WorldWideScience

Sample records for triple synchronous cancers

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

    International Nuclear Information System (INIS)

    Takada, Tsuyoshi; Honda, Masahito; Momohara, Chikahiro; Komori, Kazuhiko; Fujioka, Hideki

    2002-01-01

    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)

  2. Synchronizing a Triple Dragline Stripping System in Thick Overburden

    Directory of Open Access Journals (Sweden)

    Erdem Bülent

    2017-06-01

    Full Text Available This study addresses the use of combined stripping systems to investigate the technical feasibility of extracting thick coal seams underlying deep overburden strata. The possibility of using multiple draglines in tandem with bucket wheel excavator systems is explored. Pit geometry design alternatives incorporating a triple dragline excavation fleet with bucket wheel excavator-cross pit spreader subsystems (BWE+XPS are examined. A production simulation algorithm, which emphasizes synchronizing excavator units in the triple dragline system, is developed. The combined methodology is evaluated in Sector-D of the Afşin-Elbistan lignite basin, one of the most important resources for electricity production in Turkey. The results reveal that a combined stripping fleet may successfully perform overburden stripping at the predetermined rate and uncover coal seams.

  3. Clinicopathological comparison of triple negative breast cancers ...

    African Journals Online (AJOL)

    Conclusion: Triple negative breast cancer represented 34.4% which is higher than the range normally reported in the literature. TNBC are associated with younger age, large tumor size, high‑grade tumors, and a higher rate of axillary lymph node metastasis. Key words: Basal subtype, estrogen receptor, hormone receptors, ...

  4. Targeting Prolyl Peptidases in Triple-Negative Breast Cancer

    Science.gov (United States)

    2017-02-01

    AWARD NUMBER: W81XWH-16-1-0025 TITLE: Targeting Prolyl Peptidases in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Carl G. Maki, PhD...SUBTITLE Targeting Prolyl Peptidases in Triple-Negative Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0025 5c. PROGRAM ELEMENT NUMBER 6...SUBJECT TERMS Triple negative breast cancer, Prolyl peptidases , Breast cancer treatment, Animal model 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  5. 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

  6. Synchronous triple occurrence of MALT lymphoma, schwannoma, and adenocarcinoma of the stomach.

    Science.gov (United States)

    Choi, Kyeong W; Joo, Mee; Kim, Han S; Lee, Woo Y

    2017-06-14

    We present a case of a 56-year-old man with 3 synchronous gastric tumors. The patient presented with melena, and 3 gastric abnormalities were detected on gastroduodenoscopic examination, including a small ulcerative lesion in the gastric antrum, a submucosal mass in the gastric body, and severe erosion in the fundus. Histological examination of biopsy samples yielded respective diagnoses of gastric adenocarcinoma, gastritis, and mucosa-associated lymphoid tissue (MALT) lymphoma. The patient first received medication to eradicate any underlying Helicobacter pylori infection, which might have been a cause of the MALT lymphoma. Four weeks later, after examination of repeat biopsy samples revealed that the MALT lymphoma had resolved, the patient underwent subtotal gastrectomy. Further histological examination of resected tissue confirmed the antrum lesion as adenocarcinoma and the body lesion as schwannoma. To our knowledge, this is the first reported case of synchronous triple primary gastric adenocarcinoma, MALT lymphoma, and schwannoma.

  7. Immunohistochemical Characteristics of Triple Negative/Basal-like Breast Cancer

    OpenAIRE

    Emel Ebru PALA; Ümit BAYOL; Süheyla CUMURCU; Elif KESKİN

    2012-01-01

    Objective: Triple-negative-breast-cancer that accounts for 10-20% of all breast carcinomas is defined by the lack of estrogen receptor, progesterone receptor, HER2 expression, and agressive clinical behavior. Triple-negative-breast-cancer is categorized into basal like and other types. The basal-like subtype is characterized by the expression of myoepithelial/basal markers.Material and Method: We studied 41 immunohistochemically triplenegative- breast-cancer patients to determine EGFR, Cytoke...

  8. Targeting histone abnormality in triple negative breast cancer

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-14-1-0238 TITLE: Targeting histone abnormality in triple negative breast cancer PRINCIPAL INVESTIGATOR: Steffi...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting histone abnormality in triple negative breast cancer 5b. GRANT NUMBER W81XWH-14-1-0238 5c...PDXs). In addition, two teams collaborated in studying the functional role of LSD2 in breast cancer progression. The interactive studies between two

  9. Triple negative breast cancer: the role of metabolic pathways.

    Science.gov (United States)

    Dean, S J R; Rhodes, A

    2014-12-01

    The incidence of breast cancer in Malaysia and other Asian countries is on the increase, reflecting lifestyle changes some of which are known risk factors for the development of breast cancer. Most breast cancers are amenable to adjuvant therapies that target hormone receptors or HER2 receptors on the surface of the cancer cells and bring about significant improvement in survival. However, approximately 17% of Malaysian women with breast cancer, present with tumours that are devoid of these receptors and are consequently termed 'triple negative' breast cancers. These triple negative breast cancers typically occur in women of a younger age than receptor positive cancers, are predominantly of high grade tumours and the prognosis is usually poor. There is therefore a pressing need to understand the biological pathways that drive these tumours, in order that effective strategies are developed to treat these aggressive tumours. With the increasing affluence of developing countries, obesity and Type II Diabetes are also on the rise. These diseases are associated with an increased risk of developing a range of cancers including those of the breast. In particular, the metabolic syndrome has been shown to be associated with triple negative breast cancer. This article reviews some of the metabolic pathways and biomarkers which have been shown to be aberrantly expressed in triple negative breast cancer and highlights some of the ongoing work in this area.

  10. Prognosis of synchronous bilateral breast cancer

    DEFF Research Database (Denmark)

    Holm, Marianne; Tjønneland, Anne; Balslev, Eva

    2014-01-01

    Currently, no consistent evidence-based guidelines for the management of synchronous bilateral breast cancer (SBBC) exist and it is uncertain how presenting with SBBC affects patients' prognosis. We conducted a review of studies analyzing the association between SBBC and prognosis. The studies...... that reported adjusted effect measures were included in meta-analyses of effect of bilaterality on breast cancer mortality. From 57 initially identified records 17 studies from 11 different countries including 8,050 SBBC patients were included. The quality of the studies varied but was generally low with small...... sample sizes, and lack of consistent, detailed histo-pathological information. When doing meta-analysis on the subgroup of studies that provided adjusted effect estimates on breast cancer mortality (nine studies including 3,631 SBBC cases), we found that bilaterality in itself had a negative impact...

