2013-05-01

    Full Text Available OBJECTIVES: Biological markers that predict the development of invasive breast cancer are needed to improve personalized therapy for patients diagnosed with ductal carcinoma in situ. We investigated the role of basal cytokeratin 5/6 in the risk of invasion in breast ductal carcinoma in situ. METHODS: We constructed tissue microarrays using 236 ductal carcinoma in situ samples: 90 pure samples (group 1 and 146 samples associated with invasive carcinoma (group 2. Both groups had similar nuclear grades and were obtained from patients of similar ages. The groups were compared in terms of estrogen (ER and progesterone receptor (PR status, human epidermal growth factor receptor 2 (HER2 expression, cytokeratin 5/6 immunostaining, human epidermal growth factor receptor 1 (EGFR membrane staining and molecular subtype, as indicated by their immunohistochemistry profiles. RESULTS: ER/PR-negative status was predictive of invasion, whereas HER2 superexpression and cytokeratin 5/6-positive status were negatively associated with invasion. Among the high-grade ductal carcinoma in situ cases, a triple-positive profile (positive for estrogen receptor, progesterone receptor, and HER2 and cytokeratin 5/6 expression by neoplastic cells were negatively associated with invasion. In the low-grade ductal carcinoma in situ subgroup, only cytokeratin 5/6 expression exhibited a negative association with the probability of invasion. CONCLUSION: The immunohistochemical expression of cytokeratin 5/6 by ductal carcinoma in situ epithelial cells may provide clinically useful information regarding the risk of progression to invasive disease.

  10. Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang ZG

    2015-12-01

    Full Text Available Zhiguo Zhang,1 Yanying Zhang,2 Yeying Wang,1 Lingling Xu,3 Wanju Xu3 1Department of Clinical Laboratory, Zhangqiu Maternity and Child Care Hospital, Zhangqiu, 2Department of Clinical Laboratory, Zaozhuang City Wangkai Infection Hospital, Zaozhuang, 3Department of Clinical Laboratory, Qianfoshan Hospital, Jinan, People’s Republic of China Abstract: Currently, there is no reliable biomarker for use in diagnosing alpha-fetoprotein (AFP-negative hepatocellular carcinoma (HCC. Such a biomarker would aid in making an early diagnosis of AFP-negative HCC, ensuring the timely initiation of treatment. This study examined AFP-L3 and Golgi protein 73 (GP73 as candidate biomarkers for AFP-negative HCC. The affinity adsorption method and enzyme-linked immunoassays were separately used to determine serum levels of AFP-L3 and GP73 in 50 patients with AFP-negative HCC, 30 non-HCC patients, and 50 healthy subjects. Fifty percent of patients with AFP-negative HCC tested positive for AFP-L3, while 3.33% of non-HCC patients and 2.00% of healthy subjects were AFP-L3 positive. Patients with AFP-negative HCC had significantly higher serum levels of AFP-L3 compared to non-HCC patients and healthy individuals; however, there was no significant difference in the AFP-L3 levels of non-HCC patients and healthy subjects. Sixty-six percent of patients with AFP-negative HCC tested positive for GP73, while 10% of non-HCC patients and 0% of healthy subjects were GP73-positive. Patients with AFP-negative HCC had significantly higher serum levels of GP73 compared to non-HCC patients and healthy subjects, but there was no significant difference between the GP73 levels of non-HCC patients and healthy individuals. Moreover, 20 patients with AFP-negative HCC were both AFP-L3- and GP73-positive, while no non-HCC patients or healthy subjects tested positive for both markers. Either AFP-L3 or GP73 may be used as a biomarker for diagnosing AFP-negative HCC, while their combined use

  11. S100A8/A9 (calprotectin negatively regulates G2/M cell cycle progression and growth of squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Ali Khammanivong

    Full Text Available Malignant transformation results in abnormal cell cycle regulation and uncontrolled growth in head and neck squamous cell carcinoma (HNSCC and other cancers. S100A8/A9 (calprotectin is a calcium-binding heterodimeric protein complex implicated in cell cycle regulation, but the specific mechanism and role in cell cycle control and carcinoma growth are not well understood. In HNSCC, S100A8/A9 is downregulated at both mRNA and protein levels. We now report that downregulation of S100A8/A9 correlates strongly with a loss of cell cycle control and increased growth of carcinoma cells. To show its role in carcinogenesis in an in vitro model, S100A8/A9 was stably expressed in an S100A8/A9-negative human carcinoma cell line (KB cells, HeLa-like. S100A8/A9 expression increases PP2A phosphatase activity and p-Chk1 (Ser345 phosphorylation, which appears to signal inhibitory phosphorylation of mitotic p-Cdc25C (Ser216 and p-Cdc2 (Thr14/Tyr15 to inactivate the G2/M Cdc2/cyclin B1 complex. Cyclin B1 expression then downregulates and the cell cycle arrests at the G2/M checkpoint, reducing cell division. As expected, S100A8/A9-expressing cells show both decreased anchorage-dependent and -independent growth and mitotic progression. Using shRNA, silencing of S100A8/A9 expression in the TR146 human HNSCC cell line increases growth and survival and reduces Cdc2 inhibitory phosphorylation at Thr14/Tyr15. The level of S100A8/A9 endogenous expression correlates strongly with the reduced p-Cdc2 (Thr14/Tyr14 level in HNSCC cell lines, SCC-58, OSCC-3 and UMSCC-17B. S100A8/A9-mediated control of the G2/M cell cycle checkpoint is, therefore, a likely suppressive mechanism in human squamous cell carcinomas and may suggest new therapeutic approaches.

  12. Full Length Article Role of glypican-3 immunocytochemistry in differentiating hepatocellular carcinoma from metastatic carcinoma of the liver utilizing fine needle aspiration cytology

    International Nuclear Information System (INIS)

    Purpose: Evaluation of the sensitivity and specificity of glypican3 (GPC3) in differentiating hepatocellular carcinoma (HCC) from metastatic carcinomas of the liver in cell block material. Patients and methods: Sixty cell blocks were prepared from liver FNAs performed in the radiodiagnosis department, National Cancer Institute, in the period between August 2011 and May 2012. Cases diagnosed as hepatocellular carcinoma, or metastatic carcinoma were included in the study. Cell block sections were stained with anti GPC-3. Sensitivity, specificity, and positive and negative predictive values, of GPC3 were calculated. The final diagnosis was based on the triple approach of clinical data, radiological findings, as well as cytomorphologic features aided by GPC-3 results. Results: 70% of cases were diagnosed as HCC, and 30% as metastatic carcinomas. 95.2% of HCC cases expressed GPC3. Poorly differentiated cases showed the highest GPC3 sensitivity (100%), followed by moderately differentiated cases (96.5%), while well differentiated cases expressed GPC3 in 90% of cases. 83.3% of metastatic carcinomas were negative for GPC3. In this study, sensitivity of GPC-3 in HCC was 95.2%, specificity was 83.3%, positive and negative predictive values were 93% and 88.2% respectively, and total accuracy was 91.7%. Conclusion: Immunocytochemical staining for GPC3 in cell block material is a highly sensitive and specific method capable of distinguishing HCC from the vast majority of metastatic carcinomas of the liver

  13. 331 cases of clinically node-negative supraglottic carcinoma of the larynx: a study of a modest size fixed field radiotherapy approach

    International Nuclear Information System (INIS)

    Purpose: For node-negative supraglottic carcinoma of the larynx, radiotherapy with surgery in reserve commonly provides very good results in terms of both local control and survival, while preserving function. However uncertainty exists over the treatment of the node-negative neck. Elective whole neck radiotherapy, while effective, may be associated with significant morbidity. The purpose of this study was to examine our practice of treating a modest size, fixed field to a high biologically effective dose and compare it with the patterns of recurrence from other centers that use different dose/volume approaches. Methods and Materials: Over a 10-year period 331 patients with node-negative supraglottic carcinoma of the larynx were treated with radiotherapy at the Christie Hospital Manchester. Patients were treated with doses of 50-55 Gy in 16 fractions over 3 weeks. Data were collected retrospectively for local and regional control, survival, and morbidity. Results: Overall local control, after surgical salvage in 17 cases, was 79% (T1-92%, T2-81%, T3-67%, T4-73%). Overall regional lymph node control, after surgical salvage in 13 cases, was 84% (T1-91%, T2-88%, T3-81%, T4-72%). Five-year crude survival was 50%, but after correcting for intercurrent deaths was 70% (T1-83%, T2-78%, T3-53%, T4-61%). Serious morbidity requiring surgery was seen in 7 cases (2.1%) and was related to prescribed dose (50 Gy-0%, 52.5 Gy-1.3%, 55 Gy-3.4%). Discussion: Our results confirm that treating a modest size, fixed field to a high biologically effective dose is highly effective. It enables preservation of the larynx in most cases, with acceptable regional control and no loss of survival compared to whole neck radiotherapy regimes

  14. ARTEMIN promotes de novo angiogenesis in ER negative mammary carcinoma through activation of TWIST1-VEGF-A signalling.

    Directory of Open Access Journals (Sweden)

    Arindam Banerjee

    Full Text Available The neurotrophic factor ARTEMIN (ARTN has been reported to possess a role in mammary carcinoma progression and metastasis. Herein, we report that ARTN modulates endothelial cell behaviour and promotes angiogenesis in ER-mammary carcinoma (ER-MC. Human microvascular endothelial cells (HMEC-1 do not express ARTN but respond to exogenously added, and paracrine ARTN secreted by ER-MC cells. ARTN promoted endothelial cell proliferation, migration, invasion and 3D matrigel tube formation. Angiogenic behaviour promoted by ARTN secreted by ER-MC cells was mediated by AKT with resultant increased TWIST1 and subsequently VEGF-A expression. In a patient cohort of ER-MC, ARTN positively correlated with VEGF-A expression as measured by Spearman's rank correlation analysis. In xenograft experiments, ER-MC cells with forced expression of ARTN produced tumors with increased VEGF-A expression and increased microvessel density (CD31 and CD34 compared to tumors formed by control cells. Functional inhibition of ARTN by siRNA decreased the angiogenic effects of ER-MC cells. Bevacizumab (a humanized monoclonal anti-VEGF-A antibody partially inhibited the ARTN mediated angiogenic effects of ER-MC cells and combined inhibition of ARTN and VEGF-A by the same resulted in further significant decrease in the angiogenic effects of ER-MC cells. Thus, ARTN stimulates de novo tumor angiogenesis mediated in part by VEGF-A. ARTN therefore co-ordinately regulates multiple aspects of tumor growth and metastasis.

  15. Effect of tamoxifen on the receptor-positive T61 and the receptor-negative T60 human breast carcinomas grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L;

    1985-01-01

    A study was made of the in vivo effect of the anti-oestrogen tamoxifen on the growth and cell cycle kinetics of the oestrogen and progesterone receptor-positive T61 human breast carcinoma and of the oestrogen and progesterone receptor-negative T60 human breast carcinoma grown in nude mice. The T61...... tumour was exposed to single doses of 0.1, 1.0, 5 or 10 mg tamoxifen, resulting in serum concentrations 1 day after treatment ranging from less than 27 to 134 nM. The T60 tumour was exposed to a single dose of 1.0 mg tamoxifen. The effect on the tumour growth curves was determined according to a...... transformed Gompertz function, and the effect on the cell cycle distributions was estimated by flow cytometric DNA analysis on tumour tissue obtained by fine-needle aspirations at intervals after the treatment. The results showed that in the T61 tumour, tamoxifen induced a dose-related growth inhibition...

  16. Acinic cell carcinoma of breast: morphologic and immunohistochemical review of a rare breast cancer subtype.

    Science.gov (United States)

    Conlon, Niamh; Sadri, Navid; Corben, Adriana D; Tan, Lee K

    2016-05-01

    Acinic cell carcinoma of breast is a rare subtype of triple-negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. In this study, we perform a detailed morphologic and immunohistochemical description of 2 cases of this rare entity and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. One-third of reported cases of breast acinic cell carcinoma have been associated with the presence of a ductal carcinoma not otherwise specified component, which is frequently poorly differentiated. Breast acinic cell carcinoma can demonstrate focal morphologic features similar to microglandular adenosis; these areas are frequently negative for collagen IV and laminin on immunohistochemistry. The true relationship between these 2 entities remains unclear, but we advocate that microglandular adenosis-like areas at the periphery of a breast acinic cell carcinoma should be considered part of the carcinomatous process and re-excised if this process extends to the initial surgical margins. PMID:27067778

  17. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00.

    Science.gov (United States)

    Pruneri, Giancarlo; Gray, Kathryn P; Vingiani, Andrea; Viale, Giuseppe; Curigliano, Giuseppe; Criscitiello, Carmen; Láng, István; Ruhstaller, Thomas; Gianni, Lorenzo; Goldhirsch, Aron; Kammler, Roswitha; Price, Karen N; Cancello, Giuseppe; Munzone, Elisabetta; Gelber, Richard D; Regan, Meredith M; Colleoni, Marco

    2016-07-01

    The purpose of this study was to assess the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in the triple-negative breast cancer (TNBC) cohort of the phase III IBCSG trial 22-00, comparing low-dose oral 'metronomic' cyclophosphamide-methotrexate maintenance chemotherapy (CM-maintenance) to no-CM-maintenance in early breast cancer. TILs were evaluated in full-face hematoxylin-and-eosin-stained sections of tumor samples confirmed centrally as TNBC (cancer-free interval (BCFI). Cox proportional hazards regression model assessed the association of BCFI and secondary endpoints with TILs score. In the 647 tumor samples, the median percentage of TILs was 18 % (IQR = 8-40 %), with 18 % having TILs ≥ 50 % (lymphocyte-predominant breast cancer, LPBC). At a median follow-up of 6.9 years, TILs were associated with better prognosis. For every 10 % increase of TILs, BCFI risk reduction was 13 % (HR 0.87, 95 % CI 0.79-0.95,P = 0.003). DFS, DRFI, and OS risk reductions were 11 % (P = 0.005), 16 % (P = 0.003), and 17 % (P cancer risk reduction (HR 0.64,95 % CI 0.23-1.78) than those with non-LPBC (TILs < 50 %) (HR 0.96, 95 % CI 0.67-1.40). TILs score is a potent prognostic factor in patients with TNBC. Low-dose chemotherapy confers a greater (not statistically significant) clinical benefit in patients with LPBC. PMID:27372069

  18. 顺铂诱导三阴性乳腺癌4T1耐药小鼠模型的建立%Establishment of a cisplatin-resistant mouse model of 4T1 triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    盛佳钰; 陈红风

    2015-01-01

    Objective To establish a cisplatin-resistant 4T1 mouse model of triple negative breast cancer .Meth-ods A drug resistant mice model was established with cisplatin ( DDP ) induction and in-vivo/in-vitro tumorigenic ap-proach.Its resistance characteristics were identified by MTT assay .Changes of drug resistance gene ( MDR1, BCRP, MMP7, GST-π) and protein ( P-gp, BCRP, MMP7) expression, and phosphorate-Akt and total-Akt protein expression were evaluated by real-time PCR, immunohistochemistry and western blot method , respectively.Small animal live imaging technology was applied to detect tumor growth .Results Resistance fold (RF) of cisplatin-resistant 4T1 mouse model was 12.84.The expression of MDR1, BCRP, MMP 7, GST-πmRNA and P-gp, BCRP, MMP 7 proteins in the resistant mice were higher than that in the non-resistant mice .The result of western blot showed that a statistically higher expression of p-Akt in resistant mice than that in non-resistant mice at protein levels (P0.05 ) .Given same dose of DDP , resistant mice showed lower sensitivity than non-resistant mice significantly (P0.05). 分别给予这两种模型小鼠相同剂量的DDP治疗后,耐药小鼠对DDP的敏感性明显低于非耐药小鼠(P<0.01). 结论 初步建立了三阴性乳腺癌耐药4T1小鼠模型,为三阴性乳腺癌临床个体化治疗及耐药逆转研究等提供了良好的实验动物平台.

  19. Tumour apparent diffusion coefficient is associated with depth of myometrial invasion and is negatively correlated to tumour volume in endometrial carcinomas

    International Nuclear Information System (INIS)

    Aim: To explore possible correlations between tumour apparent diffusion coefficient (ADC), morphological tumour volume, and clinical and histological characteristics in endometrial carcinomas and to evaluate interobserver agreement for preoperative staging by MRI and for ADC measurements. Materials and methods: Preoperative conventional MRI including diffusion-weighted imaging (DWI) was performed in 105 endometrial carcinoma patients. Three radiologists independently reviewed the images for the presence of deep myometrial invasion, cervical stromal invasion, and lymph node metastases, and measured tumour ADC in regions of interest (ROIs). ADC values were analysed in relation to histomorphological characteristics and tumour volume. Kappa coefficients (κ) and intraclass correlation coefficients (ICC) for interobserver agreement for MRI staging results and ADC measurements, respectively, were calculated, and receiver operating characteristic (ROC) curves for identification of deep of myometrial invasion were generated. Results: Mean tumour ADC was significantly lower in tumours with deep myometrial invasion (ADC = 0.75 × 10−3 mm2/s) compared to tumours with superficial or no myometrial invasion (ADC = 0.85 × 10−3 mm2/s; p < 0.001). ADC was negatively correlated to tumour size (p = 0.007). The interobserver agreement was fair (κ = 0.32) for depth of myometrial invasion, good for cervical stromal invasion (κ = 0.66), and moderate for lymph node metastases (κ = 0.54), and the interobserver variability for ADC value measurements was low (ICC = 0.60). Conclusion: Tumour ADC measurements may in the future provide an adjunct tool, aiding in the preoperative identification of high-risk patients with deep myometrial infiltration. - Highlights: • Low tumour ADC is associated with deep myometrial invasion in endometrial carcinomas. • Tumour ADC value is negatively correlated to tumour size. • Preoperative staging by MRI is prone to

  20. Correlation of primary tumor FDG uptake with clinicopathologic prognostic factors in invasive ductal carcinoma of the breast

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast. We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUVmax) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUVmax compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis. In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer

  1. Efficacy Observation of Capecitabine Combined with Cisplatin in the Treatment of Advanced Triple Negative Breast Cancer%卡培他滨联合顺铂治疗晚期三阴性乳腺癌的疗效观察

    Institute of Scientific and Technical Information of China (English)

    丛雪; 王亚帝; 哈敏文; 刘维

    2012-01-01

    OBJECTIVE: To observe efficacy and toxic side effect of capecitabine combined with cisplatin in the treatment of triple negative advanced breast cancer of negative ER, PR, HER-2. METHODS: 48 cases were diagnosed as advanced metastatic breast cancer of negative ER, PR, HER-2 by immunohistochemistry, among which 24 cases received oral dose of capecitabine 2 500 mg·m-2 alone morning and night for consecutive 14 days, 21 days for the 1 cycle; other 24 cases received capecitabine combined with cisplatin DDP: intravenous infusion of 30 cisplatin mg·m-2, d1~d3, oral dose of capecitabine in 1 250 mg·m-2 morning and night for consecutive 14 days, 21 days for the 1 cycle. The number of completed treatment course in monotherapy group and chemotherapy group were (4.2 + 0.9) and (4.0 + 0.7). RESULTS:The effective rates of capecitabine monotherapy group and chemotherapy group were 29.2% and 33.4%. The median TTP of 24 patients in monotherapy group was 5 months with 1 year survival rate of 65.7%. The median TTP of 24 patients in chemotherapy group was 6 months with 1 year survival rate of 67.7%. The Ⅲ -degree hand-foot syndrome of capecitabine monotherapy group was slightly more than combination group. Toxic side effect of chemotherapy group were mainly gastrointestinal tract reaction, leucopenia, fatigue, etc., and all recovered after proper treatment. CONCLUSION: Capecitabine combined with cisplatin have good efficacy in the treatment of advanced metastatic triple negative breast cancer patients, and toxic side effects can be tolerated.%目的:观察卡培他滨联合顺铂治疗雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER-2)均阴性(三阴性)晚期乳腺癌的疗效与毒副反应.方法:48例经免疫组化证实ER、PR、HER-2阴性的晚期转移性乳腺癌患者,其中24例患者单用卡培他滨2500mg·m-2,分早晚两次口服,连服14d,21d为1个周期;24例患者接受卡培他滨+顺铂方案:顺铂30mg·m-2静脉滴注,d1

  2. Benign anal lesions, inflammatory bowel disease and risk for high-risk human papillomavirus-positive and -negative anal carcinoma.

    OpenAIRE

    Frisch, M.; Glimelius, B.; van den Brule, A J; Wohlfahrt, J.; Meijer, C J; Walboomers, J M; Adami, H. O.; Melbye, M.

    1998-01-01

    A central role in anal carcinogenesis of high-risk types of human papillomaviruses (hrHPV) was recently established, but the possible role of benign anal lesions has not been addressed in hrHPV-positive and -negative anal cancers. As part of a population-based case-control study in Denmark and Sweden, we interviewed 417 case patients (93 men and 324 women) diagnosed during the period 1991-94 with invasive or in situ anal cancer, 534 patients with adenocarcinoma of the rectum and 554 populatio...

  3. Proteomic profiling of triple-negative breast carcinomas in combination with a three-tier orthogonal technology approach identifies Mage-A4 as potential therapeutic target in estrogen receptor negative breast cancer

    DEFF Research Database (Denmark)

    Cabezón, Teresa; Gromova, Irina; Gromov, Pavel;

    2013-01-01

    Breast cancer is a very heterogeneous disease, encompassing several intrinsic subtypes with various morphological and molecular features, natural history and response to therapy. Currently, molecular targeted therapies are available for estrogen receptor (ER)(-) and human epidermal growth factor ...

  4. Response to Multiple Radiation Doses of Human Colorectal Carcinoma Cells Infected With Recombinant Adenovirus Containing Dominant-Negative Ku70 Fragment

    International Nuclear Information System (INIS)

    Purpose: To investigate the effect of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment on the response of tumor cells to multiple small radiation doses. Our ultimate goal is to demonstrate the feasibility of using this virus in gene-radiotherapy to enhance the radiation response of tumor cells. Methods and Materials: Human colorectal HCT8 and HT29 carcinoma cells were plated in glass tubes, infected with virus (25 multiplicity of infection), and irradiated with a single dose or zero to five doses of 3 Gy each at 6-h intervals. Hypoxia was induced by flushing with 100% nitrogen gas. The cells were trypsinized 0 or 6 h after the final irradiation, and cell survival was determined by colony formation. The survival data were fitted to linear-quadratic model or exponential line. Results: Virus infection enhanced the radiation response of the HCT8 and HT29 cells. The virus enhancement ratio for single-dose irradiation at a surviving fraction of 0.1 was ∼1.3 for oxic and hypoxic HCT8 and 1.4 and 1.1 for oxic and hypoxic HT29, respectively. A similar virus enhancement ratio of 1.2-1.3 was observed for both oxic and hypoxic cells irradiated with multiple doses; however, these values were smaller than the values found for dominant-negative Ku70-transfected Rat-1 cells. This difference has been discussed. The oxygen enhancement ratio for HCT8 and HT29 receiving fractionated doses was 1.2 and 2.0, respectively, and virus infection altered them slightly. Conclusion: Infection of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment enhanced the response of human colorectal cancer cells to single and multiple radiation doses.

  5. 从合成致死策略谈三阴性乳腺癌的靶向治疗*%Studies on targeted therapy for triple-negative breast cancer based on synthetic lethal strategy

    Institute of Scientific and Technical Information of China (English)

    李荣晖; 杜彩文; 黄文河; 张国君

    2013-01-01

      三阴性乳腺癌(triple negative breast cancer,TNBC)是指雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)及人表皮生长因子受体-2(human epidermal growth factor receptor-2,HER-2)均为阴性表达的乳腺癌。该亚型好发于年轻女性,侵袭性强,组织学分级高,易发生内脏转移,生存期短,预后较差。针对TNBC的治疗手段有限,其对内分泌治疗及以HER-2为靶点的靶向治疗无效。合成致死策略是指两个基因中,若仅其中的一个基因发生了变异,细胞会仍然存活,若两个基因同时发生了变异,则将引起细胞死亡。在所涉及的两个基因中,若一个突变基因是癌基因,另外的一个基因就有可能成为潜在的“靶基因”,那么针对其靶点的抑制剂可以杀死伴有癌变的恶性肿瘤细胞,但不会影响正常细胞的存活,即选择性杀死肿瘤细胞。基于合成致死策略寻找TNBC的新治疗靶点为研发抗TNBC新药提供了新的策略,与乳腺癌易感基因BRCA1协同修复DNA损伤的分子生物学机制显示PARP-1是TNBC的新靶点之一,PARP-1抑制剂有可能成为抗TNBC的新靶向治疗药物。%Triple-negative breast cancer (TNBC) is a subtype of breast cancer defined by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (Her-2). TNBC is characterized by its onset among females at a very young age, high invasiveness and histological grades, and easy metastasis to the internal organs. This type of breast cancer is prone to visceral metastases and rapid progression, thereby resulting in short survival and unfavorable prognosis. Therapeutic tools against TNBC are limited because endocrine-and Her-2-targeted therapies are both ineffective. Synthetic lethal strategy means that two genetic mutations cause cell death. However, cells survive if only one mutation gene exists in

  6. PRIMARY NONKERATINIZING SQUAMOUS CARCINOMA OF BREAST WITH IPSILATERAL AXILLARY LYMPH NODE METASTASIS: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Amoolya

    2014-04-01

    Full Text Available Primary squamous carcinoma is a rare type of metaplastic carcinoma of the breast, incidence being less than 0.1% of all breast carcinomas. The non-keratinizing variant can mimic several rare types of breast carcinomas, prognosis and therapeutic modalities of which are dissimilar. Histopathological examination is gold standard in diagnosing these tumors. Accurate diagnosis employing special stains and immunohistochemistry is mandatory as they are triple negative unlike infiltrating ductal carcinoma NOS, and have aggressive course, poor prognosis and distinctive treatment modalities. Other unique features include less frequent axillary nodal metastasis and necessity to rule out metastatic squamous carcinomas to the breast from other primary sites in these patients. We present a 60 years old lady with a hard lump in the left breast, with no significant past history. Physical examination was suggestive of carcinoma of breast with axillary lymphadenopathy. Histopathological examination revealed squamous carcinoma of breast positive for p63 and cytokeratin (CK 5/6. Her chest X-ray, abdominal ultrasonography, oral cavity, laryngobronchoscopy, cystoscopy and cervical Pap smears were unremarkable ruling out the possibility of primary squamous tumor in other common organs

  7. Jordan Triple Disystems

    CERN Document Server

    Bremner, Murray R; Sanchez-Ortega, Juana

    2011-01-01

    We take an algorithmic and computational approach to a basic problem in abstract algebra: determining the correct generalization to dialgebras of a given variety of nonassociative algebras. We give a simplified statement of the KP algorithm introduced by Kolesnikov and Pozhidaev for extending polynomial identities for algebras to corresponding identities for dialgebras. We apply the KP algorithm to the defining identities for Jordan triple systems to obtain a new variety of nonassociative triple systems, called Jordan triple disystems. We give a generalized statement of the BSO algorithm introduced by Bremner and Sanchez-Ortega for extending multilinear operations in an associative algebra to corresponding operations in an associative dialgebra. We apply the BSO algorithm to the Jordan triple product and use computer algebra to verify that the polynomial identities satisfied by the resulting operations coincide with the results of the KP algorithm; this provides a large class of examples of Jordan triple disy...

  8. PinX1 suppresses tumorigenesis by negatively regulating telomerase/telomeres in colorectal carcinoma cells and is a promising molecular marker for patient prognosis

    Science.gov (United States)

    Qian, Dong; Cheng, Jingjing; Ding, Xiaofeng; Chen, Xiuli; Chen, Xi; Guan, Yong; Zhang, Bin; Wang, Jiefu; Er, Puchun; Qiu, Minghan; Zeng, Xianliang; Guo, Yihang; Wang, Huanhuan; Zhao, Lujun; Xie, Dan; Yuan, Zhiyong; Wang, Ping; Pang, Qingsong

    2016-01-01

    PinX1 plays positive and negative roles in the maintenance of telomerase and telomeres, as well as in tumorigenesis. The aim of the present study was to investigate the expression and clinical significance of PinX1 in colorectal carcinoma (CRC) and to determine the effect of PinX1 on CRC cell proliferation and apoptosis. A total of 86 CRC patients treated with radical resection and 5-fluorouracil-based adjuvant chemotherapy were enrolled in this study. The expression dynamics of PinX1 was detected by immunohistochemistry in the CRC patients and 25 normal colonic mucosa controls. PinX1 expression was significantly reduced in tumor tissues as compared to normal tissues, and the rate of PinX1 protein low/negative expression in CRC and normal tissues was 60% (52/86) and 24% (6/25), respectively (P=0.037). In addition, PinX1 downregulation was significantly associated with short overall survival (P=0.016) and disease-free survival (P=0.042) in CRC patients. Cox proportional hazards model further revealed that PinX1 expression was an independent factor in predicting overall survival and disease-free survival for CRC patients. Furthermore, we demonstrated that ectopic overexpression of PinX1 in CRC cells inhibited their proliferation, promoted apoptosis, repressed telomerase activity, and induced telomere shortening. These findings suggest that PinX1 may be a prognostic biomarker for CRC patients’ survival and that it inhibits cell proliferation and promotes apoptosis by repressing telomerase activity and inducing telomere shortening. Targeting PinX1 may therefore provide a novel therapeutic strategy for CRC patients. PMID:27536146

  9. 卡培他滨维持治疗对联合化疗有效的复发转移三阴乳腺癌的临床观察∗%Clinical observation of capecitabine continuous maintenance in treatment recurrence of triple-negative breast cancer with reaction to combined chemoradiotherapy

    Institute of Scientific and Technical Information of China (English)

    罗海涛; 邹静荷; 古伟光; 胡建新; 贺志仁; 徐敏; 吕淑新

    2015-01-01

    Objective To evaluate the clinical efficacy and safety of capecitabine continuous maintenance in treatment of re-currence of triple-negative breast cancer,which had responded to combined chemoradiotherapy.Methods The triple-negative breast cancer was defined as negative of ER,PR and HER2.A total of 46 patients of triple-negative breast cancer were divided into the treatment group (23 patients)and the control group (23 patients).The treatment group was given capecitabine continuous mainte-nance after 6 cycles of chemotherapy.The control group was given 6 cycles of combined chemotherapy only.The clinical efficacy and safety was evaluated between the two groups.Results The PR,PD,RR,and DCR in the treatment group were significantly higher than those in the control group(P 0.05).Conclusion Capecitabine continuous maintenance after combined chemoradiotherapy in treatment of recurrence of triple-neg-ative breast cancer is more effective,lower toxicity and tolerable.%目的:评价卡培他滨维持治疗对联合化疗有效的复发转移三阴乳腺癌的疗效和安全性。方法选择浸润性乳腺癌激素受体雌激素受体(ER)、孕激素受体(PR)及人类表皮生长因子受体2(HER2)均为阴性,病灶为不可切除的局部晚期或已经转移的女性患者46例,分为治疗组(n=23)和对照组(n=23),治疗组行联合方案化疗6个疗程有效后口服卡培他滨维持治疗,对照组单纯行联合方案化疗6个疗程,比较两组疗效和不良反应。结果治疗组的部分缓解(PR)、病情进展(PD)、临床有效率(RR)及疾病控制率(DCR)率明显优于对照组,差异有统计学意义(P 0.05)。结论卡培他滨维持治疗对联合化疗有效的复发转移三阴乳腺癌效果好,可提高晚期乳腺癌的有效率、DCR,近期疗效。

  10. Breast magnetic resonance imaging in patients with occult breast carcinoma: evaluation on feasibility and correlation with histopathological findings

    Institute of Scientific and Technical Information of China (English)

    LU Hong; XU Yi-lin; ZHANG Shu-ping; LANG Rong-gang; Chi S.Zee; LIU Pei-fang; FU Li

    2011-01-01

    Background As an uncommon presentation, occult primary breast cancer remains a diagnostic and therapeutic challenge in clinical practice. This study aimed to retrospectively assess the feasibility of breast magnetic resonance imaging (MRI) in patients with malignant axillary lymphadenopathy and unknown primary malignancy, and correlation with histopathological characteristics.Methods A total of 35 women with occult breast carcinoma were evaluated with dynamic contrast-enhanced breast MRI. Whole seriate section was used in all cases. MRI performance was assessed and correlated with histopathological findings.Results Twenty-one of 35 patients were found to have primary breast carcinoma histologically. Twenty of the 21 patients had abnormal MR findings and 1 patient had a normal MRI study. Of the remaining 14 patients, 10 were negative on both MRI and surgery. Four had suspicious enhancement on MRI and no corresponding tumor was found. Lesions with mass enhancement were found in 55% (11/20) and ductual and segmental enhancement in 45%. The average diameter of the primary tumors was 15 mm. Invasive ductal carcinomas were found in 81% (17/21). One of 17 invasive ductual carcinomas was too small to be graded. Fourteen of the remaining 16 were classified as grade II and 2 as grade I. Thirty-two of the 35 patients had received estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 examinations and the 12 of 32 were triple-negative breast carcinoma.Conclusions Mass lesions with small size and lesions with ductal or segment enhancement are common MRI features in patients with occult breast cancer. The dominant types of primary tumors are invasive ductal carcinoma with moderate histopathological grade. The rate of triple-negative breast carcinoma may be higher in occult breast cancer.

  11. Prognostic Value of Volume-Based {sup 18}F-Fluorodeoxyglucose PET/CT Parameters in Patients with Clinically Node-Negative Oral Tongue Squamous Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Su Jin [Dept. of Nuclear Medicine, Ajou University School of Medicine, Suwon (Korea, Republic of); Choi, Joon Young; Lee, Hwan Joo; Hyun, Seung Hyup; Moon, Seung Hwan; Kim, Byung Tae [Dept. of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Baek, Chung Hwan; Son, Young Ik [Dept. of Otorhinolaryngology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-11-15

    To evaluate the prognostic value of volume-based metabolic parameters measured with {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) positron emission tomography (PET) in patients with clinically node-negative (cN0) oral tongue squamous cell carcinoma (OTSCC) as compared with other prognostic factors. In this study, we included a total of 57 patients who had been diagnosed with cN0 tongue cancer by radiologic, ({sup 18}F-FDG PET/CT, and physical examinations. The maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for primary tumors were measured with ({sup 18}F-FDG PET. The prognostic significances of these parameters and other clinical variables were assessed by Cox proportional hazards regression analysis. In the univariate analysis, pathological node (pN) stage, American Joint Committee on Cancer (AJCC) stage, SUVmax, SUVavg, MTV, and TLG were significant predictors for survival. On a multivariate analysis, pN stage (hazard ratio = 10.555, p = 0.049), AJCC stage (hazard ratio = 13.220, p = 0.045), and MTV (hazard ratio = 2.698, p 0.033) were significant prognostic factors in cN0 OTSCC patients. The patients with MTV {>=} 7.78 cm{sup 3} showed a worse prognosis than those with MTV < 7.78 cm{sup 3} (p = 0.037). The MTV of primary tumor as a volumetric parameter of ({sup 18}F-FDG PET, in addition to pN stage and AJCC stage, is an independent prognostic factor for survival in cN0 OTSCC.

  12. Prognostic Value of Volume-Based 18F-Fluorodeoxyglucose PET/CT Parameters in Patients with Clinically Node-Negative Oral Tongue Squamous Cell Carcinoma

    International Nuclear Information System (INIS)

    To evaluate the prognostic value of volume-based metabolic parameters measured with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in patients with clinically node-negative (cN0) oral tongue squamous cell carcinoma (OTSCC) as compared with other prognostic factors. In this study, we included a total of 57 patients who had been diagnosed with cN0 tongue cancer by radiologic, (18F-FDG PET/CT, and physical examinations. The maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for primary tumors were measured with (18F-FDG PET. The prognostic significances of these parameters and other clinical variables were assessed by Cox proportional hazards regression analysis. In the univariate analysis, pathological node (pN) stage, American Joint Committee on Cancer (AJCC) stage, SUVmax, SUVavg, MTV, and TLG were significant predictors for survival. On a multivariate analysis, pN stage (hazard ratio = 10.555, p = 0.049), AJCC stage (hazard ratio = 13.220, p = 0.045), and MTV (hazard ratio = 2.698, p 0.033) were significant prognostic factors in cN0 OTSCC patients. The patients with MTV ≥ 7.78 cm3 showed a worse prognosis than those with MTV 3 (p = 0.037). The MTV of primary tumor as a volumetric parameter of (18F-FDG PET, in addition to pN stage and AJCC stage, is an independent prognostic factor for survival in cN0 OTSCC.

  13. New blocking antibodies impede adhesion, migration and survival of ovarian cancer cells, highlighting MFGE8 as a potential therapeutic target of human ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    Lorenzo Tibaldi

    Full Text Available Milk Fat Globule--EGF--factor VIII (MFGE8, also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvβ3 and αvβ5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients.

  14. Seguimento dos doentes soropositivos e soronegativos para o HIV com carcinoma espinocelular do canal anal Follow-up for HIV negative and HIV-positive patients with anal squamous cells carcinoma

    Directory of Open Access Journals (Sweden)

    Sidney Roberto Nadal

    2009-09-01

    Full Text Available A incidência do carcinoma espinocelular (CEC anal e das neoplasias intra-epiteliais anais (NIA é maior nos pacientes infectados pelo papilomavírus humano (HPV, e está relacionada à imunidade e à infecção pelo vírus da imunodeficiência humana (HIV. A associação com viroses de transmissão sexual indica que seja tumor sexualmente transmitido. A infecção pelo HIV mudou o perfil dos portadores do CEC anal. A doença que anteriormente acometia mulheres na 6ª década de vida, hoje atinge preferencialmente homens na 3ª e 4ª décadas. Nos Estados Unidos, a expectativa de diagnóstico desse tumor aumentou de 19/100.000, na época pré-HAART (1992-1995, para 48,3/100.000 no período pós-HAART imediato (1996-1999 e para 78,2/100.000 pessoas por ano, nos anos mais recentes (2000-2003. O tratamento do CEC anal, descrito por Nigro em 1974, combina radio e quimioterapia. Operações de resgate estão indicadas caso haja persistência ou recidiva da doença. Estudos comparando, respectivamente, doentes imunodeprimidos e imunocompetentes vêm mostrado envolvimento linfonodal em 60% e 17%, recidivas em 75% e 6%, boa resposta à radio e quimioterapia em 62% e 85%, toxicidade a esse tratamento em 80% e 30%, e sobrevivência global de 1,4 e 5,3 anos. A contagem sérica baixa de linfócitos T CD4 prediz mau prognóstico. Quando acima de 200/mm³, os resultados são comparáveis aos observados entre os imunocompetentes.Anal squamous cell carcinoma (ASCC and anal intra-epithelial neoplasia (AIN incidences are bigger among human papillomavirus (HPV infections, and are associated to immunity and to HIV infection. These viruses with sexual transmission in association suggested ASCC is a sexually transmitted tumor. HIV infection changed ASCC patient profile. This kind of tumor committed women in theirs sixties, but nowadays, affects mainly men in the third and forth decades of life. In the United States of America, ASCC was diagnosed in 19/100.000, in the

  15. Is postoperative radiation beneficial in the management of Stage I-II squamous-cell carcinoma of the uterine cervix with negative metastatic nodes and positive parametrial involvement; A retrospective review of 70 patients

    Energy Technology Data Exchange (ETDEWEB)

    Takamura, Akio (Asahikawa Kosei Hospital, Hokkaido (Japan)); Mizoe, Jun-etsu; Arimoto, Takuro; Kamada, Tadashi; Shirato, Hiroki; Matsuoka, Yoshisuke; Tomita, Masayoshi; Irie, Goro

    1993-06-01

    Seventy patients having squamous-cell carcinoma of the uterine cervix FIGO (Federation Internationale de Gynecologie et d'Obstetrique : International Federation of Gynecology and Obstetrics) Stage I-II with negative lymph nodes and positive parametrial involvement received postoperative radiotherapy following radical hysterectomy and pelvic lymphadenectomy. In 48 patients with microscopic parametrial involvement had a 5-year survival rate of 75%. The overall recurrence was 13% (9 of 70). The sites of failure were 3 pelvic alone, 5 distant metastases alone, and 1 combined pelvis and para-aortic lymph node. All of those with recurrence were Stage-II cases. The absolute pelvic-control rate was 94.3% (66/70). Fifty-six percent of the patients experienced mild-to-moderate lymphedema. Severe complications requiring surgical intervention were observed in 6 patients (5 bowel obstructions and 1 femoral head fracture). A review of the literature suggests that early carcinoma can be successfully treated by surgery alone. Taking into consideration the risk and benefits involved, postoperative radiotherapy is not recommended for most patients with cervical carcinoma with negative lymph nodes and positive parametrial involvement in the present form, despite excellent local control. However, no definite conclusion can be drawn from this retrospective analysis. (author).

  16. Implementation of Triple RSA

    Directory of Open Access Journals (Sweden)

    Sapna Sejwani*1

    2014-05-01

    Full Text Available The Rivest Shamir Adleman (RSA cryptosystem, named after its creators, is one of the most popular public key cryptosystems. It is most widely used for its strong security feature and easy implementation. The RSA cryptosystem has been utilized for many e-commerce applications, various forms of authentication, and virtual private networks in any organizations. The importance of high security and faster implementations paved the way for hardware implementations of the RSA algorithm. This work consists of describing a new approach to enhance RSA security. In this paper we will enhance the security feature by introducing an advance model called Triple RSA. Although RSA has not been attacked yet, it is still prone to attacks. So to enhance its security we have implemented triple RSA just like triple DES which is extremely secure. This model provides along with confidentiality, a strong authentication, data integrity, tamper detection and non repudiation.

  17. Triple Point Topological Metals

    Science.gov (United States)

    Zhu, Ziming; Winkler, Georg W.; Wu, QuanSheng; Li, Ju; Soluyanov, Alexey A.

    2016-07-01

    Topologically protected fermionic quasiparticles appear in metals, where band degeneracies occur at the Fermi level, dictated by the band structure topology. While in some metals these quasiparticles are direct analogues of elementary fermionic particles of the relativistic quantum field theory, other metals can have symmetries that give rise to quasiparticles, fundamentally different from those known in high-energy physics. Here, we report on a new type of topological quasiparticles—triple point fermions—realized in metals with symmorphic crystal structure, which host crossings of three bands in the vicinity of the Fermi level protected by point group symmetries. We find two topologically different types of triple point fermions, both distinct from any other topological quasiparticles reported to date. We provide examples of existing materials that host triple point fermions of both types and discuss a variety of physical phenomena associated with these quasiparticles, such as the occurrence of topological surface Fermi arcs, transport anomalies, and topological Lifshitz transitions.

  18. Radiosensitization of head/neck squamous cell carcinoma by adenovirus-mediated expression of dominant negative constructs of the Nbs1 protein

    International Nuclear Information System (INIS)

    Purpose: Local failure and toxicity to adjacent critical structures is a significant problem in radiation therapy of cancers of the head and neck. We are developing a gene therapy based method of sensitizing head/neck squamous cell carcinoma (HNSCC) to radiation treatment. As patients with the rare hereditary disorder, Nijmegen breakage syndrome show radiation sensitivity we hypothesized that tumor-specific disruption of the function of the Nbs1 protein would lead to enhanced cellular sensitivity to ionizing radiation. In order to test this hypothesis we have devised recombinant adenoviruses expressing various portions of the Nbs1 protein and assessed the ability of these viruses to increase the radiation sensitivity of HNSCC cells. Materials and Methods: We constructed two recombinant adenoviruses by cloning the full-length Nbs1 cDNA as well as the C-terminal 300 amino acids of Nbs1(Nbs1-300, aa453 to aa754) into an adenovirus backbone under the control of a CMV promoter. The resulting adenoviruses were used to infect HNSCC cell line 011. These cells were evaluated for expression of the viral based constructs and assayed for growth rate and clonogenic survival following radiation exposure. Results: A constitutively expressed GFP gene in the viral backbone confirmed efficient uptake of the virus into the 011 cell line and Western blot confirmed the presence of the virally expressed Nbs1 and Nbs1-300. Following exposure to ionizing radiation cells infected with the Nbs1-300 virus showed a significant reduction in growth rate relative to cells infected with control virus. Surprisingly, this effect was even stronger with the full-length wild-type Nbs1 protein. Examination of clonogenic survival also demonstrated statistically significant sensitization, however the effects of the two constructs were distinct as Nbs1-300 expression resulted in reduction of the shoulder while expression of the full-length Nbs1 showed a change in the slope of the survival curve

  19. Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract

    International Nuclear Information System (INIS)

    Thrombospondin (TSP) is a multi-functional protein that appears to have dual roles in cancer, that is, either as a promoter or a suppressor. 4N1K is a TSP-derived peptide that has been reported to be associated with neovascularity, cell survival, and invasion. There is a little information regarding its pathological roles in human cancer tissues. Our aim was to clarify clinical significance and prognostic value of 4N1K expression in patients with urothelial carcinoma of the upper urinary tract (UC-UUT). We investigated 4N1K expression in 97 surgically excised, non-metastasized UC-UUT specimens and five normal tissues via immunohistochemistry. Microvessel density (MVD), lymph vessel density (LVD), cancer cell proliferation (PI), apoptotic index (AI), and matrix metalloproteinase (MMP)-9 expression was also determined. The relationships 4N1K expression and pT stage, grade, and prognosis were analysed. In addition, correlations with these cancer-related and TSP-related factors were also investigated. Strong and moderate 4N1K expression was found in normal urothelial tissues. Of the 97 specimens, 45 patients were positive for 4N1K expression, which was primarily located in the interstitial areas of the cancer tissue. 4N1K expression was negatively associated with pT stage (p = 0.003) and grade (p = 0.002). Survival analyses revealed that 4N1K is a predictor of metastasis-free (p = 0.036) and cause-specific survival (p = 0.009). 4N1K expression was closely associated with malignant behaviour, specifically MVD (p = 0.001), AI (p = 0.013), and MMP-9 expression (p = 0.036), but not PI and LVD, as determined via multivariate analysis models. 4N1K expression appears to be associated with cancer cell progression and survival in UC-UUT patients via the regulation of angiogenesis, apoptosis, and MMP-9 expression. There is a possibility that the 4N1K-peptide may be a useful marker and novel therapeutic target in patients with UC-UUT

  20. Pythagorean Triples from Harmonic Sequences.

    Science.gov (United States)

    DiDomenico, Angelo S.; Tanner, Randy J.

    2001-01-01

    Shows how all primitive Pythagorean triples can be generated from harmonic sequences. Use inductive and deductive reasoning to explore how Pythagorean triples are connected with another area of mathematics. (KHR)

  1. Equivariant Lorentzian Spectral Triples

    OpenAIRE

    Paschke, Mario; Sitarz, Andrzej

    2006-01-01

    We present examples of equivariant noncommutative Lorentzian spectral geometries. The equivariance with respect to a compact isometry group (or quantum group) allows to construct the algebraic data of a version of spectral triple geometry adapted to the situation of an indefinite metric. The spectrum of the equivariant Dirac operator is calculated.

  2. Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML.

    Science.gov (United States)

    Ahn, Jae-Sook; Kim, Hyeoung-Joon; Kim, Yeo-Kyeoung; Jung, Sung-Hoon; Yang, Deok-Hwan; Lee, Je-Jung; Kim, Nan Young; Choi, Seung Hyun; Jung, Chul Won; Jang, Jun-Ho; Kim, Hee Je; Moon, Joon Ho; Sohn, Sang Kyun; Won, Jong-Ho; Kim, Sung-Hyun; Kim, Dennis Dong Hwan

    2016-03-01

    The prognostic significance of molecular mutations (FLT3-ITD, NPM1, and CEBPA mutations) was examined in patients with normal-karyotype acute myeloid leukaemia (NK-AML) after allogeneic haematopoietic cell transplantation (HCT). In total, 115 patients received allogeneic HCT for NK-AML and were evaluated for FLT3-ITD, NPM1, and CEBPA mutations in diagnostic samples and for long-term outcomes following HCT, retrospectively. The prevalences of FLT3-ITD(pos), NPM1 (mut), and CEBPA (dm) (double mutations) were 32.2, 43.5, and 24.6 %, respectively. The triple-negative group (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) showed a similar transplant outcome to those in the favourable European LeukemiaNet (ELN) risk group for overall survival (OS) (60.9 vs. 63.7 %; p = 0.810), but a more favourable OS than others in the intermediate-I risk group (40.0 %; p = 0.034). Also, the triple-negative group showed a similar relapse rate at 5 years compared with those in the favourable risk group (9.7 vs. 15.5 %; p = 0.499), but a lower rate of relapse than the others in the intermediate-I risk group (15.5 vs. 48.6 %; p = 0.004). The 5-year relapse incidences were 4.0 % (NPM1 (mut)/FLT3-ITD(neg)), 14.7 % (CEBPA (dm)), 15.5 % (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)), 39.1 % (NPM1 (mut)/FLT3-ITD(pos)/non-CEBPA (dm)), and 66.7 % (NPM1 (wild)/FLT3-ITD(pos)/non-CEBPA (dm)). Thus, the triple-negative (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) group showed favourable long-term outcomes after allogeneic HCT in NK-AML, similar to those of the favourable risk group by the ELN risk classification. PMID:26692090

  3. Analysis of the tumor length and other prognosis factors in pT1-2 node-negative esophageal squamous cell carcinoma in a Chinese population

    Directory of Open Access Journals (Sweden)

    Song Zhengbo

    2012-12-01

    Full Text Available Abstract Background Tumor length is an important prognostic factor for many carcinomas, but its role in esophageal cancer remained undetermined. The aim of this study was to investigate the effect of tumor length on survival for patients with confined tumors (grade pT1-2 without lymph-node metastases in esophageal squamous cell carcinoma. Methods We enrolled 201 patients with esophageal squamous cell carcinoma (SCC who had undergone surgical resection and been confirmed as pT1-2N0M0. The relationship of tumor length with overall survival was assessed and compared with other factors detailed in the American Joint Committee on Cancer (AJCC tumor, node, metastasis (TNM staging system published in 2009. Results The overall survival (OS rates at 1, 3, and 5 years were 93.0%, 83.7%, and 69.2%, respectively. The tumor length adversely affected OS, with the 5-year rate being 93.5%, 82.0%, 68.6%, 67.9%, 55.3% and 41.1%, respectively for tumor lengths of less than 10 mm, 10 to 20 mm, 20 to 30 mm, 30 to 40 mm, 40 to 50 mm, and greater than 50 mm (PP = 0.04, as did the other current TNM factors. Conclusion Tumor length appears to affect the OS of patients with early-stage esophageal squamous cell carcinoma. It may provide additional prognostic information for the current TNM staging system.