  11. Epigenetic Subtypes of Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-10-01

    breast cancer phenotypes and their inheritance pattern, the Polyak lab has generated somatic cell fusions and performed...Determine the contribution of genetic heterogeneity to metastasis in breast cancer ; 2) Develop strategies to assess genomic heterogeneity in human tumors...Dissecting the heterogeneity of triple-negative breast cancer . J Clin Oncol 30, 1879-1887, (2012). 5 Su, Y. et al. Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast

  12. [Synchronous bilateral breast cancer in a male].

    Science.gov (United States)

    García-Mejido, José Antonio; Delgado-Jiménez, Carmen; Gutiérrez-Palomino, Laura; Sánchez-Sevilla, Miguel; Iglesias-Bravo, Eva; Caballero-Fernández, Virginia

    2013-01-01

    male breast cancer is a disease with low incidence, which is further reduced when it comes to bilateral synchronous presentation. There are few published cases in recent years. The aim is to establish guidelines for the management of this disorder that is so rare. a 75-year-old with tumors in both breasts, which were completely resected with removal of palpable nodes. The histopathological study reported ductal carcinoma. The indicated treatment was adjuvant tamoxifen and radiotherapy. The patient is currently in a disease-free period. this is a rare disease, whose main treatment is surgery, hence the importance of early diagnosis. Most cases require adjuvant chemotherapy and radiotherapy because they are usually diagnosed at an advanced stage.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

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

    Science.gov (United States)

    2017-05-22

    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. Synchronous colon and renal cancer - case report

    International Nuclear Information System (INIS)

    Luczynska, E.; Pawlik, T.; Aniol, J.; Chwalibog, A.

    2008-01-01

    Primary cancer may occur synchronously in two different organs. We present an example of pathologically proven, coexistent renal and colony double malignant tumors. A 59 year old man, was admitted to the Institute of Oncology due to left renal lesion, discovered during a routine abdominal ultrasound examination. The CT exam was performed before surgery. The CT scans reveled a second abnormality, presenting irregular shaped and thickened to 20 mm intestinal wall within a patient's large bowel. As a next diagnostic step a CT-colonoscopy was undertaken, which confirmed the presence of an exophytic sigmoid lesion, eccentrically affecting the colonic wall and protruding into the lumen moderately narrowing it, placed about 50 cm from the external rectal sphincter. Patient underwent simultaneous radical left nephrectomy and sigmoidectomy. Both tumors were confirmed in pathologic evaluation, reveling renal clear cell carcinoma (Fuhrman G II) and colonic adenocarcinoma (Astler-Coller B2). Preoperative careful imaging studies reveled neoplastic tumors in two different organs, allowing for radical resection at the same surgical procedure. (author)

  16. Management Options in Triple-Negative Breast Cancer

    Science.gov (United States)

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

    2011-01-01

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

  17. Wnt signaling in triple-negative breast cancer

    Science.gov (United States)

    Pohl, SÖ-G; Brook, N; Agostino, M; Arfuso, F; Kumar, A P; Dharmarajan, A

    2017-01-01

    Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease. PMID:28368389

  18. A Study of Triple Negative Breast Cancer at a Tertiary Cancer Care ...

    African Journals Online (AJOL)

    Breast cancer is the most common female cancer and the leading cause of cancer deaths worldwide. ... Background: Triple negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack ..... setting could provide an opportunity to study the impact of systemic therapies on breast ...

  19. Preoperative evaluation of synchronous colorectal cancer using MR colonography

    DEFF Research Database (Denmark)

    Achiam, Michael P; Holst Andersen, Lars P; Klein, Mads

    2009-01-01

    RATIONALE AND OBJECTIVES: It is well known that synchronous cancers (incidence, 2%-11%) and polyps (incidence, 12%-58%) occur in patients with colorectal cancer. Magnetic resonance colonography (MRC) seems like the obvious choice as a diagnostic tool in preoperative evaluation, because it is noni...

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

    Science.gov (United States)

    2018-03-05

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

  1. 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

  2. Derivation of a triple mosaic adenovirus for cancer gene therapy.

    Directory of Open Access Journals (Sweden)

    Yizhe Tang

    2009-12-01

    Full Text Available A safe and efficacious cancer medicine is necessary due to the increasing population of cancer patients whose particular diseases cannot be cured by the currently available treatment. Adenoviral (Ad vectors represent a promising therapeutic medicine for human cancer therapy. However, several improvements are needed in order for Ad vectors to be effective cancer therapeutics, which include, but are not limited to, improvement of cellular uptake, enhanced cancer cell killing activity, and the capability of vector visualization and tracking once injected into the patients. To this end, we attempted to develop an Ad as a multifunctional platform incorporating targeting, imaging, and therapeutic motifs. In this study, we explored the utility of this proposed platform by generating an Ad vector containing the poly-lysine (pK, the herpes simplex virus type 1 (HSV-1 thymidine kinase (TK, and the monomeric red fluorescent protein (mRFP1 as targeting, tumor cell killing, and imaging motifs, respectively. Our study herein demonstrates the generation of the triple mosaic Ad vector with pK, HSV-1 TK, and mRFP1 at the carboxyl termini of Ad minor capsid protein IX (pIX. In addition, the functionalities of pK, HSV-1 TK, and mRFP1 proteins on the Ad vector were retained as confirmed by corresponding functional assays, indicating the potential multifunctional application of this new Ad vector for cancer gene therapy. The validation of the triple mosaic Ad vectors also argues for the ability of pIX modification as a base for the development of multifunctional Ad vectors.

  3. TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple-Negative Breast Cancer

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH-15-1-0311 TITLE: TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple- Negative Breast Cancer PRINCIPAL...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Triple-negative breast cancers (TNBCs) represent only 10%-15% of all breast cancers ; however... cancers (TNBC) represent 10-15% of all breast cancers . While significant advances have been made for targeted therapy of ER and HER2-positive breast

  4. 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.

  5. Synchronous malignant renal mass in patient with a Lung cancer ...

    African Journals Online (AJOL)

    Synchronous malignant renal mass in patient with a Lung cancer: case report and literature review. A Mazouz, L Amaadour, I souaf, H El Fatemi, A Amarti, MA Erraisse, T Bouhafa, Y Tahiri, MF Tazi, S Mellas, S Arifi, N Mellas ...