  4. Clinical Observation of Low-dosage and Long-period Xeloda in Treatment of Advanced Triple Negative Breast Cancer%低剂量长周期希罗达治疗复发晚期三阴性乳腺癌的临床研究

    Institute of Scientific and Technical Information of China (English)

    容景瑜; 张少贤; 黄景彬; 林清; 陈雁秋

    2015-01-01

    目的:观察低剂量长周期希罗达治疗复发晚期三阴性乳腺癌的有效性和安全性。方法将60例经含希罗达联合化疗8个周期后疾病达缓解或稳定的复发晚期三阴性乳腺癌患者随机分为两组,治疗组继续接受低剂量长周期希罗达维持治疗,期间进展或不能耐受毒副反应者停止化疗,对照组予以观察随诊。结果低剂量长周期希罗达维持治疗复发晚期三阴性乳腺癌有效率为73.3%,中位无进展生存期为413.7天,半数患者生存期为466.3天,化疗有效维持时间为209.3天;1年生存率70.0%,2年生存率46.6%;患者生存质量提高,肿瘤指标下降,与对照组比较,有显著性差异。主要毒副反应为手足综合征(36.67%),多为Ⅰ-Ⅱ度,其次为消化道反应(26.67%)及白细胞下降(23.3%),患者可耐受。结论低剂量长周期希罗达治疗复发晚期三阴性乳腺癌,患者的耐受性好,不良反应程度低,治疗有效,为治疗复发性三阴性乳腺癌的有效、低毒的可选方案。%Objective To observe the therapeutic effects, toxicity and side effects of low-dosage and long-period xeloda in the treatment of advanced triple negative breast cancer. Methods Sixty patients with advanced triple negative breast cancer were divided into two groups after treatment of 8 cycles’combination regimen including xeloda. 30 patients in control group then got no xeloda but follow-up clinic, and another 30 in treatment group were still treated by low-dosage and long-period xeloda. Results In the treatment group, the short-term therapeutic effect rate was 73.3%, the median progression-free sur-vival (PFS) was 413.7 days. The median survival time was 466.3 days, the effective chemotherapy-maintained time was 209.3 days, with 1-year survival of 70.0%, 2-year survival of 46.6%. The life quality of patients was improved and the level of tumor marker was decreased with

  5. The Dilated Triple

    CERN Document Server

    Rodriguez, Marko A; Shinavier, Joshua

    2010-01-01

    The basic unit of meaning on the Semantic Web is the RDF statement, or triple, which combines a distinct subject, predicate and object to make a definite assertion about the world. A set of triples constitutes a graph, to which they give a collective meaning. It is upon this simple foundation that the rich, complex knowledge structures of the Semantic Web are built. Yet the very expressiveness of RDF, by inviting comparison with real-world knowledge, highlights a fundamental shortcoming, in that RDF is limited to statements of absolute fact, independent of the context in which a statement is asserted. This is in stark contrast with the thoroughly context-sensitive nature of human thought. The model presented here provides a particularly simple means of contextualizing an RDF triple by associating it with related statements in the same graph. This approach, in combination with a notion of graph similarity, is sufficient to select only those statements from an RDF graph which are subjectively most relevant to t...

  6. Molecular based subtyping of feline mammary carcinomas and clinicopathological characterization.

    Science.gov (United States)

    Soares, Maria; Madeira, Sara; Correia, Jorge; Peleteiro, Maria; Cardoso, Fátima; Ferreira, Fernando

    2016-06-01

    Molecular classification of feline mammary carcinomas (FMC) from which specific behavioral patterns may be estimated has potential applications in veterinary clinical practice and in comparative oncology. In this perspective, the main goal of this study was to characterize both the clinical and the pathological features of the different molecular phenotypes found in a population of FMC (n = 102), using the broadly accepted IHC-based classification established by St. Gallen International Expert Consensus panel. The luminal B/HER2-negative subtype was the most common (29.4%, 30/102) followed by luminal B/HER2-positive subtype (19.6%, 20/102), triple negative basal-like (16.7%, 17/102), luminal A (14.7%, 15/102), triple negative normal-like (12.7%, 13/102) and finally, HER2-positive subtype (6.9%, 7/102). Luminal A subtype was significantly associated with smaller tumors (p = 0.024) and with well differentiated ones (p feline mammary tumors and human breast cancer, reveal that feline can be a valuable model for comparative studies. PMID:27212699

  7. Correlation of primary tumor FDG uptake with clinicopathologic prognostic factors in invasive ductal carcinoma of the breast

    Energy Technology Data Exchange (ETDEWEB)

    Jo, I; Kim, Sung Hoon; Kim, Hae Won; Kang, Sung Hee [Keimyung University, School of Medicine, Daegu (Korea, Republic of); Zeon, Seok Kil [Dept. of Nuclear Medicine, Bundang Jesaeng General Hospital, Sungnam (Korea, Republic of); Kim, Su Jin [Dept. of Anesthesiology and Pain Medicine, Dongguk University, School of Medicine, Gyeongju (Korea, Republic of)

    2015-03-15

    The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast. We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUV{sub max}) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUV{sub max} of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUV{sub max} compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis. In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer.

  8. High-risk human papillomavirus (HPV) DNA sequences in metaplastic breast carcinomas of Mexican women

    International Nuclear Information System (INIS)

    Metaplastic carcinoma, an uncommon subtype of breast cancer, is part of the spectrum of basal-like, triple receptor-negative breast carcinomas. The present study examined 20 surgical specimens of metaplastic breast carcinomas, for the presence of high-risk Human papillomavirus (HPV), which is suspected to be a potential carcinogenic agent for breast carcinoma. Mastectomy specimens from patients harboring metaplastic breast carcinoma, as defined by the World Health Organization (WHO), and who attended the Instituto Nacional de Cancerologia in Mexico City, were retrieved from the files of the Department of Pathology accumulated during a 16-year period (1995–2008). Demographic and clinical information was obtained from patients’ medical records. DNA was extracted from formalin-fixed, paraffin-embedded tumors and HPV type-specific amplification was performed by means of Polymerase chain reaction (PCR). Quantitative Real-time (RT) PCR was conducted in HPV positive cases. Statistically, the association of continuous or categorical variables with HPV status was tested by the Student t, the Chi square, or Fisher’s exact tests, as appropriate. High-risk HPV DNA was detected in eight (40%) of 20 metaplastic breast carcinomas: seven (87.5%) HPV-16 and one (12.5%) HPV-18. Mean age of patients with HPV-positive cases was 49 years (range 24–72 years), the same as for HPV-negative cases (range, 30–73 years). There were not striking differences between HPV + and HPV– metaplastic carcinomas regarding clinical findings. Nearly all cases were negative for estrogen, progesterone and Human epidermal growth factor receptor 2 (HER2), but positive for Epidermal growth factor receptor (EGFR). High-risk HPV has been strongly associated with conventional breast carcinomas, although the subtle mechanism of neoplastic transformation is poorly understood. In Mexican patients, the prevalence of HPV infection among metaplastic breast carcinomas is higher than in non-metaplastic ones

  9. Triple axis spectrometers

    International Nuclear Information System (INIS)

    Conventional triple-axis neutron spectroscopy was developed by Brockhouse over thirty years ago' and remains today a versatile and powerful tool for probing the dynamics of condensed matter. The original design of the triple axis spectrometer is technically simple and probes momentum and energy space on a point-by-point basis. This ability to systematically probe the scattering function in a way which only requires a few angles to be moved under computer control and where the observed data in general can be analysed using a pencil and graph paper or a simple fitting routine, has been essential for the success of the method. These constraints were quite reasonable at the time the technique was developed. Advances in computer based data acquisition, neutron beam optics, and position sensitive area detectors have been gradually implemented on many triple axis spectrometer spectrometers, but the full potential of this has not been fully exploited yet. Further improvement in terms of efficiency (beyond point by point inspection) and increased sensitivity (use of focusing optics whenever the problem allows it) could easily be up to a factor of 10-20 over present instruments for many problems at a cost which is negligible compared to that of increasing the flux of the source. The real cost will be in complexity - finding the optimal set-up for a given scan and interpreting the data as the they are taken. On-line transformation of the data for an appropriate display in Q, ω space and analysis tools will be equally important for this task, and the success of these new ideas will crucially depend on how well we solve these problems. (author)

  10. Synchronous bilateral medullary carcinoma of breast: Is it metastasis or second primary?

    Directory of Open Access Journals (Sweden)

    Chandrika

    2012-01-01

    Full Text Available Bilateral breast cancer is a rare event accounting for 2-5% of all breast malignancies. A second tumor in contralateral breast may be either synchronous or metachronous lesion. Synchronous bilateral invasive ductal carcinoma is known but medullary carcinoma is rare. The etiology of bilateral breast cancer is uncertain and prognosis in these cases once thought to be poor but recent data suggest a similar survival compared to unilateral disease. We report a case of triple negative synchronous bilateral medullary carcinoma in a 38-year-old female who presented with lump in both the breasts for three months. Multidetector computed tomography breast scan revealed bilateral heterogeneously enhancing well-defined lesion in both the breasts. Fine needle aspiration cytology from both the breast lump was suggestive of malignancy. Patient underwent bilateral modified radical mastectomy with axillary clearance in a single sitting. Histopathology showed synchronous bilateral medullary carcinoma of breast with ER, PR and HER- 2/ neu negativity. Patient was treated with chemoradiation and she is on regular follow up for one year without any recurrence or metastasis.

  11. Phase Ⅱ clinical trial of neoadjuvant therapy with carboplatin plus paclitaxel for locally advanced triple-negative breast cancer%卡铂联合紫杉醇治疗局部晚期三阴性乳腺癌的Ⅱ期临床研究

    Institute of Scientific and Technical Information of China (English)

    马文玥; 马飞; 樊英; 徐兵河; 张频; 张柏林; 王翔; 徐晓洲; 郑闪; 王佳玉; 蔡锐刚; 袁芃

    2012-01-01

    目的 评价卡铂联合紫杉醇方案治疗局部晚期三阴性乳腺癌的疗效、安全性和远期生存,探索三阴性乳腺癌的优选化疗方案.方法 收集31例经粗针穿刺病理确诊的ⅡA~ⅢC期浸润性乳腺癌患者的临床资料,分析其新辅助化疗效果、生存状况、手术效果及其与免疫组化检测指标的关系.结果 31例乳腺癌患者中,30例患者按计划完成新辅助化疗,1例因首次应用紫杉醇过敏而改用其他方案.28例可评价临床疗效,1例未评价疗效,1例化疗1周期无法评价疗效.客观有效率为85.7%,其中完全缓解(CR)4例(14.3%),部分缓解20例(71.4%),疾病稳定3例(10.7%),疾病进展1例(3.6%).临床降期率为85.7%.31例患者均可评价不良反应.主要不良反应为粒细胞减少,发生率为93.5%,其中3~4级发生率为74.2%,无粒细胞减少性发热.行保乳手术患者4例,改良根治术23例.术后获病理完全缓解(pCR)者11例,pCR率为40.7%,其中乳腺pCR率为44.4%(12/27),腋下淋巴结pCR率为77.8% (21/27).新辅助化疗临床评价为CR的4例患者均获pCR.出现复发转移者8例,其中局部区域复发者1例,远处转移者7例;出现在确诊后2年内者6例.11例pCR患者中,无病生存者10例,确诊后45个月出现肺转移者1例,现带瘤生存.死亡6例.本组患者中位无病生存时间、总生存时间未达到,3年无病生存率、总生存率分别为62.0%和74.7%.结论 卡铂联合紫杉醇方案治疗局部晚期三阴性乳腺癌客观有效率高,pCR率优于蒽环类联合紫杉类方案,耐受性良好,是治疗局部晚期三阴性乳腺癌的优选化疗方案.%Objective To evaluate the efficacy,safety and survival of combination of carboplatin plus paclitaxel as neoadjuvant chemotherapy (NACT) for patients with locally advanced triple-negative breast cancer (TNBC),and explore an optimal regimen for TNBC.Methods Patients with core needle biopsy confirmed pathological

  12. Immunohistochemical Expression of Survivin in Breast Carcinoma: Relationship with Clinico pathological Parameters, Proliferation and Molecular Classification

    International Nuclear Information System (INIS)

    Background and Objective: Survivin is a novel member of the inhibitor of apoptosis (IAP) gene family. It is associated with more aggressive behavior and parameters of poor prognosis in most human cancers including gastric, colorectal and bladder carcinomas. However, conflicting data exist on its prognostic effect in breast cancer. This current study is designed to assess survivin expression in breast carcinoma relating results with clinico pathological parameters, proliferation (MIB-1) and molecular classification. Material and Methods: Our retrospective study com- prised of 65 archived cases of breast carcinoma. Samples from the tumor and the adjacent normal breast tissue were immuno stained for survivin and MIB-1. Nuclear and cytoplasmic survivin expression was evaluated in normal breast tissue and carcinoma regarding both the intensity and the percentage of positive cells. ER, PR, HER2 were used as surrogate markers to classify the cases into four molecular subtypes. Results: Survivin expression was detected in 78.5% of breast carcinomas. The adjacent normal breast tissue was immuno negative. Survivin expression showed significant association with increased tumor size ( p <0.0001), high histologic grade ( p =0.04), lymph node metastases ( p <0.001), advanced tumor stage ( p <0.0001), MIB-1 expression ( p =0.02), negative estrogen receptor status ( p =0.01) and negative progesterone receptor status ( p <0.0001). The subcellular localization of survivin significantly related to histologic grade, stage and lymph node involvement. The percentage of TNP (triple negative phenotype) and HER2+/ER-PR- tumors expressing survivin were significantly higher compared to the Luminal subtypes ( p =0.01). Conclusion: Survivin expression was associated with parameters of poor prognosis in breast cancer. Moreover, the cancer-specific expression of survivin, coupled with its importance in inhibiting cell death and in regulating cell division, makes it a potential target for novel

  13. 表柔比星联合卡培他滨治疗三阴性乳腺癌的疗效及安全性分析%Curative efficacy and safety of Epirubicin in combination with Capecitabine in treatment of triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    罗莉; 唐东昕; 王定雪; 王镜辉; 金露露; 杨兵

    2015-01-01

    Objective To investigate curative efficacy and safety of Epirubicin in combination with Capecitabine in the treatment of triple-negative breast cancer and its effects on level of serum vascular endothelial growth factor C ( VEGF-C).Methods 86 patients of triple-negative breast cancer who received therapy from January 2013 to December 2014 were selected as research objects.According to therapeutic schemes,those patients were divided into control group(n=42)and observation group(n=44).Control group was treated with epirubicin,while observation group was treated with Epirubicin in combination with Capecitabine.Then, the short-term curative efficacy, adverse events effects,level of VEGF-C were observed and compared.Results After the course of treatment, the short-term curative efficacy ratio in control group and observation group was 59.5% and 65.9% respectively with no statistical difference.During the treatment, the occurrence of neutropenia, hand-foot syndrome, gastrointestinal reaction, cardiac damage and liver function damage in the two groups was statistically same respectively.After post-treatment, in comparison with control group, level of VEGF-C in observation group was statistically lower ( P <0.05 ).Conclusion Epirubicin in combination with Capecitabine is effective for triple-negative breast cancer,which has high short-term curative efficacy ratio and significantly decrease level of VEGF-C with not increasing occurrence of toxic side effects.%目的:探讨表柔比星联合卡培他滨治疗三阴性乳腺癌的疗效、安全性及对患者血清血管内皮生长因子C ( vascular endothelial growth factor C,VEGF-C)水平的影响。方法选取2013年1月~2014年12月于贵阳中医学院第一附属医院接受治疗的86例三阴性乳腺癌患者作为研究对象,按照治疗方案分为对照组42例和观察组44例。对照组给予表柔比星治疗,观察组在对照组基础上联合应用卡培他滨治疗。

  14. Does 18FDG PET-CT improve the detection of posttreatment recurrence of head and neck squamous cell carcinoma in patients negative for disease on clinical follow-up?

    International Nuclear Information System (INIS)

    Introduction: post-treatment follow-up of head and neck squamous cell carcinoma (H.N.S.C.C.) recurrence is a diagnostic challenge. Tissue distortions from radiation and surgery can obscure early detection of recurrence by conventional follow-up approaches such as physical examination (P.E.), computed tomography, and magnetic resonance imaging. A number of studies have shown that 18Fluoro-fluorodeoxyglucose (18F.D.G.) Positron emission tomography (PET) may be an effective technique for the detection of persistent, recurrent, and distant metastatic HNSCC after treatment. The aim of this prospective study was to determine the benefits (sensitivity, specificity, predictive values, and accuracy) of 18F.D.G. PET using hybrid PET 'Computed tomography system (PET/CT) in the detection of HNSCC subclinical locoregional recurrence and distant metastases, in patients 12 months after curative treatment with a negative conventional follow up. Materials and Method Ninety-one patients cured from head and neck squamous cell carcinoma (HNSCC) without any clinical element for recurrence were included. Whole-body 18F.D.G. PET/CT examination was performed 11.6 ± 4.4 months after the end of the treatment. The gold standard was histopathology or 6 months imaging follow-up. Result The whole-body 18F.D.G. PET/CT of the 91 patients in this study consisted of 52 negative and 39 positive results. Nine of these patients who exhibited abnormal 18F.D.G. uptake in head and neck area did not have subsequently proven recurrent HNSCC (false positive). Thirty had proven recurrence (true positive). All 52 patients with negative readings of 18F.D.G. PET/CT remained free of disease at 6 months (true negative). The sensitivity and specificity of 18F.D.G. PET/CT in this study for the diagnosis of HNSCC recurrence were 100% (30/30) and 85% (52/61) respectively. The positive predictive value was 77% (30/39). The negative predictive value was 100% (52/52). The overall accuracy was 90% (82/91). Conclusion

  15. Morita "equivalences" of equivariant torus spectral triples

    OpenAIRE

    Venselaar, Jan Jitse

    2011-01-01

    In general, Morita equivalence of spectral triples need not be a symmetric relation. In this paper, we show that Morita equivalence of spectral triples is an equivalence relation for equivariant torus spectral triples.

  16. Krüppel-like factor 9 was down-regulated in esophageal squamous cell carcinoma and negatively regulated beta-catenin/TCF signaling.

    Science.gov (United States)

    Qiao, Fan; Yao, Feng; Chen, Ling; Lu, Chengjun; Ni, Yiqian; Fang, Wentao; Jin, Hai

    2016-03-01

    Krüppel-like factor 9 (KLF9) has been found to play suppressive roles in several types of tumor. However, the expression pattern and biological functions of KLF9 in esophageal squamous cell carcinoma (ESCC) are still unknown. In this study, it was found that the expression of KLF9 was significantly down-regulated in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, the expression of KLF9 was inversely correlated with the clinical features of ESCC patients. Moreover, in the biological function study, KLF9 was further validated to inhibit the growth, migration, and metastasis of ESCC cells in vitro and in vivo. Mechanistically, KLF9 bind with TCF4 and suppressed the beta-catenin/TCF signaling as well as the expression of its target gene Cyr61. Collectively, our study clarified the function of KLF9 in both ESCC progression and the regulation of beta-catenin/TCF signaling. PMID:25641762

  17. Triple acting radial seal

    Science.gov (United States)

    Ebert, Todd A; Carella, John A

    2012-03-13

    A triple acting radial seal used as an interstage seal assembly in a gas turbine engine, where the seal assembly includes an interstage seal support extending from a stationary inner shroud of a vane ring, the interstage seal support includes a larger annular radial inward facing groove in which an outer annular floating seal assembly is secured for radial displacement, and the outer annular floating seal assembly includes a smaller annular radial inward facing groove in which an inner annular floating seal assembly is secured also for radial displacement. A compliant seal is secured to the inner annular floating seal assembly. The outer annular floating seal assembly encapsulates the inner annular floating seal assembly which is made from a very low alpha material in order to reduce thermal stress.

  18. Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

    Science.gov (United States)

    Conlon, Niamh; Howard, Jane; Catalano, Jeffrey; Gallagher, Meighan; Tan, Lee K; Corben, Adriana D

    2016-05-01

    Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease. PMID:26923423

  19. Function of the integrin alpha 6 beta 1 in metastatic breast carcinoma cells assessed by expression of a dominant-negative receptor

    DEFF Research Database (Denmark)

    Shaw, L M; Chao, C; Wewer, U M;

    1996-01-01

    : alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1, but uses only alpha 6 beta 1 to mediate adhesion and migration on laminin matrices. To investigate the contribution of alpha 6 beta 1 to the aggressive behavior of these cells, we developed a dominant-negative strategy for knocking out alpha 6 beta 1...

  20. Can 18F-FDG-PET/CT be generally recommended in patients with differentiated thyroid carcinoma and elevated thyroglobulin levels but negative I-131 whole body scan?

    International Nuclear Information System (INIS)

    Exact localization of recurrent iodine-negative thyroid cancer is mandatory, since surgery is the only curative therapy option in patients with iodine-negative tumor tissue. The aim of this study was to evaluate the impact of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT as a routine diagnostic tool on clinical management in patients with suspected thyroid cancer recurrence and elevated serum thyroglobulin (Tg) but negative radioiodine whole body scan. After total thyroidectomy followed by radioiodine ablation, 30 consecutive patients with differentiated thyroid cancer, elevated serum thyroglobulin levels and negative whole body radioiodine scan underwent 18F-FDG-PET/CT. Results were verified by histology, ultrasound, or clinical follow-up. Diagnostic accuracy was determined for the whole study population and for subgroups with serum thyroglobulin below and above 10 ng/ml, respectively. Impact of PET/CT on clinical management was assessed. PET/CT identified FDG accumulating lesions in 19 of 30 patients. 17 were true-positive and 2 false-positive. In the true-positive group, 11 of the 17 patients had loco-regional disease, 3 had distant metastases only and 3 patients had both loco-regional and distant metastatic involvement. 18F-FDG-PET/CT was true-negative in 3 patients and false-negative in 8 patients. Overall sensitivity, specificity and accuracy were 68.0, 60.0, and 66.7%, respectively. In the subgroup of patients with serum thyroglobulin above 10 ng/ml (n=21) the sensitivity, specificity and accuracy were substantially higher with 70.0, 100.0, and 71.4%, respectively. Clinical management was changed for 17 (57%) of 30 patients, guiding to a curative surgical intervention in 9 patients (30%). 18F-FDG-PET/CT enables detection and precise localization of loco-regional recurrence and distant metastases of differentiated thyroid cancer in patients with elevated serum thyroglobulin but negative radioiodine with significant impact on patient

  1. 18F-FDG SPECT/CT in the diagnosis of differentiated thyroid carcinoma with elevated thyroglobulin and negative iodine-131 scans

    International Nuclear Information System (INIS)

    Aim of the present study was to investigate the usefulness of 18F-FDG SPECT/CT in differentiated thyroid cancer (DTC) with elevated serum thyroglobulin (Tg) but negative iodine-131 scan. This retrospective review of patients with DTC recurrence who had 18F-FDG SPECT/CT and 18F-FDG PET/CT for elevated serum Tg but negative iodine-131 scan (March 2007-October 2012). After total thyroidectomy followed by radioiodine ablation, 86 consecutive patients with elevated Tg levels underwent 18F-FDG SPECT/CT or 18F-FDG PET/CT. Of these, 45 patients had 18F-FDG SPECT/CT, the other 41 patients had 18F-FDG PET/CT 3-4 weeks after thyroid hormone withdrawal. The results of 18F-FDG PET/CT and SPECT/CT were correlated with patient follow-up information, which included the results from subsequent imaging modalities such as neck ultrasound, MRI and CT, Tg levels, and histologic examination of surgical specimens. The diagnostic accuracy of the two imaging modalities was evaluated. In 18F-FDG SPECT/CT scans, 24 (24/45) patients had positive findings, 22 true positive in 24 patients, false positive in 2 patients, true-negative and false-negative in 6, 15 patients, respectively. The overall sensitivity, specificity, and accuracy of 18F-FDG SPECT/CT were 59.5%, 75% and 62.2%, respectively. Twenty six patients had positive findings on 18F-FDG PET/CT scans, 23 true positive in 26 (26/41) patients, false positive in 3 patients, true-negative and false-negative in 9, 6 patients, respectively. The overall sensitivity, specificity, and accuracy of 18F-FDG PET/CT were 79.3%, 81.8% and 78.1%, respectively. Clinical management changed for 13 (29%) of 45 patients by 18F-FDG SPECT/CT, 14 (34%) of 41 patients by 18F-FDG PET/CT including surgery, radiation therapy, or multi kinase inhibitor. Based on the retrospective analysis of 86 patients, 18F-FDG SPECT/CT has lower sensitivity in the diagnosis of DTC recurrence with elevated Tg and negative iodine-131scan to 18F-FDG PET/CT. The clinical application

  2. “三阴”型与非“三阴”型乳腺癌患者的生物学行为差异性分析%Comparison of biological behavior between triple-negative breast cancer and non-triplenegative breast cancer

    Institute of Scientific and Technical Information of China (English)

    马吉光; 王宁菊; 于文洁

    2011-01-01

    Objective To summarize the epidemiological and biological features of triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) to provide reference for devising individualized therapy and making prognostic evaluation. Methods The 5-year follow-up data were collected from 231 patients with pathologically established diagnosis of breast cancer treated in the Affiliated Hospital of Ningxia Medical University and Yinchuan People's Hospital between Jan. 2002 and Dec. 2004. The epidemiological and clinicopathological characteristics as well as the recurrence, metastasis and 5-year survival were compared between TNBC group and non-TNBC group. Results TNBC accounted 17.3% of the total breast cancer cases enrolled in this study. The tumor size and rates of recurrence and metastasis (especially visceral metastasis) were significantly greater in TNBC group than in non-TNBC group (P<0.05). The TNBC patients showed significantly lower 3- and 5-year survival rates than the non-TNBC patients (P<0.05), and TNBC patients with positive lymph nodes in clinical stage Ⅱ had also a lower 5-year survival (P<0.05). Cox regression model analysis identified the patients' age, primary tumor size, clinical stages and triple-negativity as the independent risk factors for breast cancer. Conclusions Compared to non-TNBC patients, patients with TNBC have higher rates of local recurrence and invasion, visceral metastasis and poorer prognosis, and a lower rate of 5-year survival. The triple negativity represents an independent factor for prognosis evaluation of breast cancer.%目的 通过回顾性分析总结“三阴”型乳腺癌与非“三阴”型乳腺癌患者的流行病学及生物学行为特点,以便为指导临床个体化治疗、判定预后奠定基础.方法 收集并整理宁夏医科大学附属医院及银川市人民医院2002年1月~2004年12月收治、经病理组织学确诊,且有5年完整随访数据的乳腺癌患者231

  3. Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: Are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?

    International Nuclear Information System (INIS)

    Purpose: To report treatment compliance, toxicity and clinical outcome of chemoradiotherapy (CRT) for anal carcinoma in HIV-negative vs. HIV-positive patients treated with highly active antiretroviral therapy. Material and methods: Between 1997 and 2008, 25 HIV-positive and 45 HIV-negative patients received CRT (50.4 Gy at 1.8 Gy/fraction plus 5.4-10.8 Gy boost; 5-fluorouracil, 1000 mg/m2, Days 1-4 and 29-32, mitomycin C, 10 mg/m2, Days 1 and 29). Median follow-up was 51 (range, 3-235) months. Results: HIV-positive patients were significantly younger (mean age, 47 vs. 57 years, p < 0.001) and predominantly male (92% vs. 29%, p < 0.001). CRT could be completed in all patients with a reduction of chemotherapy and/or RT-interruption in 28% and 8%, respectively, in HIV-positive patients, and in 9% and 11%, respectively, in HIV-negative patients. Acute Grade 3/4-toxicity occurred in 44% vs. 49% (p = 0.79). Initial complete response (84% vs. 93%, p = 0.41), 5-year rates of local control (65% vs. 78%, p = 0.44), cancer-specific (78% vs. 90%, p = 0.17) and overall survival (71% vs. 77%, p = 0.76) were not significantly different. Conclusion: HIV-positive patients with anal cancer can be treated with standard CRT, with the same tolerability and toxicity as HIV-negative patients. Long-term local control and survival rates are not significantly different between these groups.

  4. Synchronous triple urogenital cancer (renal cancer, bladder cancer, prostatic cancer). A case report

    Energy Technology Data Exchange (ETDEWEB)

    Takada, Tsuyoshi; Honda, Masahito; Momohara, Chikahiro; Komori, Kazuhiko; Fujioka, Hideki [Osaka Police Hospital (Japan)

    2002-04-01

    A case of synchronous triple urogenital cancer, which was comprised of renal cell carcinoma of the left kidney, transitional cell carcinoma of the urinary bladder, and adenocarcinoma of the prostate, is reported. A 72-year-old Japanese male patient was referred to our outpatient clinic with the complaint of asymptomatic hematuria. At that time, his serum of level of PSA was elevated to 20 ng/ml. Cystourethroscopy showed a papillary bladder tumor and coagula through the left urinary orifice. Ultrasonography, computed tomography and magnetic resonance imaging showed a mass lesion measuring about 6 cm by 5 cm in the left kidney. Angiography showed a hypervascular lesion measuring about 6 cm by 5 cm at the same site. Double cancer, consisting of renal cell carcinoma and transitional cell carcinoma of the urinary bladder, was suspected and we performed left total nephroureterectomy, hilar lymphadenectomy, and transurethral rection of the bladder tumor, one month later. At the same time, we performed a biopsy of the prostate. Histological diagnosis was renal cell carcinoma, clear cell carcinoma and transitional cell carcinoma of urinary bladder. Histological diagnosis of the prostate biopsy was moderately differentiated adenocarcinoma. Since this case fulfilled the criteria of Warren and Gates, it was classified as synchronous triple urogenital cancer. A review of the literature revealed 17 authentic cases of triple urogenital cancer, of which 14 and 10 cases were reported as a combination of renal cancer, bladder cancer and prostatic cancer, in the world and in Japan, respectively. Furthermore, he had been exposed to the atomic bomb explosion in Hiroshima in 1945. This carcinogenic precursor may be related to the development of the triple cancer. (author)

  5. Synchronous triple urogenital cancer (renal cancer, bladder cancer, prostatic cancer). A case report

    International Nuclear Information System (INIS)

    A case of synchronous triple urogenital cancer, which was comprised of renal cell carcinoma of the left kidney, transitional cell carcinoma of the urinary bladder, and adenocarcinoma of the prostate, is reported. A 72-year-old Japanese male patient was referred to our outpatient clinic with the complaint of asymptomatic hematuria. At that time, his serum of level of PSA was elevated to 20 ng/ml. Cystourethroscopy showed a papillary bladder tumor and coagula through the left urinary orifice. Ultrasonography, computed tomography and magnetic resonance imaging showed a mass lesion measuring about 6 cm by 5 cm in the left kidney. Angiography showed a hypervascular lesion measuring about 6 cm by 5 cm at the same site. Double cancer, consisting of renal cell carcinoma and transitional cell carcinoma of the urinary bladder, was suspected and we performed left total nephroureterectomy, hilar lymphadenectomy, and transurethral rection of the bladder tumor, one month later. At the same time, we performed a biopsy of the prostate. Histological diagnosis was renal cell carcinoma, clear cell carcinoma and transitional cell carcinoma of urinary bladder. Histological diagnosis of the prostate biopsy was moderately differentiated adenocarcinoma. Since this case fulfilled the criteria of Warren and Gates, it was classified as synchronous triple urogenital cancer. A review of the literature revealed 17 authentic cases of triple urogenital cancer, of which 14 and 10 cases were reported as a combination of renal cancer, bladder cancer and prostatic cancer, in the world and in Japan, respectively. Furthermore, he had been exposed to the atomic bomb explosion in Hiroshima in 1945. This carcinogenic precursor may be related to the development of the triple cancer. (author)

  6. Tumor suppressor and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Juliette Martin; Jean-Frangois Dufour

    2008-01-01

    A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.

  7. Tunable supercurrent in a triangular triple quantum dot system

    International Nuclear Information System (INIS)

    The supercurrent in a triangular triple quantum dot system is investigated by using the nonequilibrium Green's function method. It is found that the sign of the supercurrent can be changed from positive to negative with increasing the strength of spin-flip scattering, resulting in the π-junction transition. The supercurrent and the π-junction transition are also modulated by tuning the system parameters such as the gate voltage and the interdot coupling. The tunable π-junction transition is explained in terms of the current carrying density of states. These results provide the ways of manipulating the supercurrent in a triple quantum dot system.

  8. On Split Lie Triple Systems

    Indian Academy of Sciences (India)

    Antonio J Calderón Martín

    2009-04-01

    We begin the study of arbitrary split Lie triple systems by focussing on those with a coherent 0-root space. We show that any such triple systems with a symmetric root system is of the form $T=\\mathcal{U}+\\sum_j I_j$ with $\\mathcal{U}$ a subspace of the 0-root space $T_0$ and any $I_j$ a well described ideal of , satisfying $[I_j,T,I_k]=0$ if $j≠ k$. Under certain conditions, it is shown that is the direct sum of the family of its minimal ideals, each one being a simple split Lie triple system, and the simplicity of is characterized. The key tool in this job is the notion of connection of roots in the framework of split Lie triple systems.

  9. Intensity-modulated radiotherapy for squamous cell carcinoma of the anal canal: Efficacy of a low daily dose to clinically negative regions

    International Nuclear Information System (INIS)

    We aimed to assess outcomes of patients with anal cancer who underwent intensity-modulated radiotherapy (IMRT) and received less than 1.80 Gy/day. We retrospectively reviewed our experience using a low fractional dose (< 1.80 Gy) of IMRT to elective nodal areas for patients receiving chemoradiotherapy for anal cancer. Three-year freedom from any disease relapse and overall survival were estimated using Kaplan-Meier curves. We documented the daily dose that was delivered to clinically uninvolved regions and to areas of gross disease. Incidence of regional failures in high (≥ 1.80 Gy) and low (< 1.80 Gy) daily dose regions was assessed. Thirty-four consecutive patients (median age, 59 years) received IMRT from June 2005 through January 2009. Median follow-up duration was 22 months. Twenty-eight patients had T1 or T2 disease and 6 had T3 or T4 disease. Fourteen patients had nodal metastases. Median treatment dose was 50.40 Gy (range, 48.60-57.60 Gy) in 25 to 32 fractions. The range of fractional doses to clinically negative volumes was 1.28 to 1.80 Gy. Seventeen patients (50%) received a fractional dose of less than 1.60 Gy, 13 (38%) received less than 1.50 Gy, and 9 (26%) received less than 1.40 Gy to at least a portion of the clinically negative volume. Three-year freedom from relapse was 80%, and 3-year overall survival was 87%. No patient had treatment failure in the clinically negative volume that received a low daily dose. Our data support using doses between 1.50 and 1.80 Gy/day to clinically uninvolved regions

  10. The role of combined detection of Ki-67 and ALDH1 in predicting the effectiveness of neoadjuvant chemotherapy in patients with triple-negative breast cancer%Ki-67和ALDH1联合检测判断三阴性乳腺癌新辅助化疗效果的价值

    Institute of Scientific and Technical Information of China (English)

    姚宇锋; 龚建平; 唐金海; 秦建伟

    2013-01-01

    目的 探讨Ki-67和乙醛脱氢酶1(ALDH1)联合检测对判断三阴性乳腺癌(TNBC)新辅助化疗(NACT)效果的价值.方法 回顾性分析完成NACT的52例TNBC患者资料,分析化疗前Ki 67和ALDH1的不同表达情况与NACT后病理完全缓解(pCR)之间的相关性.结果 52例中,20例(38.5 %)NACT后获得pCR.Ki-67阳性表达组pCR率65.2%(15/23),高于Ki-67阴性表达组的17.2%(5/29)(P<0.05).ALDH1阳性表达组pCR率15.6%(5/32),低于ALDH1阴性表达组的75.0%(15/20)(P<0.01).Ki-67阳性且ALDH1阴性表达组pCR率为93.8%(15/16),高于Ki-67阳性且ALDH1阳性表达组或Ki-67阴性且ALDH1阳性表达组(P<0.05).结论 TNBC组织中Ki-67阳性且ALDH1阴性表达患者对NACT效果好,Ki-67阳性且ALDH1阴性可作为预测TNBC的NACT疗效的分子标记物.%Objective To evaluate the role of combined detection of Ki-67 and aldehyde dehydrogenase KALDH1) in predicting the effectiveness of neoadjuvant chemotherapy(NACT) in the patients with triple-negative breast cancer(TNBC). Methods Data of 52 TNBC patients treated with NACT were retrospectively reviewed. The relationship between the different expressions of Ki-67 and ALDH1 and the pathological complete remission(pCR) rate was analyzed. Results The pCR rate in 52 cases was 38. 5% (20/52). The pCR rate of the patients with positive expression of Ki-67 was 65.2.%(15/23), which was significantly higher than 17.2% (5/29) of those with Ki-67 negative-expression(P<0. 05). The pCR rate of the patients with positive expression of ALDHI was 15. 6% (5/32), which was significantly lower than 75. 0% ( 15/20) of those with negative expression of ALDHI (P<0. 01). The pCR rate in the patients with positive expression of Ki-67 and negative expression of ALDHI was 93. 8% (15/16), which was significantly higher than that of the patients with positive expression of Ki-67 and positive expression of ALDHI or the patients with negative expression of Ki-67 and positive expression of ALDHI

  11. Investigation of Pathomorphology and Biologic Characteristics of Triple- Negative Breast Cancer and Basal- Like Breast Cancer%三阴乳腺癌与基底细胞样乳腺癌病理形态和生物学特征探讨

    Institute of Scientific and Technical Information of China (English)

    王成鑫; 黄萱; 封华

    2014-01-01

    Objective To investigate the pathomorphology,biologic characteristics and the relation⁃ships of triple-negative breast cancer (TNBC),non triple-negative breast cancer (NTNBC) and bas⁃al-like breast cancer (BLBC). Methods HER2,ER,PR,CK5/6 or EGFR protein were deter⁃mined with immunohistochemistry(IHC)in breast cancer, 3 cases of HER2 IHC 3+ and 5 cases of HER2 IHC 2+ were analysed for HER2 gene amplification with fluorescent in situ hybridization (FISH). CK5/6 or EGFR were checked in 22 cases of TNBC. The cases were divided into the TNBC,NTNBC and BLBC groups according to the examination results. The pathomorphology and bi⁃ologic characteristics of the three groups were compared. Results Of the 96 cases,27. 08%(26/96)were confirmed to be TNBC in which gradeⅡandⅢcases were 53. 85%(14/26)and 46. 15%(12/26)respectively,lymph nodes metastasis rate was 61. 11%(11/18);BLBC accounted for 63. 64%(14/22)of TNBC,in which gradeⅡ andⅢ cases were 57. 14%(8/14)and 42. 86%(6/14)respective⁃ly,lymph nodes metastasis rate was 55. 56%(5/9);There were no grade Ⅰcases in TNBC and BLBC. 72. 92%(70/96)were confirmed to be NTNBC in which gradeⅠ,ⅡandⅢcases were 28. 57%(20/70),57. 14%(40/70)and 14. 29%(10/70)respectively,lymph nodes metastasis rate was 44. 44%(16/36). The percentage of poorly differentiated cases and lymph nodes metastasis rate were higher in the TNBC and BLBC group than those in NTNBC,besides there was no gradeⅠcases in TNBC and BLBC group. Of the 5 HER2 IHC 2+ cases,one case there was gene amplification,one equivocal and three negative and of 3 HER2 IHC 3+ cases ,the FISH result was consistent with IHC. Conclu⁃sion More than 1/4 of breast cancer are TNBC or BLBC in our study. Compared with NTNBC,even though TNBC and BLBC share a great deal of overlap and have a poor differentiation with aggressive behavior and increased local recurrence or distant metastasis,indicating a poor prognosis,they may be independent histopathologic entity. CK5/6 or

  12. Guide to Understanding Triple-Negative Breast Cancer

    Science.gov (United States)

    ... Self-Care for Stress and Anxiety Coping With Stress in Relationships Fertility and Metastatic Breast Cancer Money, Insurance & Career Inflammatory Diagnosis and Testing How Cancer Is Staged Tests You May Have Biopsy PET Scan Blood Tests Bone Scans CAT Scans Chest ...

  13. Prognostic protein markers for triple negative breast cancer

    NARCIS (Netherlands)

    A. Umar (Arzu); N.Q. Liu (Ning Qing); R.B.H. Braakman (René)

    2010-01-01

    textabstractBreast cancer is the most commonly diagnosed malignancy in women in the Western world, with 13,000 new patients each year in the Netherlands alone. Extensive research on gene expression profiling has shown that breast cancer is a mixture of biologically different disease entities, referr

  14. A Comparative Analysis of Bio marker Expression and Molecular Subtypes of Pure Ductal Carcinoma In Situ and Invasive Breast Carcinoma by Image Analysis: Relationship of the Subtypes with Histologic Grade, Ki67, p53 Overexpression, and DNA Ploidy

    International Nuclear Information System (INIS)

    There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of bio markers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.Pathology.Pathology.Bio marker staining nuclei, and staining intensity expression

  15. Clinical Efficacy of Capecitabine Combined with Autologous Cytokine-induced Killer Cells Maintenance Therapy in Treatment of Metastatic Triple Negative Breast Cancer%自体CIK细胞联合卡培他滨维持治疗复发转移性三阴性乳腺癌效果观察

    Institute of Scientific and Technical Information of China (English)

    宋树玺; 刘永叶; 丁震宇; 于卉影; 韩雅玲; 谢晓冬

    2015-01-01

    Objective To analyze the clinical efficacy and safety of capecitabine combined with autologous cytokine-induced killer cells ( CIK) maintenance therapy in treatment of metastatic triple negative breast cancer ( MTNBC) . Methods The MTNBC patients undergoing capecitabine-based chemotherapy as first line treatment, whose therapeutic effect was SD or above were selected and divided into treatment group and control group randomly. The treatment group received capecitabine maintenance therapy with autologous CIK after the first line treatment. The control group underwent only capecitabine mainte-nance therapy. Baseline assessment was taken 15 d after the end of the last cycle of chemotherapy. The patients were followed up once every two cycles. The median follow-up time was 11. 2 months. T lymphocyte subpopulation in peripheral blood was measured, the side effects, PFS and OS of both groups were observed. Results CD3+CD8+CTL and CD4+CD25+Treg of treatment group were compared at the time of baseline assessment and 1 month after three cycles of chemotherapy. There was no statistically significant difference (P>0. 05). CD3+T, CD3+CD4+Th, CD3+CD56+CIK showed significant im-provement, compared with that before treatment (P0. 05). Conclusion Maintenance therapy of Capecitabine combined with autologous CIK cells in treatment of MTNBC after first-line treatment improves the immune function to enhance the ability of antitumor by natural immunity, which can prolong PFS, and is safe as well. In short, it can improve the therapeutic effect of maintenance therapy in patients with MTNBC.%目的 探讨自体细胞因子诱导杀伤细胞( CIK)免疫治疗联合卡培他滨治疗复发转移性三阴性乳腺癌( metastatic triple negative breast cancer, MTNBC)的临床效果和安全性. 方法 选取一线应用卡培他滨化疗后效果评价病情稳定( SD)或以上的MTNBC患者,随机分为治疗组和对照组. 两组均应用卡培他滨维持化疗,治疗组在此

  16. 参附注射液联合表柔比星和紫杉醇治疗三阴性乳腺癌的临床研究%Clinical study of Shenfu Injection combined with epirubicin and paclitaxel in treatment of triple negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    姚嘉; 李冠乔; 钟晓捷; 汤鹏

    2015-01-01

    Objective To explore the clinical curative effect of Shenfu Injection combined with epirubicin and paclitaxel in treatment of triple negative breast cancer. Methods Patients (150 cases) with triple negative breast cancer in Hainan General Hospital from May 2011 to May 2014 were randomly divided into control and treatment groups, and each group had 75 cases. The patients in the control group were iv administered with Epirubicin Hydrochloride for injection 60 mg/m2 on the first day of each cycle of chemotherapy, once daily. At the same time, they were iv administered with Paclitaxel Injection 120 mg/m2, once daily, and the drip time was greater than 3 h. The patients in the treatment group were iv administered with Shenfu Injection 50 mL/time on 1—10 d in each cycle of chemotherapy, the usage and dosage of Epirubicin Hydrochloride for injection and Paclitaxel Injection in the treatment group was the same with the control group. A course of treatment included 21 d, and two groups were continuous treated for two courses. After treatment, the treatment efficacy were evaluated, and the changes of tumor diameter, fork box protein A1 (FOXA1) and protein of breast cancer susceptibility gene 1 (BRCA1) in two groups before and after treatment were compared. Results After treatment, the efficacies in the control and treatment groups were 82.67%and 64.00%, respectively, and there was difference between two groups (P<0.05). After treatment, tumor diameter, FOXA1 and BRCA1 protein in two groups were significantly reduced, and the difference was statistically significant in the same group (P<0.05). And these indicators in treatment group improved better than those in the control group, with significant differences between two groups (P<0.05). The incidence of adverse reactions in the control and treatment groups were 18.67% and 13.33%, respectively, and there was difference between two groups (P < 0.05). Conclusion Shenfu Injection combined with epirubicin and paclitaxel has

  17. Age is not a limiting factor for brachytherapy for carcinoma of the node negative oral tongue in patients aged eighty or older

    International Nuclear Information System (INIS)

    To examine the role of brachytherapy for aged patients 80 or more in the trend of rapidly increasing number. We examined the outcomes for elderly patients with node negative oral tongue cancer (T1-3N0M0) treated with brachytherapy. The 21 patients (2 T1, 14 T2, and 5 T3 cases) ranged in age from 80 to 89 years (median 81), and their cancer was pathologically confirmed. All patients underwent definitive radiation therapy, with low dose rate (LDR) Ra-226 brachytherapy (n = 4; median 70Gy), with Ir-192 (n = 12; 70Gy), with Au-198 (n = 1) or with high dose rate (HDR) Ir-192 brachytherapy (n = 4; 60 Gy). Eight patients also underwent external radiotherapy (median 30 Gy). The period of observation ranged from 13 months to 14 years (median 2.5 years). We selected 226 population matched younger counterpart from our medical chart. Definitive radiation therapy was completed for all 21 patients (100%), and acute grade 2-3 mucositis related to the therapy was tolerable. Local control (initial complete response) was attained in 19 of 21 patients (90%). The 2-year and 5-year local control rates were 91%, (100% for T1, 83% for T2 and 80% for T3 tumors after 2 years). These figures was not inferior to that of younger counterpart (82% at 5-year, n.s.). The cause-specific survival rate was 83% and the regional control rate 84% at the 2-years follow-up. However, 12 patients died because of intercurrent diseases or senility, resulting in overall survival rates of 55% at 2 years and 34% at 5 years. Age is not a limiting factor for brachytherapy for appropriately selected elderly patients, and brachytherapy achieved good local control with acceptable morbidity

  18. Age is not a limiting factor for brachytherapy for carcinoma of the node negative oral tongue in patients aged eighty or older

    Directory of Open Access Journals (Sweden)

    Kakimoto Naoya

    2010-12-01

    Full Text Available Abstract Background To examine the role of brachytherapy for aged patients 80 or more in the trend of rapidly increasing number. Methods We examined the outcomes for elderly patients with node negative oral tongue cancer (T1-3N0M0 treated with brachytherapy. The 21 patients (2 T1, 14 T2, and 5 T3 cases ranged in age from 80 to 89 years (median 81, and their cancer was pathologically confirmed. All patients underwent definitive radiation therapy, with low dose rate (LDR Ra-226 brachytherapy (n = 4; median 70Gy, with Ir-192 (n = 12; 70Gy, with Au-198 (n = 1 or with high dose rate (HDR Ir-192 brachytherapy (n = 4; 60 Gy. Eight patients also underwent external radiotherapy (median 30 Gy. The period of observation ranged from 13 months to 14 years (median 2.5 years. We selected 226 population matched younger counterpart from our medical chart. Results Definitive radiation therapy was completed for all 21 patients (100%, and acute grade 2-3 mucositis related to the therapy was tolerable. Local control (initial complete response was attained in 19 of 21 patients (90%. The 2-year and 5-year local control rates were 91%, (100% for T1, 83% for T2 and 80% for T3 tumors after 2 years. These figures was not inferior to that of younger counterpart (82% at 5-year, n.s.. The cause-specific survival rate was 83% and the regional control rate 84% at the 2-years follow-up. However, 12 patients died because of intercurrent diseases or senility, resulting in overall survival rates of 55% at 2 years and 34% at 5 years. Conclusion Age is not a limiting factor for brachytherapy for appropriately selected elderly patients, and brachytherapy achieved good local control with acceptable morbidity.