  6. Genetic susceptibility to triple-negative breast cancer.

    Science.gov (United States)

    Stevens, Kristen N; Vachon, Celine M; Couch, Fergus J

    2013-04-01

    Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models. ©2012 AACR.

  7. Clinical Characteristics in Patients with Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Janet Yeh

    2017-01-01

    Full Text Available Purpose. The purpose of this study was to compare and contrast the clinical characteristics of the triple negative breast cancer (TNBC and non-TNBC patients, with a particular focus on genetic susceptibility and risk factors prior to diagnosis. Methods. Our institutional database was queried for all patients diagnosed with invasive breast cancer between January 2010 and May 2016. Results. Out of a total of 1964 patients, 190 (10% patients had TNBC. The median age for both TNBC and non-TNBC was 59 years. There was a significantly higher proportion of African American and Asian patients with TNBC (p=0.0003 compared to patients with non-TNBC. BRCA1 and BRCA2 were significantly associated with TNBC (p<0.0001, p=0.0007. A prior history of breast cancer was significantly associated with TNBC (p=0.0003. There was no relationship observed between TNBC and a history of chemoprevention or patients who had a history of AH or LCIS. Conclusions. We found that having Asian ancestry, a prior history of breast cancer, and a BRCA1 or BRCA2 mutation all appear to be positively associated with TNBC. In order to develop more effective treatments, better surveillance, and improved prevention strategies, it is necessary to improve our understanding of the population at risk for TNBC.

  8. 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.

  9. Management of synchronous rectal and prostate cancer.

    LENUS (Irish Health Repository)

    Kavanagh, D O

    2012-11-01

    Although well described, there is limited published data related to management on the coexistence of prostate and rectal cancer. The aim of this study was to describe a single institution\\'s experience with this and propose a treatment algorithm based on the best available evidence.

  10. Occurrence and survival of synchronous pulmonary metastases in colorectal cancer

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas; Krarup, Peter-Martin; Jorgensen, Lars N

    2014-01-01

    OBJECTIVE: To investigate the occurrence of synchronous colorectal cancer metastases (SCCM) confined to the lungs, risk factors for these metastases and their impact on survival. METHODS: In a nationwide cohort study of 26,200 patients data were prospectively entered into the Danish Colorectal Ca...... exaggeration of the treatment effect should be kept in mind. This study may serve as a reliable un-biased reference for future evaluation on detection strategies and potential therapeutic interventions....

  11. Triple synchronous primary malignancies of the colon, endometrium and kidney in a patient with Lynch syndrome treated via minimally invasive techniques

    Directory of Open Access Journals (Sweden)

    Luis E. Mendez

    2016-08-01

    It is important to consider hereditary cancer syndromes in women with a strong family history presenting with synchronous multiple primary malignancies. A multidisciplinary surgical approach is key to best practices and optimal patient outcomes.

  12. Synchronization

    Indian Academy of Sciences (India)

    Towards the end some real life exam- ples are also discussed. 1. Introduction. Synchronization, in simple terms, ..... certain relationship between their phases is termed as phase locking. GENERAL I ARTICLE ral frequencies beginning to oscillate at a common fre- quency owing to coupling is called frequency locking or.

  13. Synchronization

    Indian Academy of Sciences (India)

    When a swarm of fireflies gather, they have been found to flash in synchrony. GENERAL I ARTICLE node is due to synchronization of the rhythms of the collection of pacemaker cells. In a pathological case, the pacemaker cells become faulty which results in an abnormally low heart rate known as bradycardia. This results in ...

  14. "An addendum to breast cancer": the triple negative experience.

    Science.gov (United States)

    Turkman, Yasemin E; Kennedy, Holly Powell; Harris, Lyndsay N; Knobf, M Tish

    2016-09-01

    The triple negative breast cancer (TNBC) subtype, known to be aggressive with high recurrence and mortality rates, disproportionately affects African-Americans, young women, and BRCA1 carriers. TNBC does not respond to hormonal or biologic agents, limiting treatment options. The unique characteristics of the disease and the populations disproportionately affected indicate a need to examine the responses of this group. No known studies describe the psychosocial experiences of women with TNBC. The purpose of this study is to begin to fill that gap and to explore participants' psychosocial needs. An interpretive descriptive qualitative approach was used with in-depth interviews. A purposive sample of adult women with TNBC was recruited. Dominant themes were extracted through iterative and constant comparative analysis. Of the 22 participants, nearly half were women of color, and the majority was under the age of 60 years and within 5 years of diagnosis. The central theme was a perception of TNBC as "an addendum" to breast cancer. There were four subthemes: TNBC is Different: "Bottom line, it's not good"; Feeling Insecure: "Flying without a net"; Decision-Making and Understanding: "A steep learning curve"; and Looking Back: "Coulda, shoulda, woulda." Participants expressed a need for support in managing intense uncertainty with a TNBC diagnosis and in decision-making. Women with all subtypes of breast cancer have typically been studied together. This is the first study on the psychosocial needs specifically of women with TNBC. The findings suggest that women with TNBC may have unique experiences and unmet psychosocial needs.

  15. CCR 20th Anniversary Commentary: Triple-Negative Breast Cancer in 2015—Still in the Ballpark.

    Science.gov (United States)

    Narod, Steven A; Dent, Rebecca A; Foulkes, William D

    2015-09-01

    The research article by Dent and colleagues, which was published in the August 1, 2007, issue of Clinical Cancer Research, provided a clinical description of metastatic progression of triple-negative breast cancers. Finding successful treatment strategies for women with triple-negative breast cancer remains a challenge. ©2015 American Association for Cancer Research.

  16. A clinicopathologic study of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Vandana L Gaopande

    2015-01-01

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

  17. The significance of extended lymphadenectomy for colorectal cancer with isolated synchronous extraregional lymph node metastasis

    Directory of Open Access Journals (Sweden)

    Atsushi Ogura

    2017-07-01

    Conclusion: Findings from our study suggest that extended lymphadenectomy for colorectal cancer with synchronous isolated extraregional lymph node metastasis might be effective in carefully selected patients.