  19. Efficacy and safety assessment of neoadjuvant paclitaxel-based chemotherapy in Chinese triple negative breast cancer%以紫杉醇为基础的化疗在三阴性乳腺癌新辅助治疗中的疗效和安全性评价

    Institute of Scientific and Technical Information of China (English)

    李学瑞; 张国淳; 姚濛; 王坤; 祖健; 廖宁

    2011-01-01

    目的 评价以紫杉醇为基础的化疗方案在可手术的三阴性乳腺癌患者新辅助治疗中的疗效与安全性.方法 肿瘤大于2 cm,经穿刺病理确诊的ER、PR、Her均阴性的乳腺癌患者,随机分为三组进行治疗:A组为紫杉醇175mg/m2 D1,表阿霉素100mg/m2D1 q 21天;B组为紫杉醇175mg/m2D1,顺铂30 mg/m2 D1-D3 q 21天;C组为紫杉醇80 mg/m2 D1、D8、D15,顺铂30 mg/m2 D1-D3,q 28天.患者均在手术前接受4个周期新辅助治疗后进行根治性手术.比较三组的原发肿瘤病理完全缓解(tpCR)率和总体反应(OR)率,并观察患者不良反应.结果 共入组31例患者,所有患者均按计划完成术前4个周期新辅助治疗.A组tpCR率为30.0%,OR率为90%;B组tpCR率为33.3%,OR率为100%;C组tpCR率为83.3%,OR率为91.7%;C组的tpCR率明显高于A、B两组(P<0.05).三组患者均无需要调整剂量的严重不良反应.结论 紫杉醇联合顺铂每周化疗方案在可手术的三阴性乳腺癌患者新辅助治疗中有较高的tpCR率,同时具有可靠的安全性.%Objective To assess the efficacy and safety of neoadjuvant paclitexal-based chemotherapy in Chinese triple negative breast cancer. Methods Operable breast cancer patients with tumor size over 2 cm, ER negative, PgR negative, and Her-2 negative were enrolled. The included patients were randomized into 3 groups to receive 4 cycles neoadjuvant chemotherapy. Group A were treated with paclitaxel(175 mg/m2, D1) plus epirubicin (75mg/m2, D1) chemotherapy every 3 weeks; group B were treated with paclitaxel (175 mg/m2, D1) plus cisplatin(30 mg/m2, D1-D3) chemotherapy every 3 weeks; and group C were treated weekly with paclitaxel(175mg/m2, D1, D8,D15) plus cisplatin(30mg/m2, D1-D3) chemotherapy erery 4 weeks. The primary end point was primary tumor pathologic complete remission (tpCR) rate, and the secondary end point was overall response (OR) rate. Safety assessment was performed according to CTCAE v3.0. Results Thirty-one eligible

  20. Synchronous triple primary lung cancer: A rare case with radiologic pathologic correction

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo Hee; Lee, Sung Soo; Park, Heae Surng; Park, Chul Hwan; Kim, Tae Hoon [Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2015-10-15

    Synchronous multiple primary lung cancer is uncommon. They present at the same time, but are distinct and have different histologic features. Synchronous triple primary lung cancer is rare and only few cases have been reported previously. We described a case of synchronous triple primary lung cancers in an asymptomatic 64-year-old man that showed different radiologic features of lung tumors on chest computed tomography images. Anatomical resection and histological analysis revealed 3 different types of lung carcinoma with radiologic-pathologic correlation.

  1. Vaccine Therapy and Pembrolizumab in Treating Patients With Solid Tumors That Have Failed Prior Therapy

    Science.gov (United States)

    2016-06-16

    Adult Solid Neoplasm; Bladder Carcinoma; Colon Carcinoma; Estrogen Receptor Negative; Head and Neck Squamous Cell Carcinoma; Hepatocellular Carcinoma; HER2/Neu Negative; Melanoma; Non-Small Cell Lung Carcinoma; Pancreatic Carcinoma; Progesterone Receptor Negative; Rectal Carcinoma; Renal Cell Carcinoma; Soft Tissue Sarcoma; Triple-Negative Breast Carcinoma

  2. Spectral triples for hyperbolic dynamical systems

    OpenAIRE

    Whittaker, Michael F.

    2010-01-01

    Spectral triples are defined for C*-algebras associated with hyperbolic dynamical systems known as Smale spaces. The spectral dimension of one of these spectral triples is shown to recover the topological entropy of the Smale space.

  3. Harmonic analysis on triple spaces

    DEFF Research Database (Denmark)

    Danielsen, Thomas Hjortgaard

    properties of symmetric spaces. The algebras of invariant differential operators for these spaces are studied and the conclusion is that most of them are non-commutative. Finally, we restrict our attention to a single triple space, giving a specific polar decomposition and corresponding integration formula...

  4. Spectral triples and Toeplitz operators

    OpenAIRE

    Englis, M.; Falk, K.; Iochum, B.

    2014-01-01

    We give examples of spectral triples, in the sense of A. Connes, constructed using the algebra of Toeplitz operators on smoothly bounded strictly pseudoconvex domains in $C^n$, or the star product for the Berezin-Toeplitz quantization. Our main tool is the theory of generalized Toeplitz operators on the boundary of such domains, due to Boutet de Monvel and Guillemin.

  5. Spectral triples and Toeplitz operators

    Czech Academy of Sciences Publication Activity Database

    Engliš, Miroslav; Falk, K.; Iochum, B.

    2015-01-01

    Roč. 9, č. 4 (2015), s. 1041-1076. ISSN 1661-6952 Institutional support: RVO:67985840 Keywords : Toeplitz operator * pseudoconvex domain * spectral triple Subject RIV: BA - General Mathematics Impact factor: 0.947, year: 2014 http://www.ems-ph.org/journals/show_abstract.php?issn=1661-6952&vol=9&iss=4&rank=1

  6. Solution Patterns Predicting Pythagorean Triples

    Science.gov (United States)

    Ezenweani, Ugwunna Louis

    2013-01-01

    Pythagoras Theorem is an old mathematical treatise that has traversed the school curricula from secondary to tertiary levels. The patterns it produced are quite interesting that many researchers have tried to generate a kind of predictive approach to identifying triples. Two attempts, namely Diophantine equation and Brahmagupta trapezium presented…

  7. Triple Crossing Numb ers of Graphs

    Institute of Scientific and Technical Information of China (English)

    Tanaka Hiroyuki; Teragaito Masakazu

    2016-01-01

    We introduce the triple crossing number, a variation of the crossing number, of a graph, which is the minimal number of crossing points in all drawings of the graph with only triple crossings. It is defined to be zero for planar graphs, and to be infinite for non-planar graphs which do not admit a drawing with only triple crossings. In this paper, we determine the triple crossing numbers for all complete multipartite graphs which include all complete graphs.

  8. Spectral Triples and Generalized Crossed Products

    OpenAIRE

    Gabriel, Olivier; Grensing, Martin

    2013-01-01

    We give a construction allowing to lift spectral triples to crossed products by Hilbert bimodules. The spectral triple one obtains is a concrete unbounded representative of the Kasparov product of the spectral triple and the Pimsner-Toeplitz extension associated to the crossed product by the Hilbert bimodule. To prove that the lifted spectral triple is the above-mentioned Kasparov product, we rely on operator-$*$-algebras and connexions.

  9. Twisted Spectral Triples and Connes' Character Formula

    OpenAIRE

    Fathizadeh, Farzad; Khalkhali, Masoud

    2011-01-01

    We give a proof of an analogue of Connes' Hochschild character theorem for twisted spectral triples obtained from twisting a spectral triple by scaling automorphisms, under some suitable conditions. We also survey some of the properties of twisted spectral triples that are known so far.

  10. Prevalence of androgen receptors in invasive breast carcinoma and its relation with estrogen receptor, progesterone receptor and Her2/neu expression

    International Nuclear Information System (INIS)

    Background and aims: Although Breast carcinoma had many targeted bio markers for its treatment, however, it is a heterogeneous disease with different outcomes and need new markers especially for the triple negative group when estrogen receptor, progesterone receptors and Her2/ neu are negative. Androgen receptor is a new target with unclear role. The aim of this study was to examine the prevalence of androgen receptors in invasive breast cancer and tries to elucidate its relation to some well recognized clinico pathological and immunohistochemical markers. Materials and methods: One hundred and fifty cases of invasive breast carcinoma were evaluated for type, grade and stage and studied immunohistochemically for estrogen receptor, progesterone receptor, Her2/neu and androgen expression. Androgen receptor expression was correlated with histopathological factors and the three studied markers separately then the studied cases were classified into three groups according to estrogen, progesterone receptor and Her2/neu expression and correlated with androgen receptor expression. Results: Androgen receptor was expressed in 71% of breast cancer cases. Its expression is associated significantly with both the stage and the grade. Also it was significantly associated with estrogen receptor and Her2/neu expression. It was expressed in a significant number of triple negative breast carcinoma, in Her2/neu positive cases and in estrogen negative cases which indicate that androgen receptor could be a new target for the treatment of these groups. Conclusions: Although the impact of androgen receptor on breast cancer outcomes had not been clearly established, this result may provide evidence that androgen receptor is a good prognostic and predictive marker.

  11. Parotid carcinoma

    DEFF Research Database (Denmark)

    Sørensen, Kristine Bjørndal; Godballe, Christian; de Stricker, Karin;

    2006-01-01

    OBJECTIVES: Our aim is to investigate the expression of kit protein (KIT) and epidermal growth factor receptor (EGFR) in parotid carcinomas in order to correlate the expression to histology and prognosis. Further we want to perform mutation analysis of KIT-positive adenoid cystic carcinomas....... PATIENTS AND METHODS: Formalin-fixed paraffin-embedded sections from 73 patients with parotid gland carcinomas were used for the study. The sections were stained with both KIT and EGFR polyclonal antibodies. Twelve KIT-positive adenoid cystic carcinomas were examined for c-kit mutation in codon 816....... RESULTS: Of all carcinomas 25% were KIT-positive and 79% were EGFR-positive. Ninety-two percentage of the adenoid cystic carcinomas were KIT-positive. None of the adenoid cystic carcinomas had mutations in codon 816 of the c-kit gene. CONCLUSION: Neither KIT- nor EGFR-expression seem to harbour...

  12. Search and test algorithms for Triple Product Property triples

    CERN Document Server

    Hedtke, Ivo

    2011-01-01

    In 2003 COHN and UMANS introduced a group-theoretic approach to fast matrix multiplication. This involves finding large subsets of a group $G$ satisfying the Triple Product Property (TPP) as a means to bound the exponent $\\omega$ of matrix multiplication. We present two new characterizations of the TPP, which are useful for theoretical considerations and for TPP test algorithms. With this we describe all known TPP tests and implement them in GAP algorithms. We also compare their runtime. Furthermore we show that the search for subgroup TPP triples of nontrivial size in a nonabelian group can be restricted to the set of all nonnormal subgroups of that group. Finally we describe brute-force search algorithms for maximal subgroup and subset TPP triples. In addition we present the results of the subset brute-force search for all groups of order less than 25 and selected results of the subgroup brute-force search for 2-groups, $SL(n,q)$ and $PSL(2,q)$.

  13. PROGNOSTIC FACTORS IN CERVICAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    路平; 梁秋冬; 魏磊; 郑全庆

    2002-01-01

    Objective: To evaluate factors for prognosis of cervical carcinoma. Methods: Expressions of mn23- HI, erbB3 and erbB4 were examined by immunohistochemical staining. The apoptosis was detected in situ by the TdT mediated duip-biotin nick end-labeling (TUNEL) technique. Mitotic cell were counted by HE dyeing. Results: FIGO stage and lymph node metastasis were the most important factors for evaluating prognosis in adenocarcinoma or squamous cell carcinoma. AI/MI was positively correlated with 5-year survival of cervical carcinoma. Positive expression of nm23-H1 combed with negative expression of erbB4 [nm23-H1(+)/erbB4(-)] predicted good prognosis for adeno-carcinoma. In multivariable Cox regression analysis, only FIGO stage and AI/MI were into equation. Conclusion: FIGO stage and AI/MI were independent evaluating parameter for adenocarcinoma or squamous cell carcinoma.

  14. Modal planes are spectral triples

    International Nuclear Information System (INIS)

    Axioms for nonunital spectral triples, extending those introduced in the unital case by Connes, are proposed. As a guide, and for the sake of their importance in noncommutative quantum field theory, the spaces R2N endowed with Moyal products are intensively investigated. Some physical applications, such as the construction of noncommutative Wick monomials and the computation of the Connes-Lott functional action, are given for these noncommutative hyperplanes. (author)

  15. Early onset sebaceous carcinoma

    Directory of Open Access Journals (Sweden)

    Kaltreider Sara A

    2011-09-01

    Full Text Available Abstract Background Ocular sebaceous carcinoma can masquerade as benign lesions resulting in delay of diagnosis. Early recognition is even more difficult in young patients where the disease rarely occurs. Here, we provide a clinicopathological correlation of ocular sebaceous carcinoma in a young individual lacking history of hereditary cancer or immunosuppression. Findings A detailed histopathological study including p53 DNA sequencing was performed on an aggressive sebaceous carcinoma presenting in a healthy 32 year-old Caucasian woman. She had no history of retinoblastoma, evidence for a hereditary cancer syndrome, or radiation therapy. However, she potentially was at risk for excessive UV light exposure. A detailed review of the literature is also provided. A moderately well differentiated sebaceous carcinoma was established histopathologically arising from the meibomian gland of the upper eyelid. In most areas, the cytoplasm contained small but distinct Oil-red-O positive vacuoles. Direct sequencing of p53 identified a G:C→A:T mutation at a dipyrimidine site. The mutation results in substitution of arginine for the highly conserved glycine at residue 199 located at the p53 dimer-dimer interface. Energy minimization structural modeling predicts that G199R will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues. Discussion This study points to the importance of recognizing that sebaceous carcinoma can occur in young patients with no evidence for hereditary cancer risk or radiation therapy. The G199R substitution is anticipated to alter the stability of the p53 tetrameric complex. The role of UV light in the etiology of sebaceous carcinoma deserves further study. Our findings, taken together with those of others, suggest that different environmental factors could lead to the development of sebaceous carcinoma in different patients.

  16. First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report

    International Nuclear Information System (INIS)

    Acinic cell carcinoma (ACC) is a rare malignant epithelial neoplasm characterized by the presence of malignant tubular acinar exocrine gland structures. Diagnosis is generally made in salivary glands and in the pancreas. ACC of the breast has been reported in few cases only. Carriers of inherited mutations in the BRCA1 gene are prone to the development of breast cancer, mainly invasive ductal or medullary type carcinomas. We describe for the first time a BRCA1 mutation carrier with a diagnosis of ACC of the breast. The patient developed an invasive ductal carcinoma (IDC) at the age of 40 years and an ACC in the contralateral breast at 44 years. Immunohistochemical examination of the ACC revealed a triple negative status (i.e., negativity for estrogen receptor, progesterone receptor and HER2 protein) and positivity for p53. Using a combination of loss of heterozygosity (LOH) and sequencing analyses, the loss of the wild-type BRCA1 allele was detected in both the ACC and the IDC. In addition, two different somatic TP53 mutations, one in the ACC only and another one in the IDC only, were observed. Both the immunohistochemical and molecular features observed in the ACC are typical of BRCA1-associated breast cancers and suggest an involvement of the patient’s germline mutation in the disease. The occurrence of rare histological types of breast cancers, including malignant phyllodes tumor, atypical medullary carcinoma and metaplastic carcinoma, in BRCA1 mutation carriers has been already reported. Our findings further broaden the spectrum of BRCA1-associated breast malignancies

  17. The immune microenvironment of breast ductal carcinoma in situ.

    Science.gov (United States)

    Thompson, Elizabeth; Taube, Janis M; Elwood, Hillary; Sharma, Rajni; Meeker, Alan; Warzecha, Hind Nassar; Argani, Pedram; Cimino-Mathews, Ashley; Emens, Leisha A

    2016-03-01

    The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ (DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1-tumor infiltrating lymphocytes were seen only in ER+/HER-2-DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention. PMID:26769139

  18. Energy Efficient Triple IG Automation EEE (Triple-E)

    Energy Technology Data Exchange (ETDEWEB)

    McGlinchy, Timothy B

    2013-02-28

    GED Integrated Solutions collaborated with US window and door manufactures to investigate, design and verify technical and cost feasibility for producing high performance, high volume, low material and labor cost window, utilizing a modified window design containing a triple insulating glass unit (IGU). This window design approach when combined with a high volume IGU manufacturing system, can produce R5 rated windows for an approximate additional consumer cost of only $4 per square foot when compared to conventional Low-E argon dual pane IG windows, resulting in a verify practical, reliable and affordable high performance window for public use.

  19. Vinorelbine Combined with Capecitabine in Triple Negative Metastatic Breast Cancer Patients%长春瑞滨联合卡培他滨治疗蒽环类及紫杉类耐药的转移性三阴乳腺癌的临床观察

    Institute of Scientific and Technical Information of China (English)

    高津; 周国仁

    2012-01-01

      Objective To evaluate efficacy and toxicity of combination chemotherapy of vinorelbine and capecitabine for anthracycline- and taxane-resistant metastatic triple negative breast cancer(TNBC). Methods Thirty-two cases of anthracycline- and taxane- resistant metastatic TNBC patients received vinorelbine 25 mg /m2on day 1 and day 8, and capecitabine 825 mg /m2-1000 mg /m2 twice a day on day 1 through 14. Treatment was repeated every 21 days and all patients received at least 2 cycles of chemotherapy. Results In total, 152 cycles were given. The median number of treatment was 4 cycles(2-6 cycles). PR 37.5%, SD 28.1%, including 5 patients maintained SD≥6 months, PD 37.5%. The median time to progression was 5.4 months. Myelosuppression, gastrointestinal tract reaction and hand-foot syndrome were the most common toxicities. Conclusion Combination therapy of vinorelbine and capecitabine is an effective and well tolerated regimen in anthracycline- and taxane- resistant metastatic TNBC patients.%  目的观察长春瑞滨联合卡培他滨治疗蒽环类及紫杉类耐药的转移性三阴性乳腺癌患者的疗效和不良反应.方法32例蒽环类及紫杉类耐药的复发转移性三阴性乳腺癌患者接受长春瑞滨联合卡培他滨化疗,长春瑞滨25mg/m2,静脉滴注,第1天和第8天,采用深静脉穿刺置管技术静脉滴注;卡培他滨825~1000mg/m2,口服,每天2次,第1~14天;21d 重复.统计分析其疗效与不良反应.结果32例患者共接受152个周期治疗,中位治疗周期数为4个周期(2~6个周期);11例患者获得部分缓解(PR,占34.4%),9例患者获得稳定(SD,占28.1%),其中5例患者稳定维持6个月以上;12例患者获进展(PD,占37.5%).总有效率(CR+PR)34.4%(11/32),疾病控制率(PR+SD)62.5%(20/32),中位疾病进展时间(TTP)为5.4个月.常见不良反应为骨髓抑制,恶心、呕吐和手足综合征等.结论长春瑞滨联合卡培他滨方案近期疗效好,毒性可以耐受,可作为

  20. Almost all cancellative triple systems are tripartite

    CERN Document Server

    Balogh, Jozsef

    2009-01-01

    A triple system is cancellative if no three of its distinct edges satisfy $A \\cup B=A \\cup C$. It is tripartite if it has a vertex partition into three parts such that every edge has exactly one point in each part. It is easy to see that every tripartite triple system is cancellative. We prove that almost all cancellative triple systems with vertex set [n] are tripartite. This sharpens a theorem of Nagle and Rodl on the number of cancellative triple systems. It also extends recent work of Person and Schacht who proved a similar result for triple systems without the Fano configuration. Our proof uses the hypergraph regularity lemma of Frankl and Rodl, and a stability theorem for cancellative triple systems due to Keevash and the second author.

  1. Basisquamous Carcinoma

    Directory of Open Access Journals (Sweden)

    Yesudian Devakar P

    1997-01-01

    Full Text Available A 50 year old woman presented with an ulceroproliferative mass in the value of 4 month duration. Biopsy of the lesion showed features of a basisquamous cell carcinoma. This is a rare tumour showing histopathological features of both basal cell and squamous cell carcinomas. The clinical, histopathological and histogenetic status of this tumour are discussed.

  2. An overview of Triple infection with Hepatitis B, C and D viruses

    Directory of Open Access Journals (Sweden)

    Kanwal Hifza

    2011-07-01

    Full Text Available Abstract Viral hepatitis is one of the major health problems worldwide, particularly in South East Asian countries including Pakistan where hepatitis C virus (HCV and hepatitis B virus (HBV infections are highly endemic. Hepatitis delta virus (HDV is also not uncommon world-wide. HCV, HBV, and HDV share parallel routes of transmission due to which dual or triple viral infection can occur in a proportion of patients at the same time. HBV and HCV are important factors in the development of liver cirrhosis (LC and hepatocellular carcinoma (HCC. In addition to LC and HCC, chronic HDV infection also plays an important role in liver damage with oncogenic potential. The current article reviews the available literature about the epidemiology, pathogenesis, transmission, symptoms, diagnosis, replication, disease outcome, treatment and preventive measures of triple hepatitis infection by using key words; epidemiology of triple infection, risk factors, awareness status, treatment and replication cycle in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ and Google Scholar. Total data from 74 different studies published from 1983 to 2010 on triple hepatitis infections were reviewed and included in this study. The present article briefly describes triple infection with HCV, HBV and HDV.

  3. An overview of triple infection with hepatitis B, C and D viruses.

    Science.gov (United States)

    Riaz, Mehwish; Idrees, Muhamad; Kanwal, Hifza; Kabir, Firoz

    2011-01-01

    Viral hepatitis is one of the major health problems worldwide, particularly in South East Asian countries including Pakistan where hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are highly endemic. Hepatitis delta virus (HDV) is also not uncommon world-wide. HCV, HBV, and HDV share parallel routes of transmission due to which dual or triple viral infection can occur in a proportion of patients at the same time. HBV and HCV are important factors in the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In addition to LC and HCC, chronic HDV infection also plays an important role in liver damage with oncogenic potential.The current article reviews the available literature about the epidemiology, pathogenesis, transmission, symptoms, diagnosis, replication, disease outcome, treatment and preventive measures of triple hepatitis infection by using key words; epidemiology of triple infection, risk factors, awareness status, treatment and replication cycle in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. Total data from 74 different studies published from 1983 to 2010 on triple hepatitis infections were reviewed and included in this study. The present article briefly describes triple infection with HCV, HBV and HDV. PMID:21791115

  4. Spectral triples and the geometry of fractals

    DEFF Research Database (Denmark)

    Christensen, Erik; Ivan, Cristina; Schroe, Elmar

    2012-01-01

    It is shown that one can construct a spectral triple for the Sierpinski gasket such that it represents any given K-homology class, On the other hand if the geodesic distance and the dimension has to be part of the data from the triple, there are certain restriction.......It is shown that one can construct a spectral triple for the Sierpinski gasket such that it represents any given K-homology class, On the other hand if the geodesic distance and the dimension has to be part of the data from the triple, there are certain restriction....

  5. Almost all cancellative triple systems are tripartite

    OpenAIRE

    Balogh, Jozsef; Mubayi, Dhruv

    2009-01-01

    A triple system is cancellative if no three of its distinct edges satisfy $A \\cup B=A \\cup C$. It is tripartite if it has a vertex partition into three parts such that every edge has exactly one point in each part. It is easy to see that every tripartite triple system is cancellative. We prove that almost all cancellative triple systems with vertex set [n] are tripartite. This sharpens a theorem of Nagle and Rodl on the number of cancellative triple systems. It also extends recent work of Per...

  6. Negative Happiness

    OpenAIRE

    Adam Barkman

    2009-01-01

    In this paper, I will compare the philosophies of the Buddha and Epicurus. Unusual? Yes. But my intention herein is not a general comparison; rather, I want to explore to what extent these two men accepted what I call “negative happiness.” What is negative, and by extension, positive, happiness? I think we can prepare ourselves for this distinction with two analogous distinctions: (1) the distinction between positive and negative freedom, wherein positive freedom sees true freedom as interna...

  7. Synergies Between Human and Animal Health Syndromic Surveillance: Triple-S Outputs

    OpenAIRE

    Dupuy, Céline; Perrin, Jean-Baptiste; Bronner, Anne; Calavas, Didier; Hendrikx, Pascal; Fouillet, Anne

    2013-01-01

    Objective The objective of this study, based on the Triple-S project outputs, was to present the existing synergies between human and animal health syndromic surveillance (SyS) systems in Europe and a proposal to enhance this kind of collaboration. Introduction The Triple-S project (Syndromic Surveillance Systems in Europe, www.syndromicsurveillance.eu), co-financed by the European Commission and involving twenty four organizations from fourteen countries was launched in September 2010 with t...

  8. Fractal negations

    OpenAIRE

    Mayor Forteza, Gaspar; Calvo Sánchez, Tomasa

    1994-01-01

    From the concept of attractor of a family of contractive affine transformations in the Euclidean plane R², we study the fractality property of the De Rham function and other singular functions wich derive from it. In particular, we show as fractals the strong negations called k-negations.