  18. Colorectal cancer with synchronous lung metastases: clinical characteristics, treatment, prognosis

    Directory of Open Access Journals (Sweden)

    A. O. Rasulov

    2016-01-01

    Full Text Available Objective: to evaluate the impact of cytoreductive surgery on treatment results in patients with colorectal cancer and synchronous lung metastases.Materials and methods. This retrospective investigation analyzed the results of therapy in patients with colorectal cancer and synchronous lung metastases who had been treated in the period 2000 to 2012. The investigators studied the following indicators: the impact of cytoreductive surgery on the survival of patients with this condition, the clinical characteristics of a group of patients with isolated lung involvement, the dissimilarity of this group from a group of patients with extrapulmonary metastases, the possibility of performing complete cytoreductive surgery in patients with varying degrees of a metastatic process, and the number of patients with complications in primary tumor.Results. The investigations included the data of 112 patients with colorectal cancer and synchronous lung metastases. Out of them, 38 (33.9 % patients had isolated lung involvement and the latter was associated with extrapulmonary metastases in 74 (64.1 %. In 16 of the 38 patients, isolated lung metastases were regarded as resectable and complete cytoreductive surgeries were performed. The median follow-up in the examined group was 15.2 months. One- and two-year overall survival rates were 63 and 45 %, respectively. The patients with isolated lung metastases were observed to have higher 2-year overall survival rates than those with multiple metastases (63.0 and 37.5 %, respectively; p = 0.055 and there were significantly higher 2-year overall survival rates in patients after removal of primary tumors than in those who had not undergone cytoreductive surgery (21.0 and 52.5 %, respectively; p = 0.004. Two-year overall survival rates were 72.5 % in the complete cytoreductive treatment group.Conclusion. The prognosis in the patients with colorectal cancer and synchronous lung metastases was better than that in those with

  19. Inadequate preoperative colonic evaluation for synchronous colorectal cancer

    DEFF Research Database (Denmark)

    Achiam, M P; Burgdorf, S K; Wilhelmsen, M

    2009-01-01

    BACKGROUND AND AIMS: Synchronous cancers (SC) are well known (2-11%) in patients with colorectal carcinoma (CRC). One study has shown that intraoperative palpation can miss up to 69% of the SC while other studies have shown altered planned surgical procedure due to preoperatively diagnosed...... in our department were reviewed. Only patients with CRC were included. Information regarding pre-, per- and postoperative colonic evaluation were obtained and occurrences of SC were evaluated. RESULTS: Of the 534 patients included 124 (23%) patients had an impassable stenosis. Full preoperative colonic...

  20. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer.

    Science.gov (United States)

    Phipps, Amanda I; Chlebowski, Rowan T; Prentice, Ross; McTiernan, Anne; Wactawski-Wende, Jean; Kuller, Lewis H; Adams-Campbell, Lucile L; Lane, Dorothy; Stefanick, Marcia L; Vitolins, Mara; Kabat, Geoffrey C; Rohan, Thomas E; Li, Christopher I

    2011-03-16

    Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers. Using data from 155,723 women enrolled in the Women's Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs). Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10,000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10,000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype. The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further

  1. Australian contemporary management of synchronous metastatic colorectal cancer.

    Science.gov (United States)

    Malouf, Phillip; Gibbs, Peter; Shapiro, Jeremy; Sockler, Jim; Bell, Stephen

    2018-01-01

    This article outlines the current Australian multidisciplinary treatment of synchronous metastatic colorectal adenocarcinoma and assesses the factors that influence patient outcome. This is a retrospective analysis of the prospective 'Treatment of Recurrent and Advanced Colorectal Cancer' registry, describing the patient treatment pathway and documenting the extent of disease, resection of the colorectal primary and metastases, chemotherapy and biological therapy use. Cox regression models for progression-free and overall survival were constructed with a comprehensive set of clinical variables. Analysis was intentionn-ton-treat, quantifying the effect of treatment intent decided at the multidisciplinary team meeting (MDT). One thousand one hundred and nine patients presented with synchronous metastatic disease between July 2009 and November 2015. Median follow-up was 15.8 months; 4.4% (group 1) had already curative resections of primary and metastases prior to MDT, 22.2% (group 2) were considered curative but were referred to MDT for opinion and/or medical oncology treatment prior to resection and 70.2% were considered palliative at MDT (group 3). Overall, 83% received chemotherapy, 55% had their primary resected and 23% had their metastases resected; 13% of resections were synchronous, 20% were staged with primary resected first and 62% had only the colorectal primary managed surgically. Performance status, metastasis resection (R0 versus R1 versus R2 versus no resection), resection of the colorectal primary and treatment intent determined at MDT were the most significant factors for progression-free and overall survival. This is the largest Australian series of synchronous metastatic colorectal adenocarcinoma and offers insight into the nature and utility of contemporary practice. © 2016 Royal Australasian College of Surgeons.

  2. TMEPAI genome editing in triple negative breast cancer cells

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    Bantari W.K. Wardhani

    2017-05-01

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

  3. Mismatch repair status and synchronous metastases in colorectal cancer

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas; Krarup, Peter-Martin; Morton, Dion

    2015-01-01

    The causality between the metastatic potential, mismatch repair status (MMR) and survival in colorectal cancer (CRC) is complex. This study aimed to investigate the impact of MMR in CRC on the occurrence of synchronous metastases (SCCM) and survival in patients with SCCM on a national basis....... A nationwide cohort study of 6,692 patients diagnosed with CRC between 2010 and 2012 was conducted. Data were prospectively entered into the Danish Colorectal Cancer Group's database and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable and multinomial...... factors. The metastatic pattern varied according to MMR status. MMR had no impact on survival in patients with UICC Stage IV CRC. These findings may be important for the understanding of the metastatic processes and thus for optimizing staging and treatment in CRC patients....

  4. Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer.

    Science.gov (United States)

    Miah, Sayem; Banks, Charles A S; Adams, Mark K; Florens, Laurence; Lukong, Kiven E; Washburn, Michael P

    2016-12-20

    Understanding the complexity of cancer biology requires extensive information about the cancer proteome over the course of the disease. The recent advances in mass spectrometry-based proteomics technologies have led to the accumulation of an incredible amount of such proteomic information. This information allows us to identify protein signatures or protein biomarkers, which can be used to improve cancer diagnosis, prognosis and treatment. For example, mass spectrometry-based proteomics has been used in breast cancer research for over two decades to elucidate protein function. Breast cancer is a heterogeneous group of diseases with distinct molecular features that are reflected in tumour characteristics and clinical outcomes. Compared with all other subtypes of breast cancer, triple-negative breast cancer is perhaps the most distinct in nature and heterogeneity. In this review, we provide an introductory overview of the application of advanced proteomic technologies to triple-negative breast cancer research.