  9. Holonomy loops, spectral triples and quantum gravity

    DEFF Research Database (Denmark)

    Johannes, Aastrup; Grimstrup, Jesper Møller; Nest, Ryszard

    2009-01-01

    We review the motivation, construction and physical interpretation of a semi-finite spectral triple obtained through a rearrangement of central elements of loop quantum gravity. The triple is based on a countable set of oriented graphs and the algebra consists of generalized holonomy loops...

  10. Introductory lecture on triple-axis spectrometer

    International Nuclear Information System (INIS)

    Triple-axis spectrometer is a multi-purpose instrument for powder neutron diffraction, single crystal neutron diffraction, powder inelastic neutron scattering, single crystal inelastic neutron scattering, and neutron polarization analysis. In this lecture how to use the triple-axis spectrometer is explained for the beginners. (author)

  11. Discrete spectral triples and their symmetries

    CERN Document Server

    Paschke, M; Paschke, Mario; Sitarz, Andrzej

    1996-01-01

    We classify 0-dimensional spectral triples over complex and real algebras and provide some general statements about their differential structure. We investigate also whether such spectral triples admit a symmetry arising from the Hopf algebra structure of the finite algebra. We discuss examples of commutative algebras and group algebras.

  12. Discrete spectral triples and their symmetries

    OpenAIRE

    Paschke, Mario; Sitarz, Andrzej

    1996-01-01

    We classify 0-dimensional spectral triples over complex and real algebras and provide some general statements about their differential structure. We investigate also whether such spectral triples admit a symmetry arising from the Hopf algebra structure of the finite algebra. We discuss examples of commutative algebras and groups algebras.

  13. Focus of tricholemmal differentiation (tricholemmal carcinoma) within Bowen's disease/carcinoma.

    Science.gov (United States)

    Misago, Noriyuki; Toda, Shuji; Nakao, Tomokazu

    2016-04-01

    Bowen's disease (BD)/carcinoma is a type of squamous cell carcinoma of the skin, however, the possibility of adnexal differentiation (the development of sebaceous carcinoma or porocarcinoma) occurring in BD/carcinoma has been suggested. We herein describe a case of BD with superficial invasive carcinoma, which showed a clear cell focus, demonstrating tricholemmal differentiation. This clear cell focus showed the following findings: primarily composed of clear cells, somewhat columnar clear cells aligned in a palisade along a discernible basement membrane, tricholemmal keratinization and glycogen contained within the cells. In addition, the immunohistochemical profile in this clear cell focus, namely, negative staining for cytokeratin (CK)1 and positive staining for CK17 and calretinin in the inner cells of the neoplastic lobule, corresponded to that of the outer root sheath cells. This case suggested that adnexal differentiation can rarely occur within true BD/carcinoma, although adnexal carcinomas are commonly associated with a simple bowenoid change. PMID:26365015

  14. Jordan triple systems by the grid approach

    CERN Document Server

    Neher, Erhard

    1987-01-01

    Grids are special families of tripotents in Jordan triple systems. This research monograph presents a theory of grids including their classification and coordinization of their cover. Among the applications given are - classification of simple Jordan triple systems covered by a grid, reproving and extending most of the known classification theorems for Jordan algebras and Jordan pairs - a Jordan-theoretic interpretation of the geometry of the 27 lines on a cubic surface - structure theories for Hilbert-triples and JBW*-triples, the Jordan analogues of Hilbert-triples and W*-algebras which describe certain symmetric Banach manifolds. The notes are essentially self-contained and independent of the structure theory of Jordan algebras and Jordan pairs. They can be read by anyone with a basic knowledge in algebraic geometry or functional analysis. The book is intended to serve both as a reference for researchers in Jordan theory and as an introductory textbook for newcomers to the subject.

  15. Sebaceous Carcinoma

    Science.gov (United States)

    ... of the Year Award Arnold P. Gold Foundation Humanism in Medicine Award Diversity Mentorship Program Eugene Van ... What causes sebaceous carcinoma? SC is rare, so scientists still have much to learn, including what causes ...

  16. Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients – a retrospective study of clinical and tumor characteristics

    International Nuclear Information System (INIS)

    Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity

  17. A Short Note on Disjointness Conditions for Triples of Group Subsets Satisfying the Triple Product Property

    CERN Document Server

    Murthy, Sandeep

    2009-01-01

    We deduce some elementary pairwise disjointness and semi-disjointness conditions on triples of subsets in arbitrary groups satisfying the so-called triple product property (TPP) as originally defined by H. Cohn and C. Umans in 2003. This property TPP for a triple of group subsets, called a TPP triple, allows the group to "realize" matrix multiplication of dimensions the sizes of the subsets, with the subsets acting as indexing sets for input matrices which are embedded into the regular algebra of the group. We derive nine different disjointness casetypes for an arbitrary TPP triple, and classify these into four different disjointness classes based on an integer measure of the degree of pairwise disjointness among the subsets. Finally, we derive lower and upper bounds for the sum of sizes of the subsets forming a TPP triple, which is the additive equivalent of the multiplicative bounds originally derived by Cohn and Umans for the product of sizes of subsets forming a TPP triple.

  18. Negative Happiness

    Directory of Open Access Journals (Sweden)

    Adam Barkman

    2009-06-01

    Full Text Available In this paper, I will compare the philosophies of the Buddha and Epicurus. Unusual? Yes. But my intention herein is not a general comparison; rather, I want to explore to what extent these two men accepted what I call “negative happiness.” What is negative, and by extension, positive, happiness? I think we can prepare ourselves for this distinction with two analogous distinctions: (1 the distinction between positive and negative freedom, wherein positive freedom sees true freedom as internal control over oneself, while negative freedom sees true freedom as the lack of external coercion, and (2 the distinction between charity and unselfishness, wherein charity stresses selfdenial,though not as an end in itself, whereas unselfishness emphasizes notprimarily doing good things for others but rather going without them ourselves. Thus, in regard to positive and negative happiness, we can say that while positive happiness sees true happiness as a substantial good that makes virtue a constituent of happiness and regards happiness as something more than the avoidance of suffering, negative happiness sees true happiness as simply the absence of suffering.

  19. The triple system Zeta Aquarii

    CERN Document Server

    Tokovinin, Andrei

    2016-01-01

    Zeta Aquarii is a bright and nearby (28 pc) triple star with a 26-year astrometric subsystem. Almost a half of the outer 540-year visual orbit has been covered in 238 years of its observations. Both inner and outer orbits are revised here taking into account recent direct resolution of the inner pair Aa,Ab. The inner orbit has a high eccentricity of 0.87 and is inclined to the outer orbit by 140+-10 degrees, suggesting that Kozai-Lidov cycles take place. The masses of the stars Aa, B, and Ab are 1.4, 1.4, and 0.6 solar. The age of the system is about 3 Gyr, and the two main components have just left the main sequence. Hypothetically, this system could have formed by a dynamical capture of the small star Ab in the twin binary Aa,B.

  20. Isobologram analysis of triple therapies

    International Nuclear Information System (INIS)

    New concepts in radiation oncology are based on the concept that combinations of irradiation and molecular targeted drugs can yield synergistic or at least additive effects. Up to now the combination of two treatment modalities has been tested in almost all cases. Similar to conventional anti-cancer agents, the efficacy of targeted approaches is also subject to predefined resistance mechanisms. Therefore, it seems reasonable to speculate that a combination of more than two agents will ultimately increase the therapeutic gain. No tools for a bio-mathematical evaluation of a given degree of interaction for more than two anti-neoplastic agents are currently available. The present work introduces a new method for an evaluation of triple therapies and provides some graphical examples in order to visualize the results

  1. Simulation of triple coincidences in PET

    International Nuclear Information System (INIS)

    Although current PET scanners are designed and optimized to detect double coincidence events, there is a significant amount of triple coincidences in any PET acquisition. Triple coincidences may arise from causes such as: inter-detector scatter (IDS), random triple interactions (RT), or the detection of prompt gamma rays in coincidence with annihilation photons when non-pure positron-emitting radionuclides are used (β+γ events). Depending on the data acquisition settings of the PET scanner, these triple events are discarded or processed as a set of double coincidences if the energy of the three detected events is within the scanner’s energy window. This latter option introduces noise in the data, as at most, only one of the possible lines-of-response defined by triple interactions corresponds to the line along which the decay occurred. Several novel works have pointed out the possibility of using triple events to increase the sensitivity of PET scanners or to expand PET imaging capabilities by allowing differentiation between radiotracers labeled with non-pure and pure positron-emitting radionuclides. In this work, we extended the Monte Carlo simulator PeneloPET to assess the proportion of triple coincidences in PET acquisitions and to evaluate their possible applications. We validated the results of the simulator against experimental data acquired with a modified version of a commercial preclinical PET/CT scanner, which was enabled to acquire and process triple-coincidence events. We used as figures of merit the energy spectra for double and triple coincidences and the triples-to-doubles ratio for different energy windows and radionuclides. After validation, the simulator was used to predict the relative quantity of triple-coincidence events in two clinical scanners assuming different acquisition settings. Good agreement between simulations and preclinical experiments was found, with differences below 10% for most of the observables considered. For clinical

  2. Resonant transitions between split energy levels triple-barrier nanostructures and their application perspectives in submillimeter-wave devices

    CERN Document Server

    Golant, E I

    2002-01-01

    A mathematical model has been developed for electronic coherent tunneling through the triple-barrier quantum-dimensional semiconductor heterostructures in the terahertz electric field. Using this model the frequency dependences of the negative dynamic conductivity for triple-barrier structures with coherent electron tunneling through the split energy levels are investigated. It has been shown that these structures can be employed in far-infrared coherent quantum lasers, the wave length being 600 mu m (5 THz)

  3. Reverse triple I method of fuzzy reasoning

    Institute of Scientific and Technical Information of China (English)

    宋士吉; 吴澄

    2002-01-01

    A theory of reverse triple I method with sustention degree is presented by using the implication operator R0 in every step of the fuzzy reasoning. Its computation formulas of supremum for fuzzy modus ponens and infimum for fuzzy modus tollens are given respectively. Moreover, through the generalization of this problem, the corresponding formulas of ?-reverse triple I method with sustention degree are also obtained. In addition, the theory of reverse triple I method with restriction degree is proposed as well by using the operator R0, and the computation formulas of infimum for fuzzy modus ponens and supremum for fuzzy modus tollens are shown.

  4. The probability of involvement of human papillomavirus in the carcinogenesis of bladder small cell carcinoma, prostatic ductal adenocarcinoma, and penile squamous cell carcinoma: a case report

    OpenAIRE

    Ogawa, Soichiro; Yasui, Takahiro; Taguchi, Kazumi; Umemoto, Yukihiro; Kojima, Yoshiyuki; Kohri, Kenjiro

    2014-01-01

    Background Human papillomavirus is associated with urogenital carcinogenesis such as penile and uterine cervix cancer. On the other hand, association between human papillomavirus infection and risk of bladder and prostatic cancer remains controversial. Case presentation We report a rare case of a 67-year-old Japanese man with synchronous triple urogenital cancer including bladder small cell carcinoma, prostatic ductal adenocarcinoma, and penile squamous cell carcinoma, who presented with a hi...

  5. Carcinoma multiplex

    International Nuclear Information System (INIS)

    Multiple primaries in a single patient are uncommon, though not very rare. The existence of such cancers in two un-related, non-paired organs is even more un-common. Here, we present a case of 55 years old male who presented to us with a mucoepidermoid carcinoma of the parotid gland and was operated. Later on, he presented with a large cystic swelling in the pelvis which turned out to be pseudomyxoma peritonei. A review of slides and immunohistochemistry indicated it to be adenocarcinoma colon. He presented again with recurrent mucoepidermoid carcinoma of the parotid which was operated successfully with the use of myocutaneous flap for wound closure. He is currently undergoing chemotherapy. In order to establish a separate mono-clonal etiology of both tumours, immunohistochemistry was performed. To the best of our knowledge, carcinoma multiplex in the colon and the parotid has never been reported before. (author)

  6. Parotid carcinoma

    DEFF Research Database (Denmark)

    Godballe, Christian; Schultz, Joyce H; Krogdahl, Annelise;

    2003-01-01

    OBJECTIVE: To analyze clinical data and possible prognostic factors of patients with primary carcinoma of the parotid gland. STUDY DESIGN: A retrospective study was made of 85 patients with suspected parotid cancer who were admitted to the Center of Head and Neck Oncology at Odense University...... guidelines from the World Health Organization. Five tumors (6%) did not fulfill the criteria of malignancy and were reclassified as benign. In another five cases the assumed primary parotid carcinomas were found to be metastatic disease from cancers of the breast, prostate, skin, and lungs. Ten patients (12...... significant influence on survival. CONCLUSIONS: A thorough histological revision is pivotal in retrospective parotid carcinoma studies, and tumor size; histological appearance; T, N, and M status; stage; facial nerve dysfunction; and pain from the face and/or neck seem to be significant prognostic indicators...

  7. SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma

    Directory of Open Access Journals (Sweden)

    Dongquan Chen

    2015-01-01

    Full Text Available Breast cancer (BC is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Research has focused heavily on BC metastasis. Multiple signaling pathways have been implicated in regulating BC metastasis. Our knowledge of regulation of BC metastasis is, however, far from complete. Identification of new factors during metastasis is an essential step towards future therapy. Our labs have focused on Semaphorin 6D (SEMA6D, which was implicated in immune responses, heart development, and neurogenesis. It will be interesting to know SEMA6D-related genomic expression profile and its implications in clinical outcome. In this study, we examined the public datasets of breast invasive carcinoma from The Cancer Genome Atlas (TCGA. We analyzed the expression of SEMA6D along with its related genes, their functions, pathways, and potential as copredictors for BC patients’ survival. We found 6-gene expression profile that can be used as such predictors. Our study provides evidences for the first time that breast invasive carcinoma may contain a subtype based on SEMA6D expression. The expression of SEMA6D gene may play an important role in promoting patient survival, especially among triple negative breast cancer patients.

  8. Bridging disparate symptoms of schizophrenia: a Triple network dysfunction theory

    Directory of Open Access Journals (Sweden)

    Tereza eNekovarova

    2014-05-01

    Full Text Available Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. Yet, the etiology of this disorder has yet to be fully understood.Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of triple brain network model of the dysfunctional switching between default mode and central executive network related to the aberrant activity of salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of SELF (self-awareness and self-representation and theory of mind (ToM dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of SELF and ToM in schizophrenia together with neuroimaging data elucidating the triple brain network model as a common neuronal substrate of this dysfunction.

  9. Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory.

    Science.gov (United States)

    Nekovarova, Tereza; Fajnerova, Iveta; Horacek, Jiri; Spaniel, Filip

    2014-01-01

    Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction. PMID:24910597

  10. Triple Pulsar Tests Mass Triplets

    CERN Document Server

    Shao, Lijing

    2016-01-01

    Three conceptually different masses appear in equations of motion for objects under gravity, namely, inertial mass, $m_{\\cal I}$, passive gravitational mass, $m_{\\cal P}$, and active gravitational mass, $m_{\\cal A}$. It is assumed that, for any objects, $m_{\\cal I} = m_{\\cal P} = m_{\\cal A}$ in Newtonian gravity, and $m_{\\cal I} = m_{\\cal P}$ in Einsteinian gravity, oblivious to objects' sophisticated internal structure. Empirical examination of the equivalence probes deep into gravity theories. We propose new tests based on pulsar timing of the stellar triple system, PSR J0337+1715. Various machine-precision three-body simulations are performed, from which, equivalence-violating parameters are extracted with Markov chain Monte Carlo sampling that takes full correlations into account. We show that the difference in masses can be probed to $3\\times10^{-8}$, improving the post-Newtonian constraints of strong equivalence principle by $10^3$--$10^6$. The test of $m_{\\cal P}=m_{\\cal A}$ presents the first test of ...

  11. Triple ion beam irradiation facility

    International Nuclear Information System (INIS)

    A unique ion irradiation facility consisting of three accelerators is described. The accelerators can be operated simultaneously to deliver three ion beams on one target sample. The energy ranges of the ions are 50 to 400 keV, 200 keV to 2.5 MeV, and 1.0 to 5.0 MeV. Three different ions in the appropriate mass range can be simultaneously implanted to the same depth in a target specimen as large as 100 mm2 in area. Typical depth ranges are 0.1 to 1.0 μm. The X-Y profiles of all three ion beams are measured by a system of miniature Faraday cups. The low-voltage accelerator can periodically ramp the ion beam energy during the implantation. Three different types of target chambers are in use at this facility. The triple-beam high-vacuum chamber can hold nine transmission electron microscopy specimens at elevated temperature during a irradiation by the three simultaneous beams. A second high-vacuum chamber on the medium-voltage accelerator beamline houses a low- and high-temperature translator and a two-axis goniometer for ion channeling measurements. The third chamber on the high-energy beamline can be gas-filled for special stressed specimen irradiations. Special applications for the surface modification of materials with this facility are described. Appendixes containing operating procedures are also included. 18 refs., 27 figs., 1 tab

  12. Theoretical investigation of compounds with triple bonds

    International Nuclear Information System (INIS)

    In this thesis, compounds with potential triple-bonding character involving the heavier main-group elements, Group 4 transition metals, and the actinides uranium and thorium were studied by using molecular quantum mechanics. The triple bonds are described in terms of the individual orbital contributions (σ, π parallel, and π perpendicular to), involving electron-sharing covalent or donor-acceptor interactions between the orbitals of two atoms or fragments. Energy decomposition, natural bond orbital, and atoms in molecules analyses were used for the bonding analysis of the triple bonds. The results of this thesis suggest that the triple-bonding character between the heavier elements of the periodic table is important and worth further study and exploration.

  13. Triple fixation of Bacillus subtilis dormant spores.

    OpenAIRE

    Kozuka, S; Tochikubo, K

    1983-01-01

    A triple-fixation method with a sequential application of 5% glutaraldehyde, 1% osmium tetroxide, and 2% potassium permanganate gave superior preservation of the ultrastructure of Bacillus subtilis dormant spores with a thick spore coat.

  14. The graded product of real spectral triples

    CERN Document Server

    Farnsworth, Shane

    2016-01-01

    Forming the product of two geometric spaces is one of the most basic operations in geometry, but in the spectral-triple formulation of non-commutative geometry, the standard prescription for taking the product of two real spectral triples is problematic: among other drawbacks, it is non-commutative, non-associative, does not transform properly under unitaries, and often fails to define a proper spectral triple. In this paper, we explain that these various problems result from using the ungraded tensor product; by switching to the graded tensor product, we obtain a new prescription where all of the earlier problems are neatly resolved: in particular, the new product is commutative, associative, transforms correctly under unitaries, and always forms a well defined spectral triple.

  15. A COMPARATIVE STUDY OF HELICOBACTER PYLORI, BIOPSY SAMPLES FROM DIFFERENT GASTRIC LESIONS WITH TRIPLE STAINING AND MODIFIED GIEMSA STAINING

    OpenAIRE

    Pavan Kumar Pindi

    2013-01-01

    Helicobacter pylori are associated with most of the disorders of gastro-duodenal tract, such as gastritis, gastric ulcers, dyspepsia and gastric carcinoma. Many staining methods have been developed for the detection of these bacteria from gastric biopsies. However most of the methods adopted were shown to be more expensive, less sensitive, time consuming with less background information. In view of this, the present study was carried out to check the validity of triple staining method against...

  16. Theoretical Investigation of Compounds with Triple Bonds

    OpenAIRE

    Devarajan, Deepa

    2011-01-01

    In this thesis, compounds with potential triple-bonding character involving the heavier main-group elements, Group 4 transition metals, and the actinides uranium and thorium were studied by using molecular quantum mechanics. The triple bonds are described in terms of the individual orbital contributions (σ, π||, and π┴), involving electron-sharing covalent or donor–acceptor interactions between the orbitals of two atoms or fragmen...

  17. Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study

    OpenAIRE

    Croner, R.S.; Geppert, C-I; Bader, F G; Nitsche, U.; Späth, C; Rosenberg, R.; Zettl, A.; Matias-Guiu, X; Tarragona, J; Güller, U.; Stürzl, M; Zuber, M

    2014-01-01

    Background: Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in ∼20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node...

  18. Carcinoma vulvar

    Directory of Open Access Journals (Sweden)

    Yamit Peñas Zayas

    2015-11-01

    Full Text Available El carcinoma de la vulva tiene una incidencia de aproximadamente un 3-5% dentro de todas las enfermedades ginecológicas malignas. El 90% de los tumores malignos de la vulva está constituido por carcinoma epidermoide, el resto son adenocarcinomas, carcinomas de células basales y melanomas. Se realiza la presentación de un caso de una paciente femenina de 25 años de edad con antecedentes  de Diabetes Mellitus tipo II y trombopatia, que ingresa en el servicio de ginecología con un cuadro cutáneo polimorfo, localizado en labios mayores y menores, dado por lesiones eritematoerosivas y vegetante, sospechándose clínicamente el diagnóstico  de un carcinoma epidermoide, corroborándose el mismo histológicamente al realizarse biopsia de piel. Se indicó tratamiento con quimioterapia. Por la edad de la paciente y ser menos frecuente en mucosa que en la piel,  motivo la presentación del caso.

  19. Parathyroid carcinoma

    DEFF Research Database (Denmark)

    Qvist, N; Krøll, L; Ladefoged, C;

    1986-01-01

    Parathyroid carcinoma is a slow growing tumor, and the patients most often die from complications to the hypercalcemia. Therefore, any attempt should be made to remove local recurrence and metastasis surgically, as medical treatment is disappointing. A case treated with extensive vascular surgery...

  20. Cyclin D1 expression in ductal carcinoma of the breast and its correlation with other prognostic parameters

    Directory of Open Access Journals (Sweden)

    Gayatri Ravikumar

    2014-01-01

    Full Text Available Purpose: Cyclin D1 is a cell cycle regulatory gene emerging as a potentially significant oncogene in invasive breast cancers. In this study, we attempted to see the expression of Cyclin D1 in invasive ductal carcinomas of the breast in our population and correlate its expression with other known prognostic parameters. Materials and Methods: A total of 39 cases were selected from our case files from January 2011. Immunohistochemistry for Cyclin D1 was performed and interpreted as positive when >10% of the tumor cells expressed the marker with a moderate to strong intensity of staining. Clinicopathological parameters such as laterality, focality, tumor size, grade, ductal carcinoma in situ (DCIS, axillary lymph node (ALN metastasis, hormone receptor status and human epidermal growth factor receptor 2 status were analyzed and correlated with Cyclin D1 expression. Results: The patients′ age ranged from 30 to 76 years (mean = 53.18. The tumors were unilateral and unifocal in 38 cases; one patient had bilateral synchronous tumors. The majority were grade2 (67.5% and tumor size T2 (57.5%. Nearly 35% were associated with DCIS and 57.5% had ALN metastasis. Estrogen receptors (ER and progesterone receptor (PgR positivity was seen in 65% of the cases and 25% was triple negative. Cyclin D1 expression was seen in 67.5% of the cases in our study. Among the ER, PgR positive and Her-2 negative tumors, Cyclin D1 expression was seen in the majority of cases (92% cases, whereas none of the triple negative tumors showed Cyclin D1 expression. The other prognostic parameters such as tumor size, grade and lymph node status did not show any association with Cyclin D 1 positivity. Conclusions: Cyclin D1 expression was seen in 67.5% of ductal carcinoma and it showed a significant correlation with ER, PgR expression (92% in this study, which is in concordance with other similar studies in literature.

  1. Medullary carcinoma of thyroid

    Science.gov (United States)

    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC ... The cause of medullary carcinoma of the thyroid (MTC) is unknown. Unlike other types of thyroid cancer, MTC is less likely to be caused by radiation therapy to the neck given ...

  2. Basal Cell Carcinoma (BCC)

    Science.gov (United States)

    ... epithelioma, is the most common form of skin cancer. Basal cell carcinoma usually occurs on sun-damaged skin, especially ... other health issues. Infiltrating or morpheaform basal cell carcinomas: Infiltrating basal cell carcinomas can be more aggressive and locally destructive ...

  3. Building a Distributed Infrastructure for Scalable Triple Stores

    Institute of Scientific and Technical Information of China (English)

    Jing Zhou; Wendy Hall; David De Roure

    2009-01-01

    Built specifically for the Semantic Web, triple stores are required to accommodate a large number of RDF triples and remain primarily centralized. As triple stores grow and evolve with time, there is a demanding need for scalable techniques to remove resource and performance bottlenecks in such systems. To this end, we propose a fully decentralized peer-to-peer architecture for large scale triple stores in which triples are maintained by individual stakeholders, and a semantics-directed search protocol, mediated by topology reorganization, for locating triples of interest. We test our design through simulations and the results show anticipated improvements over existing techniques for distributed triple stores. In addition to engineering future large scale triple stores, our work will in particular benefit the federation of stand-alone triple stores of today to achieve desired scalability.