  5. The efficacy of betulinic acid in triple-negative breast cancer

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    Daniel Weber

    2014-09-01

    Full Text Available Purpose: The treatment of triple-negative breast cancer remains a daunting challenge with the standard-of-care treatments eventually failing due to acquired drug resistance, toxic side effects and the presence of a deregulated immune response. New treatments for overcoming these drawbacks include the use of plant extracts. Study design: In this study, the efficacy of betulinic acid, a naturally abundant phytochemical exhibiting anti-inflammatory and anti-proliferative activity, has been evaluated for the treatment of triple-negative breast cancer MDA-MB-231 and MDA-MB-468 cell lines. Furthermore, the ability of betulinic acid to inhibit angiogenesis was also determined. Results: Here, we report that betulinic acid was able to inhibit the inflammatory response, inhibit angiogenesis and cause cell cycle arrest ultimately causing apoptosis in triple-negative breast cancer cells. Our findings support that the identification of naturally occurring anti-tumour compounds may provide a chemotherapeutic approach for the treatment of triple-negative breast cancer. Conclusion: Overall, our results provide a molecular basis for the ability of betulinic acid to mediate apoptosis, suppress inflammation and inhibit angiogenesis in triple-negative breast cancer cell lines.

  6. Pattern of triple negative epithelial ovarian cancer in indigenous African women [version 1; referees: 2 approved

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    Mustapha Akanji Ajani

    2016-09-01

    Full Text Available Background: Triple negative epithelial ovarian cancer (TNEOC  refers to ovarian carcinomas that do not express estrogen receptor (ER, progesterone receptor (PR and human epidermal growth factor receptor- type 2 (HER-2/neu.  The aim of this study is to determine the pattern of triple negative epithelial ovarian cancer in indigenous African women. Methods: We performed a retrospective review of ER, PR and HER-2/neu expression in 90 Nigerian patients with histologically diagnosed epithelial ovarian cancer. Lack of expression of ER, PR and HER2/neu antigens was used to determine carcinomas that are among the TNEOC. We also compared the clinicopathological parameters (age, International Federation of Gynaecology and Obstetrics (FIGO stage, grade and histological subtype in patients with TNEOC and non- TNEOC . Results: Thirty-eight (42.2% of the 90 tumours diagnosed as EOC were negative for ER, PR and HER2/neu expression. There was no significant association between TNEOC with other parameters such as age, FIGO stage and histological grade. Sixteen (66.7% of the 24 mucinous carcinomas were triple negative, while only 21 (33.3% of the 63 serous carcinomas were triple-negative and one (50% of the two endometrioid carcinomas was triple negative. There was a significant association between triple-negative tumours and histological subtypes of EOC (p = 0.034. Conclusions: A subtype of epithelial ovarian cancer that is negative for ER, PR and HER-2/neu has been discovered in indigenous African women. TNEOC expression is high and is comparable to the triple negative breast cancer subtype seen in people of African ancestry. Future study of TNEOC in a large sample size should be considered.

  7. Adjuvant versus neoadjuvant chemotherapy in triple-negative breast cancer patients with BRCA mutations.

    Science.gov (United States)

    Clifton, Katherine; Gutierrez-Barrera, Angelica; Ma, Junsheng; Bassett, Roland; Litton, Jennifer; Kuerer, Henry; Moulder, Stacy; Albarracin, Constance; Hortobagyi, Gabriel; Arun, Banu

    2018-02-22

    As triple-negative breast cancers are associated with earlier recurrences and poorer survival, optimal treatment of early-stage breast cancer is essential. Several retrospective studies in triple-negative breast cancer have reported conflicting results in overall survival in patients receiving neoadjuvant or adjuvant systemic therapy. This study aims to analyze outcomes of adjuvant versus neoadjuvant in patients with early-stage triple-negative breast cancer with and without BRCA germline mutations. Patients with stage I or II triple-negative breast cancer who had BRCA testing were identified from a prospective cohort study of 4027 patients. Clinical, demographic, genetic test results, chemotherapy, recurrence, and survival data were analyzed. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. 319 patients with stage I and II triple-negative breast cancer who met eligibility criteria were included in the analysis. 187 received adjuvant chemotherapy (58.6%) and 132 received neoadjuvant chemotherapy (41.4%). 135 were BRCA positive (42.3%) and 184 were BRCA negative (57.7%). There was no significant association between overall survival or disease-free survival and treatment with neoadjuvant versus adjuvant in the overall cohort. Furthermore, there were no significant differences between patient subgroups (neoadjuvant BRCA positive, neoadjuvant BRCA negative, adjuvant BRCA positive, and adjuvant BRCA negative) with respect to either overall survival or disease-free survival. Neoadjuvant versus adjuvant with standard anthracycline- and taxane-containing regimens results in similar disease-free survival and overall survival among patients with stage I and II triple-negative breast cancer regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents.

  8. The Effects of Race Conditions When Implementing Single-Source Redundant Clock Trees in Triple Modular Redundant Synchronous Architectures

    Science.gov (United States)

    Berg, Melanie D.; Kim, Hak S.; Phan, Anthony M.; Seidleck, Christina M.; Label, Kenneth A.; Pellish, Jonathan A.; Campola, Michael J.

    2016-01-01

    We present the challenges that arise when using redundant clock domains due to their time-skew. Radiation data show that a singular clock domain provides an improved triple modular redundant (TMR) scheme over redundant clocks.

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

    Directory of Open Access Journals (Sweden)

    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

  10. Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry

    OpenAIRE

    Brewster, Abenaa M; Chavez-MacGregor, Mariana; Brown, Powel

    2014-01-01

    Breast cancer incidence is increasing worldwide, and breast cancer-related mortality is highest in women of African ancestry, who are more likely to have basal-like or triple-negative breast cancer (TNBC) than are women of European ancestry. Identification of cultural, epidemiological, and genetic risk factors that predispose women of African ancestry to TNBC is an active area of research. Despite the aggressive behaviour of TNBC, achievement of a pathological complete response with chemother...

  11. CLINICAL AND BIOLOGICAL RELEVANCE OF EZH2 IN TRIPLE NEGATIVE BREAST CANCER

    OpenAIRE

    Hussein, Yaser R.; Sood, Anil K.; Bandyopadhyay, Sudeshna; Albashiti, Bassam; Semaan, Assaad; Nahleh, Zeina; Roh, Juwon; Han, Hee Dong; Lopez-Berestein, Gabriel; Ali-Fehmi, Rouba

    2012-01-01

    The polycomb group protein, enhancer of zeste homolog 2 (EZH2), is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of EZH2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with EZH2, cytokeratin 5/6, epidermal growth factor receptor 1(EGFR) and p53. The expression of these markers was correlated with ...

  12. TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple Negative Breast Cancer

    Science.gov (United States)

    2016-10-01

    luminal B (D) breast cancer patients. The red line represents the survival curve of patients with high expression of TNK2 and the black line represents...for public release; distribution unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be... Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Triple-negative breast cancers (TNBCs) represent only 10%-15% of all breast cancers; however

  13. Incidence of metachronous gastric cancer in the remnant stomach after synchronous multiple cancer surgery.

    Science.gov (United States)

    Nozaki, Isao; Hato, Shinji; Kobatake, Takaya; Ohta, Koji; Kubo, Yoshirou; Nishimura, Rieko; Kurita, Akira

    2014-01-01

    In the preoperative evaluation for gastric cancer, high-resolution endoscopic technologies allow us to detect small accessory lesions. However, it is not known if the gastric remnant after partial gastrectomy for synchronous multiple gastric cancers has a greater risk for metachronous cancer. The purpose of this study was to determine the incidence of metachronous cancer in this patient subset compared with that after solitary cancer surgery. Data on a consecutive series of 1,281 patients gastrectomized for early gastric cancer from 1991 to 2007 were analyzed retrospectively. The 715 gastric remnants after distal gastrectomy were periodically surveyed by endoscopic examination in Shikoku Cancer Center. Among those surveyed cases, 642 patients were pathologically diagnosed with solitary lesion (SO group) and 73 patients with synchronous multiple lesions (MU group) at the time of the initial surgery. In the follow-up period, 15 patients in the SO group and 3 patients in the MU group were diagnosed as having metachronous cancer in the gastric remnant. The cumulative 4-year incidence rate was 1.9 % in the SO group and 5.5 % in the MU group. The difference did not reach the significant level by the log-rank test. The incidence of metachronous cancer is higher after multiple cancer surgery; however, the difference is not statistically significant.

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

    Directory of Open Access Journals (Sweden)

    Ruchi Upadhyay

    2015-01-01

    Full Text Available 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 was delivered with a cesarean at 37 weeks for obstetric indication. After delivery, the patient completed her chemotherapy that was followed by radical mastectomy and radiotherapy. Case two is a 28-year-old female para 6-0-1-5, who presented while breast-feeding with signs and symptoms of mastitis, and an engorged and tender right breast, five months postpartum. However, the sonogram revealed a fluid filled cavity. Aspiration and cytology did not reflect an infection and were negative for malignancy. High suspicion and lack of improvement led to biopsy that identified an invasive ductal carcinoma, found to be triple negative. The patient underwent chemotherapy followed by modified radical mastectomy. Conclusions. Triple negative breast cancer, during pregnancy or postpartum, poses a unique challenge and requires a multidisciplinary team to optimize treatment for these women.

  15. Isolated metachronous splenic metastasis from synchronous colon cancer

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    Aker Fugen

    2006-07-01

    Full Text Available Abstract Background Isolated splenic metastases from colorectal cancer are very rare and there are only 13 cases reported in the English literature so far. Most cases are asymptomatic and the diagnosis is usually made by imaging studies during the evaluation of rising CEA level postoperatively. Case presentation A 76-year-old man underwent an extended left hemicolectomy for synchronous colon cancers located at the left flexure and the sigmoid colon. The tumors were staged as IIIC (T3N2M0 clinically and the patient received adjuvant chemotherapy. During the first year follow-up period, the patient remained asymptomatic with normal levels of laboratory tests including CEA measurement. However, a gradually rising CEA level after the 14th postoperative month necessitated further imaging studies including computed tomography of the abdomen which revealed a mass in the spleen that was subsequently confirmed by 18FDG- PET scanning to be an isolated metastasis. The patient underwent splenectomy 17 months after his previous cancer surgery. Histological diagnosis confirmed a metastatic adenocarcinoma with no capsule invasion. After an uneventful postoperative period, the patient has been symptom-free during the one-year of follow-up with normal blood CEA levels, although he did not accept to receive any further adjuvant therapy. To the best of our knowledge, this 14th case of isolated splenic metastasis from colorectal carcinoma is also the first reported case of splenic metastasis demonstrated preoperatively by 18FDG PET-CT fusion scanning which revealed its solitary nature as well. Conclusion Isolated splenic metastasis is a rare finding in the follow-up of colorectal cancer patients and long-term survival can be achieved with splenectomy.

  16. Synchronous rectal and prostate cancer – The impact of MRI on incidence and imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Sturludóttir, Margrét, E-mail: margret.sturludottir@karolinska.se [Department of Radiology, Karolinska University Hospital, 17176 Solna (Sweden); Martling, Anna, E-mail: anna.martling@ki.se [Center of Surgical Gastroenterology, Karolinska University Hospital, 17176 Solna (Sweden); Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Solna (Sweden); Carlsson, Stefan, E-mail: stefan.carlsson@ki.se [Department of Urology, Karolinska University Hospital, 17176 Solna (Sweden); Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Solna (Sweden); Blomqvist, Lennart, E-mail: lennart.k.blomqvist@ki.se [Department of Radiology, Karolinska University Hospital, 17176 Solna (Sweden); Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Solna (Sweden)

    2015-04-15

    Highlights: •Prostate and rectal cancers are two of the most common cancers in male. •Synchronous diagnosis of prostate and rectal cancer is a rare identity. •Strong increase in the synchronous diagnosis likely due to improved diagnostic methods. •Pre-treatment MRI for rectal cancer has led to increased synchronous diagnosis. -- Abstract: Objective: To evaluate the incidence of synchronous diagnosis of rectal and prostate cancer and to identify how the role of magnetic resonance imaging (MRI) for preoperative staging of rectal cancer has affected the incidence. Methods: Regional data from the Swedish Colorectal Cancer Registry and the Regional Cancer Registry in Stockholm-Gotland area (two million inhabitants) between the years 1995–2011 were used. Patients were included when the rectal cancer was diagnosed prior to the prostate cancer. Medical records and pre-treatment MRI were retrospectively reviewed. Results: Of 29,849 patients diagnosed with either disease, synchronous diagnosis was made in 29 patients (0.1%). Two patients were diagnosed in the years 1995–1999, seven patients between the years 2000–2005 and 20 patients between the years 2006–2011. The most common presentation, for the prostate cancer was incidental finding during staging for rectal cancer, n = 20, and of those led MRI to the diagnosis in 14 cases. At retrospective review, all patients had focal lesions in the prostate on MRI and patients with higher suspicion of malignancy on MRI had more locally advanced disease. Conclusion: Synchronous rectal and prostate cancer are a rare entity, but a strong increase in synchronous diagnosis is seen which may be attributed to improved diagnostic methods, including the use of pre-treatment MRI in routine work-up for rectal cancer.