  4. On Split Lie Triple Systems II

    Indian Academy of Sciences (India)

    Antonio J Calderón Martín; M Forero Piulestán

    2010-04-01

    In [4] it is studied that the structure of split Lie triple systems with a coherent 0-root space, that is, satisfying $[T_0,T_0,T]=0$ and $[T_0,T_,T_0]≠ 0$ for any nonzero root and where $T_0$ denotes the 0-root space and $T_$ the -root space, by showing that any of such triple systems with a symmetric root system is of the form $T=\\mathcal{U}+\\sum_j I_j$ with $\\mathcal{U}$ a subspace of the 0-root space $T_0$ and any $I_j$ a well described ideal of , satisfying $[I_j,T,I_k]=0$ if $j≠ k$. It is also shown in [4] that under certain conditions, a split Lie triple system with a coherent 0-root space is the direct sum of the family of its minimal ideals, each one being a simple split Lie triple system, and the simplicity of is characterized. In the present paper we extend these results to arbitrary split Lie triple systems with no restrictions on their 0-root spaces.

  5. Dynamical states of nearly triple stars

    International Nuclear Information System (INIS)

    The classification of dynamical states has been proposed for triple systems; the most important of their characteristics is the total energy Etr and the relative pair energies Eb of the bodies in these systems. For eight triple stars (ADS 1630, 2926, 6175, 6650, 6811, 7114, 9626 and 9909 with the observation data possessing greater accuracy) probabilities of the dynamical states and the values Etr ± σEtr and Eb ± σEb have been obtained by statistical tests. Only three triple stars, namely ADS 1630 (r ∼ 80 pc), 6175 (r ∼ 14 pc) and 9909 (r ∼ 22 pc), appear to be certain physical systems. The last two systems with a probability P > 0.80 are dynamically unhierachial non-stable triple systems with a complicate motion of the components; the final state of these systems is the state of ''escape''. In the triple system ADS 1630 the qualitative course of the component motions has not been determined because of large errors in the observational data

  6. Cytokeratin 7-negative mammary Paget's disease: A diagnostic pitfall.

    Science.gov (United States)

    Ozerdem, Ugur; McNiff, Jennifer M; Tavassoli, Fattaneh A

    2016-04-01

    Pathologists should be aware of the existence of a rare CK7-negative variant of breast carcinoma in general, and of Paget's disease in particular. Cytokeratin 7-negative Paget's disease and CK7-negative ductal intraepithelial neoplasia (ductal carcinoma in situ) present a major diagnostic challenge for pathologists since there is limited awareness of their existence. When there is classic Paget's morphology on H&E sections, GATA3 positivity should resolve any doubts about the diagnosis in the setting of a CK7-negative neoplastic cell population. PMID:26944832

  7. Carcinomas mamários de tipo basal: perfil clínico-patológico e evolutivo Basal-like breast cancers: clinicopathological features and outcome

    Directory of Open Access Journals (Sweden)

    Marina De Brot

    2009-01-01

    Full Text Available OBJETIVO: Investigar a frequência de carcinomas mamários de fenótipo basal em uma série de tumores triplo-negativos (TTN, definidos pela negatividade para receptores de estrógeno (RE, de progesterona (RP e HER2. MÉTODOS: Selecionamos 140 TTN, obtendo-se características clínico-patológicas e sobrevida. Microarranjo de tecido (2 cilindros de cada tumor foi construído e submetido à imunoistoquímica para RE, RP, HER2, citoqueratinas (Cks 5 e 14, EGFR, p63 e p53. Consideramos carcinomas de fenótipo basal os tumores negativos para RE, RP e HER2, e positivos para CK5. RESULTADOS: Encontramos 105 carcinomas de fenótipo basal entre 140 TTN (frequência=75%. A idade média das pacientes foi de 54,8 anos, sendo que 34,3% estavam na pré-menopausa. A maioria dos tumores foi classificada como carcinoma ductal invasor de alto grau. Os TTN exibiram positividade para CK5 (75,0%, CK14 (29%, EGFR (36,4%, p63 (28,6% e p53 (67,1%. Estadiamento avançado da doença foi observado em 52 pacientes (50%, com diâmetro tumoral maior que 5 cm em 41 casos (39% e metástases axilares em 61 casos (59,2%. Seguimento clínico foi obtido em 89 pacientes (média=51 meses. Destas, 45 pacientes (50,5% evoluíram sem doença; 6 (6,7% estavam vivas com doença e 38 (42,6% morreram pelo câncer. Recidiva sistêmica ocorreu em 42 pacientes (47,1%, sendo pulmões, cérebro e ossos os principais sítios de metástases. As médias das sobrevidas global e livre de doença foram de 36 e 28 meses, respectivamente. CONCLUSÕES: Nosso estudo confirma comportamento clínico agressivo e elevada frequência dos carcinomas de fenótipo basal entre os TTN, semelhante ao descrito em casuísticas norte-americanas e europeias.OBJECTIVE: The aim of our study was to investigate basal phenotype in a series of triple-negative (estrogen and progesterone receptors-negative and HER2-negative invasive mammary carcinomas. METHODS: We selected 140 previously tested triple-negative tumors

  8. H pylori eradication:A randomized prospective study of triple therapy with or without ecabet sodium

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM:To investigate whether adding ecabet sodium to the standard triple therapy for Hpylori infection improve eradication rate.METHODS:Two hundred and fifty-seven H pyloriinfected patients were randomly assigned to standard triple therapy (group A, n=129) or triple therapy plus ecabet sodium(group B, n=128).Successful eradication was defined as a negative 13C-urea breath test 6-8 wk after completion of treatment.RESULTS:After completion of therapy,194/257 patients showed negative 13C-urea breath test results.According to intention-to-treat analysis,the infection was eradicated in 93/129(72.1%)patients in group A and 101/128 (78.9%) in group B (P=0.204).Per-protocol analysis showed successful eradication in 93/118(78.8%)patients from group A and 101/114 (88.6%) from group B (P = 0.044).There were no significant differences in the side effects experienced by the patients in the two treatment groups.CONCLUSION:Our results suggest that the addition of ecabet sodium improves the efficacy of the standard triple therapy for H pylori.

  9. CLINICO PATHOLOGICAL STUDY OF CARCINOMA BREAST: A PROSPECTIVE STUDY

    Directory of Open Access Journals (Sweden)

    Madhu Shankar

    2015-12-01

    Full Text Available BACKGROUND Breast cancer is the most frequently diagnosed cancer in women and the second most cause of death in cancer. Over the past several decades there has been increase in incidence of the disease. Analysis of the incidence, clinical presentations, various risk factors, accuracy of FNAC and frozen section, incidence of various pathological types, stage at presentation and ER, PR, HER-2/neu status. METHODS In this prospective study, 51 consecutive patients who were diagnosed to have carcinoma breast admitted between April 2013 to April 2014 in the Department of Surgery, Rajarajeshwari Hospital, Bangalore, were included in the study. A detailed clinical history was elicited from all patients at the time of admission. All patients who had triple assessment evidence of malignancy were worked up for surgery with necessary investigations. Written consent was obtained from each patient for surgery. After data collection, it was checked, verified, edited manually for consistency to reduce error. Descriptive and graphical methods were used in analysing the data. The important variables were considered and analysed to fulfil the objective of the study. RESULTS In our study, the incidence of carcinoma breast is 5.6 per 1000, 32% of them were between 41-50 year age group, 63.3% had early menarche, 14.3% were nulliparous. Nearly 84.3% of them presented with lump of which 54% left sided involving upper outer quadrant 54.9%. Most cases belong to stage II and stage III at the time of presentation. FNAC was done in all cases with accuracy rate of 82.4%, followed by frozen section which showed about 71.4% of accuracy for those false negative cases. CONCLUSION Various risk factors in relation to breast carcinoma have been proved. As most of the cases presented late in our series because of lack of awareness, proper awareness and early screening by breast self-examination and mammogram should be emphasized. FNAC proved to be a simple and reliable procedure

  10. Drop evaporation and triple line dynamics

    Science.gov (United States)

    Sobac, Benjamin; Brutin, David; Gavillet, Jerome; Université de Provence Team; Cea Liten Team

    2011-03-01

    Sessile drop evaporation is a phenomenon commonly came across in nature or in industry with cooling, paintings or DNA mapping. However, the evaporation of a drop deposited on a substrate is not completely understood due to the complexity of the problem. Here we investigate, with several nano-coating of the substrate (PTFE, SiOx, SiOc and CF), the influence of the dynamic of the triple line on the evaporation process. The experiment consists in analyzing simultaneously the motion of the triple line, the kinetics of evaporation, the internal thermal motion and the heat and mass transfer. Measurements of temperature, heat-flux and visualizations with visible and infrared cameras are performed. The dynamics of the evaporative heat flux appears clearly different depending of the motion of the triple line

  11. Fascin Expression in Invasive Ductal Carcinoma of Breast

    OpenAIRE

    Gülgün ERDOĞAN; H. Elif PEŞTERELİ; Taner ÇOLAL; F. Şeyda KARAVELİ; Mustafa AKAYDIN

    2010-01-01

    Objective: Fascin is an actin-binding protein that regulates the rearrangement of cytoskeletal elements. It takes part in the formation of cellular membrane protrusions and in cell motility. It is upregulated in several types of carcinomas.Material and Method: We examined the expression of fascin in the invasive ductal carcinomas whether lymph node negative (n=16) or lymph node positive (n=16) and in metastatic lymph nodes, microinvasion + invasive ductal carcinoma with extensive in situ comp...

  12. Normalization for triple-target microarray experiments

    Directory of Open Access Journals (Sweden)

    Magniette Frederic

    2008-04-01

    Full Text Available Abstract Background Most microarray studies are made using labelling with one or two dyes which allows the hybridization of one or two samples on the same slide. In such experiments, the most frequently used dyes are Cy3 and Cy5. Recent improvements in the technology (dye-labelling, scanner and, image analysis allow hybridization up to four samples simultaneously. The two additional dyes are Alexa488 and Alexa494. The triple-target or four-target technology is very promising, since it allows more flexibility in the design of experiments, an increase in the statistical power when comparing gene expressions induced by different conditions and a scaled down number of slides. However, there have been few methods proposed for statistical analysis of such data. Moreover the lowess correction of the global dye effect is available for only two-color experiments, and even if its application can be derived, it does not allow simultaneous correction of the raw data. Results We propose a two-step normalization procedure for triple-target experiments. First the dye bleeding is evaluated and corrected if necessary. Then the signal in each channel is normalized using a generalized lowess procedure to correct a global dye bias. The normalization procedure is validated using triple-self experiments and by comparing the results of triple-target and two-color experiments. Although the focus is on triple-target microarrays, the proposed method can be used to normalize p differently labelled targets co-hybridized on a same array, for any value of p greater than 2. Conclusion The proposed normalization procedure is effective: the technical biases are reduced, the number of false positives is under control in the analysis of differentially expressed genes, and the triple-target experiments are more powerful than the corresponding two-color experiments. There is room for improving the microarray experiments by simultaneously hybridizing more than two samples.

  13. The triple point of sulfur hexafluoride

    Science.gov (United States)

    Rourke, P. M. C.

    2016-04-01

    A cryogenic fixed point cell has been filled with high purity (99.999%) sulfur hexafluoride (SF6) and measured in an adiabatic closed-cycle cryostat system. Temperature measurements of the SF6 melting curve were performed using a capsule-type standard platinum resistance thermometer (CSPRT) calibrated over the International Temperature Scale of 1990 (ITS-90) subrange from the triple point of equilibrium hydrogen to the triple point of water. The measured temperatures were corrected by 0.37 mK for the effects of thermometer self-heating, and the liquidus-point temperature estimated by extrapolation to melted fraction F  =  1 of a simple linear regression versus melted fraction F in the range F  =  0.53 to 0.84. Based on this measurement, the temperature of the triple point of sulfur hexafluoride is shown to be 223.555 23(49) K (k  =  1) on the ITS-90. This value is in excellent agreement with the best prior measurements reported in the literature, but with considerably smaller uncertainty. An analysis of the detailed uncertainty budget of this measurement suggests that if the triple point of sulfur hexafluoride were to be included as a defining fixed point of the next revision of the International Temperature Scale, it could do so with a total realization uncertainty of approximately 0.43 mK, slightly larger than the realization uncertainties of the defining fixed points of the ITS-90. Since the combined standard uncertainty of this SF6 triple point temperature determination is dominated by chemical impurity effects, further research exploring gas purification techniques and the influence of specific impurity species on the SF6 triple point temperature may bring the realization uncertainty of SF6 as a fixed point material into the range of the defining fixed points of the ITS-90.

  14. Krein Spectral Triples and the Fermionic Action

    Science.gov (United States)

    van den Dungen, Koen

    2016-03-01

    Motivated by the space of spinors on a Lorentzian manifold, we define Krein spectral triples, which generalise spectral triples from Hilbert spaces to Krein spaces. This Krein space approach allows for an improved formulation of the fermionic action for almost-commutative manifolds. We show by explicit calculation that this action functional recovers the correct Lagrangians for the cases of electrodynamics, the electro-weak theory, and the Standard Model. The description of these examples does not require a real structure, unless one includes Majorana masses, in which case the internal spaces also exhibit a Krein space structure.

  15. Spindle cell carcinoma of the breast as complex cystic lesion:a case report

    Institute of Scientific and Technical Information of China (English)

    Masahiro Kitada; Satoshi Hayashi; Yoshinari Matsuda; Kei Ishibashi; Keisuke Oikawa; Naoyuki Miyokawa

    2014-01-01

    Spindle cell carcinoma of the breast is a rare tumor. hTis tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography (US) revealed a complex cystic lesion, and ifne-needle aspiration (FNA) cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin (AE1/AE3) and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) were administered. Radiotherapy was performed. hTis case is discussed with reference to the literature.

  16. Hypertrophic osteopathy associated with hepatocellular carcinoma in a dog

    OpenAIRE

    Randall, Victoria D.; Souza, Carlos; Vanderhart, Daniel; Boston, Sarah

    2015-01-01

    A 9-year-old spayed female dog diagnosed with hepatocellular carcinoma and hypertrophic osteopathy was negative for additional lesions on computed tomography of the thorax and abdomen. Resection of the affected liver lobe resulted in resolution of clinical signs. This is the first case of hypertrophic osteopathy secondary to hepatocellular carcinoma.

  17. New inequalities of Ostrowski and Gruss type for triple integrals

    OpenAIRE

    B. G. Pachpatte

    2009-01-01

    In the present paper we establish new inequalities of Ostrowski and Gruss type for triple integrals involving three functions and their partial derivatives. The discrete Ostrowski and Gruss type inequalities for triple sums are also given.

  18. New inequalities of Ostrowski and Gruss type for triple integrals

    Directory of Open Access Journals (Sweden)

    B. G. Pachpatte

    2009-06-01

    Full Text Available In the present paper we establish new inequalities of Ostrowski and Gruss type for triple integrals involving three functions and their partial derivatives. The discrete Ostrowski and Gruss type inequalities for triple sums are also given.

  19. MEIR-KEELER TYPE CONTRACTIONS FOR TRIPLED FIXED POINTS

    Institute of Scientific and Technical Information of China (English)

    Hassen Aydi; Erdal Karapinar; Calogero Vetro

    2012-01-01

    In 2011,Berinde and Borcut [6] introduced the notion of tripled fixed point in partially ordered metric spaces.In our paper,we give some new tripled fixed point theorems by using a generalization of Meir-Keeler contraction.

  20. Thyroid carcinoma

    International Nuclear Information System (INIS)

    Differentiated thyroid carcinoma was studied with regard to mode of presentation, initial findings, treatment and survival. The classic signs, symptoms, physical and scan findings were found to be present in approximately 70% of the patients. Prognosis was found to be dependent on age of presentation more than any other factor. Patients with prior exposure to radiation were found to have more extensive disease and require more extensive surgery but ultimately had the same prognosis for 15-year cure. Treatment for distant metastatic disease by surgery, radioactive iodine and external radiation all resulted in long-term survival in certain cases

  1. Resolution of a triple axis spectrometer

    DEFF Research Database (Denmark)

    Nielsen, Mourits; Bjerrum Møller, Hans

    A new method for obtaining the resolution function for a triple-axis neutron spectrometer is described, involving a combination of direct measurement and analytical calculation. All factors which contribute to the finite resolution of the instrument may be taken into account, and Gaussian or...

  2. Triple-axis spectrometer DruechaL

    International Nuclear Information System (INIS)

    DruechaL is a triple-axis spectrometer located at a cold guide. The characteristics of guide and instrument allow the use of a broad spectral range of neutrons. The resolution in momentum and energy transfer can be tuned to match the experimental requirements by using either collimators or focusing systems (monochromator, antitrumpet, analyser). (author) figs., tabs., refs

  3. Triple mode filters with coaxial excitation

    NARCIS (Netherlands)

    Gerini, G.; Bustamante, F.D.; Guglielmi, M.

    2004-01-01

    In this paper we describe triple mode filters in a square waveguide with integrated coaxial input/output excitation. An important feature of the structure proposed is that it is easily amenable to an accurate full wave analysis. In addition to theory, a practical six pole filter with two transmissio

  4. Detecting triple systems with gravitational wave observations

    CERN Document Server

    Meiron, Yohai; Loeb, Abraham

    2016-01-01

    The Laser Interferometer Gravitational Wave Observatory (LIGO) has recently discovered gravitational waves (GWs) emitted by merging black hole binaries. We examine whether future GW detections may identify triple companions of merging binaries. Such a triple companion causes variations in the GW signal due to (1) the varying path length along the line of sight during the orbit around the center of mass, (2) relativistic beaming, Doppler, and gravitational redshift, and (3) the variation of the "light"-travel time in the gravitational field of the triple companion, known respectively as Roemer-, Einstein-, and Shapiro-delays in pulsar binaries. We find that the prospects for detecting the triple companion are the highest for low-mass compact object binaries which spend the longest time in the LIGO frequency band with circular orbits. In particular, for merging neutron star binaries, LIGO may detect a white dwarf or M-dwarf perturber at signal to noise ratio of 8, if it is within 0.4 solar radius distance from ...

  5. Overcoming the triple hurdle of diversity management

    OpenAIRE

    Ruigrok, Winfried

    2012-01-01

    Diversity management is a key instrument to position a company as a preferred employer. Fail to recite this mantra and you risk losing the attention of the majority of young graduates in Europe today. Explore the triple hurdle of diversity management that companies need to overcome in order to successfully develop their diversity management policies.

  6. Triple-axis spectrometer DruechaL

    Energy Technology Data Exchange (ETDEWEB)

    Buehrer, W.; Keller, P. [Lab. for Neutron Scattering ETH Zurich, Zurich (Switzerland) and Paul Scherrer Institute, Villigen (Switzerland)

    1996-11-01

    DruechaL is a triple-axis spectrometer located at a cold guide. The characteristics of guide and instrument allow the use of a broad spectral range of neutrons. The resolution in momentum and energy transfer can be tuned to match the experimental requirements by using either collimators or focusing systems (monochromator, antitrumpet, analyser). (author) figs., tabs., refs.

  7. Construction of Pure Mendelsohn Triple Systems

    Institute of Scientific and Technical Information of China (English)

    XIA Xing-wu; SHEN Hao

    2005-01-01

    This paper determined the existence of λ-fold pure Mendelsohn triple system of order v satisfying λv(v-1)≡0 (mod 3) and v≥4λ+5, or v=2λ+2, and in the caseof λ=4,5,6,which completely settled their existence.

  8. Real structures on almost-commutative spectral triples

    OpenAIRE

    Ćaćić, Branimir

    2012-01-01

    We refine the reconstruction theorem for almost-commutative spectral triples to a result for real almost-commutative spectral triples, clarifying, in the process, both concrete and abstract definitions of real commutative and almost-commutative spectral triples. In particular, we find that a real almost-commutative spectral triple algebraically encodes the commutative *-algebra of the base manifold in a canonical way, and that a compact oriented Riemannian manifold admits real (almost-)commut...

  9. A reconstruction theorem for almost-commutative spectral triples

    OpenAIRE

    Ćaćić, Branimir

    2012-01-01

    We propose an expansion of the definition of almost-commutative spectral triple that accommodates non-trivial fibrations and is stable under inner fluctuation of the metric, and then prove a reconstruction theorem for almost-commutative spectral triples under this definition as a simple consequence of Connes's reconstruction theorem for commutative spectral triples. Along the way, we weaken the orientability hypothesis in the reconstruction theorem for commutative spectral triples, and follow...

  10. Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

    Science.gov (United States)

    Conde, João; Oliva, Nuria; Atilano, Mariana; Song, Hyun Seok; Artzi, Natalie

    2016-03-01

    The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs--a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)--provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

  11. Classification of solvable 3-dimensional Lie triple systems

    OpenAIRE

    Bouetou, Thomas Bouetou

    2003-01-01

    We give the classification of solvable and splitting Lie triple system and it turn that, up to isomorphism there exist 7 non isomorphic canonical Lie triple systems and 6 non isomorphic splitting canonical Lie triple systems and find the solvable Lie algebras associated.

  12. CATHEPSIN B EXPRESSION AND ITS RELATIONSHIP WITH MICROVESSEL DENSITY AND BIOLOGICAL BEHAVIOUR OF COLORECTAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    王娅兰; 林晓

    2002-01-01

    Objective: To investigate cathepsin B(CB) expression in colorectal carcinoma and its relationship with microvessel density (MVD) and biological behavior. Methods: CB and MVD were detected by immunohistochemistry in 47 cases of colorectal carcinoma. Results: The expression of CB in mucinous colorectal carcinoma was significantly higher than that in no-mucinous colorectal carcinoma. There was significant difference (P<0.05). The MVD in group with positive CB was stronger than that in group with negative CB. There was also significant difference (P<0.05). Conclusion: The results suggest that CB expression has correlation with MVD, invasion and metastasis in colorectal carcinoma, especially in mucinous colorectal carcinoma.

  13. Carcinoma verrugoso

    Directory of Open Access Journals (Sweden)

    Esteban Quesada Jiménez

    2004-09-01

    Full Text Available Se presenta el caso de un paciente masculino de 76 años, vecino de Turrialba, agricultor, que consultó por una lesión de 3 años de evolución, localizada en la palma de la mano derecha a nivel palmar y compromiso de los dedos de la misma mano, caracterizada como una neoformación exofítica verrugosa de 5 por 11 cm. aproximadamente, con material caseoso entre sus crestas. La lesión ha estado creciendo de forma acelerada en los últimos 3 meses, causándole dolor y que le imposibilita ellaborar. Se le realizaron exámenes y se descartaron varias causas infecciosas, y concluyendo luego de varias biopsias con el diagnóstico de un carcinoma verrugoso. El paciente fue tratado mediante una amputación parcial de la mano. Este tumor es una variante del carcinoma epidermoide y presentamos su clasificación, patogénesis, histopatología, manifestaciones clínicas más frecuentes y diagnóstico diferencial.

  14. Salivary duct carcinoma of the parotid gland

    Directory of Open Access Journals (Sweden)

    Mona Mlika

    2012-01-01

    Full Text Available Salivary duct carcinoma of the parotid gland is an uncommon tumor, highly aggressive. About 200 cases have been reported in the English literature. Pathomorphologically, these tumors showed great similarities to ductal carcinoma of the female breast, which is why they described this tumor as "salivary duct carcinoma." The authors describe a new case of salivary duct carcinoma of the parotid gland. We present the case of a 50-year-old patient with progressive facial paralysis. The MRI examination of the head showed two ill-defined formations. A malignant tumor was strongly suspected, so that a total left parotidectomy with excision of the adjacent facial nerve and left lymph node dissection was performed. Microscopic examination concluded to a salivary duct carcinoma of the left parotid gland negative with Her2/neu antibody with lymph node metastasis. There were no recurrences or metastases within 3 years of follow-up. Salivary duct carcinoma of the parotid gland is a rare tumor with an aggressive behavior. This is due to its propensity to infiltrate distant organs. The diagnosis is based on microscopic examination. Treatment modalities are non-consensual, but some authors advocate the necessity of aggressive approach, especially in tumors negative with Heur2/neu antibody. This is due to the fact that the overexpression of this antigen was reported to be associated with a poor prognosis.

  15. Chromophobe Renal Cell Carcinoma

    OpenAIRE

    Jyotsna Vijaykumar Wader; Sujata S Kumbhar; Huddedar AD; Wasim GM Khatib

    2013-01-01

    Renal cell carcinoma is the most common neoplasm of the kidney comprised of different histological variants. Chromophobe renal cell carcinoma (ChRCC) is a rare subtype of renal cell carcinoma (RCC) mainly diagnosed in the sixth decade of life. It is important to identify this entity because it has significantly better prognosis than the clear cell (conventional) and papillary renal cell carcinomas. The chromophobe renal cell carcinoma should be differentiated from oncocytoma and clear cell ca...