  17. Synchronous rectal and prostate cancer – The impact of MRI on incidence and imaging findings

    International Nuclear Information System (INIS)

    Sturludóttir, Margrét; Martling, Anna; Carlsson, Stefan; Blomqvist, Lennart

    2015-01-01

    Highlights: •Prostate and rectal cancers are two of the most common cancers in male. •Synchronous diagnosis of prostate and rectal cancer is a rare identity. •Strong increase in the synchronous diagnosis likely due to improved diagnostic methods. •Pre-treatment MRI for rectal cancer has led to increased synchronous diagnosis. -- Abstract: Objective: To evaluate the incidence of synchronous diagnosis of rectal and prostate cancer and to identify how the role of magnetic resonance imaging (MRI) for preoperative staging of rectal cancer has affected the incidence. Methods: Regional data from the Swedish Colorectal Cancer Registry and the Regional Cancer Registry in Stockholm-Gotland area (two million inhabitants) between the years 1995–2011 were used. Patients were included when the rectal cancer was diagnosed prior to the prostate cancer. Medical records and pre-treatment MRI were retrospectively reviewed. Results: Of 29,849 patients diagnosed with either disease, synchronous diagnosis was made in 29 patients (0.1%). Two patients were diagnosed in the years 1995–1999, seven patients between the years 2000–2005 and 20 patients between the years 2006–2011. The most common presentation, for the prostate cancer was incidental finding during staging for rectal cancer, n = 20, and of those led MRI to the diagnosis in 14 cases. At retrospective review, all patients had focal lesions in the prostate on MRI and patients with higher suspicion of malignancy on MRI had more locally advanced disease. Conclusion: Synchronous rectal and prostate cancer are a rare entity, but a strong increase in synchronous diagnosis is seen which may be attributed to improved diagnostic methods, including the use of pre-treatment MRI in routine work-up for rectal cancer

  18. The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Han Wonshik

    2008-10-01

    Full Text Available Abstract Background Triple-negative (TN breast cancer, which is defined as being negative for the estrogen receptor (ER, the progesterone receptor (PR, and the human epidermal growth factor receptor 2 (HER-2, represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer. Methods Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated. Results Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (p = 0.003, and higher histologic and nuclear grade (p p p = 0.003, and a high level of p53 (p p p = 0.004. Relapse free survival (RFS was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001. On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS. Conclusion TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer.

  19. Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression.

    Directory of Open Access Journals (Sweden)

    Alicja M Kmiecik

    Full Text Available It has been recently found that metallothionein-3 (MT3 enhances the invasiveness and tumorigenesis of prostate cancer cells. This finding is in contrast to those of earlier studies, which indicated that overexpression of MT3 in breast cancer and prostate cancer cell lines inhibits their growth in vitro. Therefore, to clarify the role of MT3 in breast cancer progression, we analyzed the effect of MT3-overexpression on proliferation, invasiveness, migration, and tumorigenesis of breast cancer MDA-MB-231/BO2 cells. It was found that MDA-MB-231/BO2 cells overexpressing MT3 were characterized by increased invasiveness in vitro, compared to the control cells. Interestingly, this increased invasiveness correlated with a highly increased concentration of MMP3 in the culture supernatants (p<0.0001. Our data suggest that MT3 may regulate breast cancer cell invasiveness by modulating the expression of MMP3. These experimental results, obtained using triple-negative MDA-MB-231/BO2 cells, were further supported by clinical data. It was found that, in triple-negative breast cancer (TNBC, nuclear MT3 immunoreactivity in cancer cells tended to be associated with patients' shorter disease-specific survival, suggesting that nuclear MT3 expression may be a potential marker of poor prognosis of triple-negative TNBC cases.

  20. Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression.

    Science.gov (United States)

    Kmiecik, Alicja M; Pula, Bartosz; Suchanski, Jaroslaw; Olbromski, Mateusz; Gomulkiewicz, Agnieszka; Owczarek, Tomasz; Kruczak, Anna; Ambicka, Aleksandra; Rys, Janusz; Ugorski, Maciej; Podhorska-Okolow, Marzena; Dziegiel, Piotr

    2015-01-01

    It has been recently found that metallothionein-3 (MT3) enhances the invasiveness and tumorigenesis of prostate cancer cells. This finding is in contrast to those of earlier studies, which indicated that overexpression of MT3 in breast cancer and prostate cancer cell lines inhibits their growth in vitro. Therefore, to clarify the role of MT3 in breast cancer progression, we analyzed the effect of MT3-overexpression on proliferation, invasiveness, migration, and tumorigenesis of breast cancer MDA-MB-231/BO2 cells. It was found that MDA-MB-231/BO2 cells overexpressing MT3 were characterized by increased invasiveness in vitro, compared to the control cells. Interestingly, this increased invasiveness correlated with a highly increased concentration of MMP3 in the culture supernatants (p<0.0001). Our data suggest that MT3 may regulate breast cancer cell invasiveness by modulating the expression of MMP3. These experimental results, obtained using triple-negative MDA-MB-231/BO2 cells, were further supported by clinical data. It was found that, in triple-negative breast cancer (TNBC), nuclear MT3 immunoreactivity in cancer cells tended to be associated with patients' shorter disease-specific survival, suggesting that nuclear MT3 expression may be a potential marker of poor prognosis of triple-negative TNBC cases.

  1. 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.

  2. Synchronous Carcinoma of the Ampulla of Vater and Colon Cancer

    Directory of Open Access Journals (Sweden)

    Anastasios J. Karayiannakis

    2011-05-01

    Full Text Available Carcinoma of the papilla of Vater is a relatively rare tumor and its coexistence with other primary sporadic cancers is very exceptional. Here we report the case of a 76-year-old man who presented with painless obstructive jaundice, pathologically elevated liver function tests and increased serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen. Endoscopic retrograde cholangiography revealed a large polypoid mass in the ampulla of Vater. A large tumor in the ascending colon was also incidentally detected by abdominal computed tomography. Endoscopic biopsies from both lesions showed adenocarcinomas. Metastases to the liver and to the hepatoduodenal ligament and hepatic artery lymph nodes were found during surgery. Right colectomy and a biliary bypass were performed. Histological analysis showed an ampullary adenocarcinoma with metastases to regional lymph nodes and the liver and a colonic adenocarcinoma with local invasion into the pericolic fat. Treatment with gemcitabine plus cisplatin was suggested postoperatively. The association of sporadic ampullary and colonic adenocarcinomas and the mutually increased risk of developing either a synchronous or a metachronous tumor following each other should be considered in patients with primary ampullary or colorectal cancer during the preoperative evaluation and postoperative follow-up of these patients.