  16. A COMPARATIVE STUDY OF HELICOBACTER PYLORI, BIOPSY SAMPLES FROM DIFFERENT GASTRIC LESIONS WITH TRIPLE STAINING AND MODIFIED GIEMSA STAINING

    Directory of Open Access Journals (Sweden)

    Pavan Kumar Pindi

    2013-02-01

    Full Text Available Helicobacter pylori are associated with most of the disorders of gastro-duodenal tract, such as gastritis, gastric ulcers, dyspepsia and gastric carcinoma. Many staining methods have been developed for the detection of these bacteria from gastric biopsies. However most of the methods adopted were shown to be more expensive, less sensitive, time consuming with less background information. In view of this, the present study was carried out to check the validity of triple staining method against modified Giemsa staining. For this study, 60 biopsy specimens were selected from different gastric lesions as chronic gastritis (30, gastric ulcers (10 and gastric carcinoma (20. These specimens were subjected to modified Giemsa staining showed purple to dark purple bacteria with bluish background. The results showed 56.66, 40 and 15 percentage positivity for chronic gastritis, benign gastric ulcers and malignant gastric lesions, respectively. The stained sections of triple staining showed black to dark brown bacteria with pink colored background with 70, 50 and 10 percentage positivity for chronic gastritis, benign gastric ulcers and malignant gastric lesions, respectively. From the present study it is clear that triple staining method is more sensitive than the modified Giemsa staining.

  17. Comparison of nuclear grade and immunohistochemical features in situ and invasive components of ductal carcinoma of breast Comparação do grau nuclear e perfil imunoistoquímico nos componentes in situ e invasivo de carcinoma mamário

    Directory of Open Access Journals (Sweden)

    Fernando Nalesso Aguiar

    2013-03-01

    Full Text Available PURPOSE:To compare the prognostic and predictive features between in situ and invasive components of ductal breast carcinomas. METHODS:We selected 146 consecutive breast samples with ductal carcinoma in situ (DCIS associated with adjacent invasive breast carcinoma (IBC. We evaluated nuclear grade and immunohistochemical expression of estrogen receptor (ER, progesterone receptor (PR, human epidermal growth factor receptor 2 (HER2, cytokeratin 5/6 (CK5/6, and epidermal growth factor receptor (EGFR in both components, in situ and invasive, and the Ki-67 percentage of cells in the invasive part. The DCIS and IBC were classified in molecular surrogate types determined by the immunohistochemical profile as luminal (RE/PR-positive/ HER2-negative, triple-positive (RE/RP/HER2-positive, HER2-enriched (ER/PR-negative/HER2-positive, and triple-negative (RE/RP/HER2-negative. Discrimination between luminal A and luminal B was not performed due to statistical purposes. Correlations between the categories in the two groups were made using the Spearman correlation method. RESULTS:There was a significant correlation between nuclear grade (pOBJETIVO: Comparar características prognósticas e preditivas entre os componentes in situ e invasivo de carcinomas ductais da mama. MÉTODOS: Selecionamos 146 amostras mamárias consecutivas com carcinoma ductal in situ (CDIS associado com carcinoma invasivo (CI adjacente. Avaliamos grau nuclear e a expressão imunoistoquímica de receptor de estrogênio (RE, receptor de progesterona (RP, receptor do fator de crescimento epidérmico humano 2 (HER2, citoqueratina 5/6 (CK5/6 e o receptor do fator de crescimento epidérmico (EGFR em ambos componentes, in situ e invasor, e a porcentagem de células marcadas pelo Ki-67 no componente invasivo. CDIS e CI foram classificados nos tipos moleculares, determinados pelo perfil imunoistoquímico, como luminal (RE/RP-positivo/HER2-negativo, triplo-positivo (RE/RP/HER2-positivo, HER2-puro

  18. 心灵关怀对放化疗联合治疗鼻咽癌患者负性情绪与生活质量的影响%Effects of mind and heart care on negative emotions and quality of life in nasopharyngeal carcinoma patients undergoing radiotherapy and chem-otherapy

    Institute of Scientific and Technical Information of China (English)

    戴叶花; 侯爱和; 瞿舒培

    2012-01-01

    目的 探讨心灵关怀对鼻咽癌患者负性情绪及生活质量的影响.方法 将92例鼻咽癌治疗患者分为对照组47例和干预组45例.对照组给予常规护理,干预组在常规护理基础上实施心灵关怀护理.采用医院焦虑抑郁量表、欧洲癌症患者生活质量调查问卷分别在患者人院时、入院4周和人院8周进行问卷调查.结果 干预组焦虑、抑郁水平低于对照组(P<0.01),总体生活质量优于对照组(P<0.05).结论 心灵关怀能有效缓解鼻咽癌患者的焦虑、抑郁情绪,改善其生活质量,为肿瘤的治疗康复护理提供了新的思路.%Objective To determine the effects of mind and heart care on negative emotions and quality of life in nasopharyngeal carcinoma patients. Methods A total of 92 nascpharyngeal carcinoma patients were divided into control group ( 47 cases) and intervention group (45 cases). The control group received routine care,and the intervention group received mind and heart cane in addition. The Hospital Anxiely) and Depression Scale ( HAD) ,European Organization for Research and Treatment of Cancer Quality of Life Core Questionmaire were used to collect data before intervention, after 4 weeks and 8 weeks later. Results After intervention,the scores of anxiety and depression in the intervention group were significantly lower than the control group(P<0.01) ,and the o-verall quality of life was significantly higher than the control group (P < 0.05 ). Conclusion Mind and heart care can effectively relieve anxiety and depression of nasopharyngeal carcinoma patients,improve their quality of life,and provide a new method for the treatment and rehabilitation of tumor.

  19. Plasmacytoid urothelial carcinoma of the bladder: a case report

    OpenAIRE

    Aldousari, Saad; Sircar, Kanishka; Kassouf, Wassim

    2009-01-01

    Plasmacytoid bladder cancer is a rare variant of transitional cell carcinoma. A 57-year-old man was referred to our institution for management of invasive transitional cell carcinoma diagnosed at a peripheral hospital. His complaints were of vague lower abdominal pain with associated urgency and frequency requiring oxybutynin. Metastatic workup was negative and was subsequently scheduled for a radical cystectomy. Routine colonoscopy 3 weeks prior to surgery was negative. Intraoperatively, he ...

  20. Triple-Error-Correcting BCH-Like Codes

    OpenAIRE

    Bracken, Carl; Helleseth, Tor

    2009-01-01

    The binary primitive triple-error-correcting BCH code is a cyclic code of minimum distance 7 with generator polynomial having zeros $\\alpha$, $\\alpha^3$ and $\\alpha^5$ where $\\alpha$ is a primitive root of unity. The zero set of the code is said to be {1,3,5}. In the 1970's Kasami showed that one can construct similar triple-error-correcting codes using zero sets consisting of different triples than the BCH codes. Furthermore, in 2000 Chang et. al. found new triples leading to triple-error-co...

  1. Vulvar carcinoma

    International Nuclear Information System (INIS)

    Purpose: Controversies exist regarding the use of radiation therapy in the treatment of vulvar carcinoma. A retrospective review was performed to evaluate our institution's experience with surgery and radiation for this disease. Methods and Materials: The medical records of 47 patients treated for squamous cell carcinoma of the vulva at our institution (1974-1992) were reviewed for TNM stage (AJCC criteria), treatment modality, and associated 5-year local control and survival based on Kaplan-Meier analysis. Results: Twenty-eight patients (60%) presented with Stage I and II disease and their 5-year survival was 69%. Stage III patients accounted for 12 (25%) of the patients and their 5-year survival was 73%. Seven patients presented with Stage IV disease and five died within 13 months of diagnosis after predominantly palliative therapy. The 40 patients with Stages I, II, and III disease were treated aggressively and were further evaluated for treatment-modality-associated survival and local control. Radiation therapy was used as primary treatment in nine patients, of whom seven were treated with radiation alone and two were treated postoperatively after wide excision. Surgery alone was performed in 31 patients consisting of either radical vulvectomy (20 patients) or wide excision (11 patients). When comparing outcomes of radical vulvectomy vs. radiation therapy, we noted that the 5-year actuarial survivals were comparable (74% for either modality), despite the presence of more favorable prognostic factors in the group treated with radical vulvectomy. Patients treated with wide excision alone had a trend for a poorer 5-year actuarial survival (51%) and local control (50%). Conclusions: Radical vulvectomy offers good locoregional control and survival. This retrospective review further supports the use of radiation therapy with conservative surgery as an alternative treatment option for patients with vulvar carcinoma treated with curative intent. In contrast, the use of

  2. Giant basal cell carcinoma Carcinoma basocelular gigante

    Directory of Open Access Journals (Sweden)

    Nilton Nasser

    2012-06-01

    Full Text Available The basal cell carcinoma is the most common skin cancer but the giant vegetating basal cell carcinoma reaches less than 0.5 % of all basal cell carcinoma types. The Giant BCC, defined as a lesion with more than 5 cm at its largest diameter, is a rare form of BCC and commonly occurs on the trunk. This patient, male, 42 years old presents a Giant Basal Cell Carcinoma which reaches 180 cm2 on the right shoulder and was negligent in looking for treatment. Surgical treatment was performed and no signs of dissemination or local recurrence have been detected after follow up of five years.O carcinoma basocelular é o tipo mais comum de câncer de pele, mas o carcinoma basocelular gigante vegetante não atinge 0,5% de todos os tipos de carcinomas basocelulares. O Carcinoma Basocelular Gigante, definido como lesão maior que 5 cm no maior diâmetro, é uma forma rara de carcinoma basocelular e comumente ocorre no tronco. Este paciente apresenta um Carcinoma Basocelular Gigante com 180cm² no ombro direito e foi negligente em procurar tratamento. Foi realizado tratamento cirúrgico e nenhum sinal de disseminação ou recorrência local foi detectada após 5 anos.

  3. Prostata carcinomas

    International Nuclear Information System (INIS)

    Pre-operative staging, using transrectal prostatic sonography and CT, was carried out in 30 patients with cytologically confirmed carcinomas of the prostate and the results compared with the clinical findings. All patients underwent radical prostatectomy and the pre-operative findings could be verified histologically. Transrectal prostatic sonography is better than CT or clinical examination for determining local tumour spread or penetration of the capsule. A high proportion of enlarged pelvic lymphnodes shown by CT had non-specific changes; failure to demonstrate enlarged nodes excludes lymph node metastases with considerable certainty. Transrectal prostatic sonography provides a higher degree of information regarding local tumour spread, whereas CT indicates the presence or absence of lymph node metastases. (orig.)

  4. 11C-Acetate PET imaging for renal cell carcinoma

    International Nuclear Information System (INIS)

    In this study, we investigated the effectiveness of positron emission tomography (PET) with 11C-acetate (AC) for evaluation of renal cell carcinoma. Enrolled in the study were 20 patients with suspected renal tumour, one of whom had three renal lesions. In all, 22 renal lesions were evaluated. Following administration of 350 MBq (10 mCi) of AC, whole-body PET images were obtained. Based on these PET findings, kidney lesions were scored as positive or negative. The PET results were correlated with the CT findings and histological diagnosis after surgery. In 18 patients, 20 tumours were diagnosed as renal cell carcinoma. Lesions in the remaining two patients were diagnosed as complicated cyst without malignant tissue. Of the 20 renal cell carcinomas. 14 (70%) showed positive AC PET findings; 6 were negative. The two patients with complicated cyst had negative AC PET findings. Of the 20 renal cell carcinomas, 19 were clear-cell carcinoma and 1 was a papillary cell carcinoma. This papillary cell carcinoma showed high AC uptake. AC demonstrates marked uptake in renal cell carcinoma. These preliminary data show that AC is a possible PET tracer for detection of renal cancer. (orig.)

  5. Double Planet Meets Triple Star

    Science.gov (United States)

    2002-08-01

    atmosphere, a large campaign involving more than twenty scientists and engineers from the Paris Observatory and associated institutions [1] was organized to observe the July 20, 2002, event involving an occultation of a star of visual magnitude 11 (i.e., about 100 times fainter than what can be perceived with then unaided eye), referred to as "P126" in McDonald and Elliot's catalogue. In May 2002, preparatory observations showed that star to be double, with the brighter component of the system ( "P126 A" ) being likely to be occulted by Pluto, as seen from South America. However, because of the duplicity, the predictions of exactly where the shadow of Pluto would sweep the ground were uncertain by about 0.1 arcsec in the sky, corresponding to more than 2000 km on the ground. The NACO images ESO PR Photo 21b/02 ESO PR Photo 21b/02 [Preview - JPEG: 400 x 469 pix - 47k] [Normal - JPEG: 800 x 937 pix - 208k] ESO PR Photo 21c/02 ESO PR Photo 21c/02 [Preview - JPEG: 400 x 467 pix - 53k] [Normal - JPEG: 800 x 933 pix - 232k] Caption : PR Photo 21b/02 shows one of the images obtained with the NAOS-CONICA (NACO) adaptive optics (AO) camera mounted on the ESO VLT 8.2-m YEPUN telescope at the Paranal Observatory in connection with a stellar occultation by Pluto on July 20, 2002. The star was found to be triple - the three components (A, B and C), as well as Pluto and its moon, Charon, are indicated in PR Photo 21c/02 for easy orientation. The images are based on data available from the NACO data webpage. See the text for details. In the end, the close approach (an "appulse" in astronomical terminology) of Pluto and P126 A was indeed observed from various sites in South America, with several mobile telescopes and also including major facilities at the ESO La Silla and Paranal Observatories. In particular, unique and very sharp images were obtained with the NAOS-CONICA (NACO) adaptive optics (AO) camera mounted on the ESO VLT 8.2-m YEPUN telescope . One of the NACO images is shown in PR

  6. Multi-slice spiral CT and pathological correlation of renal cell carcinoma

    International Nuclear Information System (INIS)

    Objective: To analyze relationship between characteristics on multi-slice spiral CT (MSCT) and pathology of renal cell carcinoma. Methods: Multi-slice spiral CT and surgical pathological results on 32 cases of renal cell carcinoma were retrospectively analyzed. Results: Of the 32 cases, 28 were pathologically diagnosed as clear cell carcinoma, with tumor contrast enhancement similar to the normal cortex in the renal cortical phase (146-175HU), slight contrast washout in the renal parenchyma phase and significant contrast washout from the tumor in the pyelographic phase. Granular cell carcinoma in 4 patients showed no or mild contrast enhancement (38- 55HU) in all three phase. The overall diagnostic accordance rate was 100%, with preoperative staging accordance rate of 96.42%. Conclusion: The triple-phase contrast-enhanced MSCT is useful in predicting the tumor cell type and staging of renal cell carcinoma. (authors)

  7. Nevoid Basal Cell Carcinoma Syndrome

    Science.gov (United States)

    ... Nevoid Basal Cell Carcinoma Syndrome Request Permissions Nevoid Basal Cell Carcinoma Syndrome Approved by the Cancer.Net Editorial Board , 04/2016 What is Nevoid Basal Cell Carcinoma Syndrome? Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is ...

  8. Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells.

    Science.gov (United States)

    Coombs, Melanie R Power; Harrison, Megan E; Hoskin, David W

    2016-10-01

    Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses. PMID:27378243

  9. Rankin Triple Products and Quantum Chaos

    CERN Document Server

    Watson, Thomas C

    2008-01-01

    We prove explicit Harris-Kudla type formulas for triples of Maass forms, holomorphic forms, and combinations thereof, on the hyperbolic plane modulo congruence groups and co-compact lattices arising from Eichler orders of quaternion algebras. These formulas relate the central value of the corresponding Rankin triple product L-function to a squared trilinear period integral. Assuming subconvexity estimates for these L-values, we prove Quantum Unique Ergodicity on such quotients; the relevant Lindelof hypotheses imply a quantitative form of QUE, with an optimal rate. In connection with the Berry/Hejhal Random Wave conjecture, we prove decay of third moments in the high energy limit, making use of a subconvexity result of Iwaniec/Ivic/Jutila and Kim-Shahidi's result on cuspidality of the symmetric cube.

  10. On Spectral Triples in Quantum Gravity I

    DEFF Research Database (Denmark)

    Aastrup, Johannes; M. Grimstrup, Jesper; Nest, Ryszard

    2009-01-01

    This paper establishes a link between Noncommutative Geometry and canonical quantum gravity. A semi-finite spectral triple over a space of connections is presented. The triple involves an algebra of holonomy loops and a Dirac type operator which resembles a global functional derivation operator....... The interaction between the Dirac operator and the algebra reproduces the Poisson structure of General Relativity. Moreover, the associated Hilbert space corresponds, up to a discrete symmetry group, to the Hilbert space of diffeomorphism invariant states known from Loop Quantum Gravity....... Correspondingly, the square of the Dirac operator has, in terms of canonical quantum gravity, the form of a global area-squared operator. Furthermore, the spectral action resembles a partition function of Quantum Gravity. The construction is background independent and is based on an inductive system of...

  11. A rare case of triple thyroid ectopia

    Directory of Open Access Journals (Sweden)

    Mukund Rahalkar

    2014-01-01

    Full Text Available Various anomalies of thyro-glossal duct have been described, in which the duct may form a cyst or may present as a solid nodule to form an ectopic gland. The ectopic gland can develop along the tract of the duct to give rise to ectopic lingual, sublingual (pre-hyoid or sub-hyoid (pyramidal gland, with or without normal pre-tracheal thyroid gland.There are a few reports of double ectopia of thyroid but triple ectopia of thyroid is extremely rare. We have come across a case of triple thyroid ectopia, i.e., thyroid tissue at three locations along the tract of descent of thyro-glossal duct on CT, which hast been rarely reported in the world literature, and hence this report.

  12. The Triple Helix of the Organizational Knowledge

    OpenAIRE

    Contantin BRĂTIANU

    2013-01-01

    The purpose of this paper is to present the inner triple helix dynamics of the organizationalknowledge. This is a new perspective of the classical view of tacit knowledge– explicit knowledge dyad of the organizational knowledge promoted by Nonaka and hisco-workers. The new perspective is based on the metaphor that organizational knowledge isa "eld rather than a stock, or stocks and flows. It is a complex metaphor using the thermodynamicsprinciples. The organizational knowledge is composed of ...

  13. Triple Teeth: Report of an Unusual Case

    OpenAIRE

    Prashant Babaji; M. A. Prasanth; Ajith R. Gowda; Soumya Ajith; Henston D'Souza; Ashok, K. P.

    2012-01-01

    Fusion or synodontia is a union of two or more than two developing teeth. Commonly fusion occurs between teeth of the same dentition, mixed dentition, or between normal and supernumerary teeth. Fused primary teeth present with several clinical problems like caries, periodontal problem, arch asymmetry, delayed eruption, ectopic eruption of succedaneous teeth, aesthetic, and other complications. This paper presents a rare and unusual case of triple teeth in mandibular primary dentition.

  14. Asteroid Systems: Binaries, Triples, and Pairs

    CERN Document Server

    Margot, Jean-Luc; Taylor, Patrick; Carry, Benoît; Jacobson, Seth

    2015-01-01

    In the past decade, the number of known binary near-Earth asteroids has more than quadrupled and the number of known large main belt asteroids with satellites has doubled. Half a dozen triple asteroids have been discovered, and the previously unrecognized populations of asteroid pairs and small main belt binaries have been identified. The current observational evidence confirms that small (20 km) binaries with small satellites are most likely created during large collisions.

  15. Gauging triple stores with actual biological data

    OpenAIRE

    2012-01-01

    Background: Semantic Web technologies have been developed to overcome the limitations of the current Web and conventional data integration solutions. The Semantic Web is expected to link all the data present on the Internet instead of linking just documents. One of the foundations of the Semantic Web technologies is the knowledge representation language Resource Description Framework (RDF). Knowledge expressed in RDF is typically stored in so-called triple stores (also known as RDF stores), f...

  16. A Tulczyjew triple for classical fields

    International Nuclear Information System (INIS)

    The geometrical structure known as the Tulczyjew triple has proved to be very useful in describing mechanical systems, even those with singular Lagrangians or subject to constraints. Starting from basic concepts of the variational calculus, we construct the Tulczyjew triple for first-order field theory. The important feature of our approach is that we do not postulate ad hoc the ingredients of the theory, but obtain them as unavoidable consequences of the variational calculus. This picture of field theory is covariant and complete, containing not only the Lagrangian formalism and Euler–Lagrange equations but also the phase space, the phase dynamics and the Hamiltonian formalism. Since the configuration space turns out to be an affine bundle, we have to use affine geometry, in particular the notion of the affine duality. In our formulation, the two maps α and β which constitute the Tulczyjew triple are morphisms of double structures of affine-vector bundles. We also discuss the Legendre transformation, i.e. the transition between the Lagrangian and the Hamiltonian formulation of the first-order field theory. (paper)

  17. A Tulczyjew triple for classical fields

    Science.gov (United States)

    Grabowska, Katarzyna

    2012-04-01

    The geometrical structure known as the Tulczyjew triple has proved to be very useful in describing mechanical systems, even those with singular Lagrangians or subject to constraints. Starting from basic concepts of the variational calculus, we construct the Tulczyjew triple for first-order field theory. The important feature of our approach is that we do not postulate ad hoc the ingredients of the theory, but obtain them as unavoidable consequences of the variational calculus. This picture of field theory is covariant and complete, containing not only the Lagrangian formalism and Euler-Lagrange equations but also the phase space, the phase dynamics and the Hamiltonian formalism. Since the configuration space turns out to be an affine bundle, we have to use affine geometry, in particular the notion of the affine duality. In our formulation, the two maps α and β which constitute the Tulczyjew triple are morphisms of double structures of affine-vector bundles. We also discuss the Legendre transformation, i.e. the transition between the Lagrangian and the Hamiltonian formulation of the first-order field theory.

  18. Carcinoma in accessory axillary breast.

    Science.gov (United States)

    Khanna, Seema; Mishra, Shashi Prakash; Kumar, Satendra; Khanna, Ajay Kumar

    2015-01-01

    We present a rare case of carcinoma developing in an accessory breast. The patient presented with a progressive lump in her right axilla for 1 year. On examination, there was a well-developed nipple areola complex in the right axilla overlying a hard, fixed 5 × 3 cm lump. On investigation, core biopsy revealed poorly differentiated carcinoma of the breast. Mammography also revealed features of a malignant lesion with skin and muscle infiltration. Neoadjuvant chemotherapy was administered followed by modified radical mastectomy after three cycles. Immunohistochemistry study showed positive status of oestrogen and progesterone receptors, and negative HER-2 neu. Three more cycles of chemotherapy along with 50 Gy radiotherapy were given in an adjuvant setting followed by hormone therapy. PMID:26260957

  19. Clinical implications of basic research in hepatocellular carcinoma.

    Science.gov (United States)

    Dhanasekaran, Renumathy; Venkatesh, Sudhakar K; Torbenson, Michael S; Roberts, Lewis R

    2016-03-01

    A 58-year old Caucasian female has compensated hepatitis C related cirrhosis. Her surveillance ultrasound showed hypodense liver nodules and subsequent triple phase CT scan showed five tumor nodules with diameters ranging from 3-5cms involving both hepatic lobes. The nodules showed characteristic radiologic findings on the CT scan and she was diagnosed with hepatocellular carcinoma (HCC) based on non-invasive criteria. There was also associated right portal vein tumor thrombosis. Her functional capacity at diagnosis was slightly limited, but she was capable of performing all activities of daily living and self-care. Her laboratory tests at diagnosis were as follows: sodium 129mmol/L, potassium 3.6mmol/L, blood urea nitrogen 22mg/dL, creatinine 1.0mg/dL, albumin 2.9g/dl, bilirubin 1.8mg/dl, alanine aminotransferase 87U/L, aspartate aminotransferase 68U/L, alkaline phosphatase 139U/L, white blood cell 3.5x10(9)/L, hemoglobin 10.4, platelet count 73x10(9)/L, international normalized ratio 1.9 and alpha-fetoprotein 5200ng/ml. An upper endoscopy was negative for esophageal or gastric varices. Based on the tumor burden, presence of macrovascular invasion, ECOG performance status of 1 and Child-Pugh class A she was classified to have BCLC stage C HCC. She was started on sorafenib therapy at 400mg oral twice daily but unfortunately this had to be discontinued since she experienced severe diarrhea and skin rash. She now returns for follow-up and requests information on the available therapeutic options. This particular case scenario is not uncommon and does raise several clinically relevant questions: This review provides a comprehensive overview of the current state of HCC management and also examines the clinical implications of recent basic research in HCC. PMID:26450813

  20. Giant basal cell carcinoma Carcinoma basocelular gigante

    OpenAIRE

    Nilton Nasser; Nilton Nasser Filho; Bruno Trauczynski Neto; Lissandra Melati da Silva

    2012-01-01

    The basal cell carcinoma is the most common skin cancer but the giant vegetating basal cell carcinoma reaches less than 0.5 % of all basal cell carcinoma types. The Giant BCC, defined as a lesion with more than 5 cm at its largest diameter, is a rare form of BCC and commonly occurs on the trunk. This patient, male, 42 years old presents a Giant Basal Cell Carcinoma which reaches 180 cm2 on the right shoulder and was negligent in looking for treatment. Surgical treatment was performed and no s...