  3. 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.

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

    Science.gov (United States)

    2015-09-03

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

  5. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2016-08-01

    Bethesda, MD 11 th Annual Advances in Cancer Treatment Research, Albert Einstein College of Medicine, New York City, NY Recent Advances in the...California Cancer Consortium study. Clin Cancer Res 2008; 14: 7138–7142. 40 Modesitt SC, Sill M, Hoffman JS, Bender DP. A phase II study of vorinostat in the

  6. Triple primary urogenital cancer. A case of secondary cancers following combination therapy comprising chemotherapy plus radiation therapy for testicular cancer

    International Nuclear Information System (INIS)

    Iuchi, Hiromichi; Watabe, Yoshihiko; Hashimoto, Hiroshi; Kitahara, Katsuyuki; Takeyama, Yoshihiro; Fujita, Shinji

    2012-01-01

    A 68-year-old man was referred to our outpatient clinic with left renal cell cancer and bladder cancer. He had undergone combination therapy comprising chemotherapy plus radiation therapy following radical orchiectomy for testicular cancer at the age of 48 years. The right testis could be felt within the scrotum, however the left testis could not. Blood tests showed no abnormality in regard to testicular tumor markers. Urine cytology was class V. Computed tomography revealed a 3.0 x 3.4 cm mass in the left kidney and a 4.5 x 1.5 cm mass in the left wall of the bladder. We made it a priority to treat the bladder cancer which was strongly suspected to be invasive cancer. At first the patient underwent radical cystectomy. Then left partial nephrectomy was carried out. Our case would appear to be the 24th case of triple primary urogenital cancer in Japan that consisted of left testicular cancer, left renal cancer and bladder cancer. Our case was also thought to be a case of secondary cancer that developed following treatment for testicular cancer. (author)

  7. Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases

    NARCIS (Netherlands)

    Mekenkamp, L. J. M.; Koopman, M.; Teerenstra, S.; van Krieken, J. H. J. M.; Mol, L.; Nagtegaal, I. D.; Punt, C. J. A.

    2010-01-01

    Synchronous metastases of colorectal cancer (CRC) are considered to be of worse prognostic value compared with metachronous metastases, but only few and conflicting data have been reported on this issue. We retrospectively investigated patient demographics, primary tumour characteristics and overall

  8. MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis.

    Science.gov (United States)

    Dutta, Pranabananda; Sarkissyan, Marianna; Paico, Kimberly; Wu, Yanyuan; Vadgama, Jaydutt V

    2018-03-28

    Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression. ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay. Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities.

  9. Myc mediates cancer stem-like cells and EMT changes in triple negative breast cancers cells.

    Directory of Open Access Journals (Sweden)

    Shuping Yin

    Full Text Available Women with triple negative breast cancer (TNBC have poor prognosis compared to other breast cancer subtypes. There were several reports indicating racial disparity in breast cancer outcomes between African American (AA and European American (EA women. For example, the mortality rates of AA breast cancer patients were three times higher than of EA patients, even though, the incidence is lower in AA women. Our in vitro studies indicate that cancer stem-like cells (CSCs derived from AA TNBC cell lines have significantly higher self-renewal potential (mammosphere formation than CSCs derived from EA cell lines. TNBC tumors express high levels of Myc compared to luminal A or HER2 expressing breast cancers. We studied the effects of c-Myc overexpression on CSCs and chemotherapy in AA, and EA derived TNBC cell line(s. Overexpression of c-Myc in AA derived MDA-MB-468 (Myc/MDA-468 cells resulted in a significant increase in CSCs and with minimal changes in epithelial-to-mesenchymal transition (EMT compared to the control group. In contrast, overexpression of c-Myc in EA derived MDA-MB-231(Myc/MDA-231 cells led to increased epithelial-to-mesenchymal transition (EMT, with a minimal increase in CSCs compared to the control group. Myc/MDA-468 cells were resistant to standard chemotherapeutic treatments such as iniparib (PARP inhibitor plus cisplatin, / iniparib, cisplatin, paclitaxel and docetaxel. However, Myc/MDA-231 cells, which showed EMT changes responded to iniparib with cisplatin, but were resistant to other drugs, such as iniparib, cisplatin, paclitaxel and docetaxel. Collectively, our results indicate that intrinsic differences in the tumor biology may contribute to the breast cancer disparities.

  10. Triple negative breast cancer in a male-to-female transsexual.

    Science.gov (United States)

    Pattison, S T; McLaren, B R

    2013-02-01

    There is limited published literature on the risk of breast cancer in transgender patients. We report a case of an aggressive triple negative inflammatory breast cancer in a male-to-female transsexual. This patient had a complicated psychiatric history with significant antipsychotic use, and the case raises several questions about the pathogenesis of this breast cancer. The literature on breast cancer in transgender patients and in relation to hyperprolactinaemia is reviewed. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

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

    Science.gov (United States)

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

    2017-10-01

    Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH) 2 D 3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH) 2 D 3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest

  12. CLINICAL AND BIOLOGICAL RELEVANCE OF EZH2 IN TRIPLE NEGATIVE BREAST CANCER

    Science.gov (United States)

    Hussein, Yaser R.; Sood, Anil K.; Bandyopadhyay, Sudeshna; Albashiti, Bassam; Semaan, Assaad; Nahleh, Zeina; Roh, Juwon; Han, Hee Dong; Lopez-Berestein, Gabriel; Ali-Fehmi, Rouba

    2014-01-01

    The polycomb group protein, enhancer of zeste homolog 2 (EZH2), is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of EZH2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with EZH2, cytokeratin 5/6, epidermal growth factor receptor 1(EGFR) and p53. The expression of these markers was correlated with clinicopathologic variables and patients’ outcome. Furthermore, in vivo EZH2 gene silencing was achieved using siRNA incorporated into chitosan nanoparticles. Out of 261 cases of invasive breast cancer, high expression of EZH2 was detected in 87 (33%) cases, and it was strongly associated with a triple-negative breast cancer phenotype (P<.001) compared to all other non-triple negative breast cancers. Furthermore, high EZH2 was significantly associated with high histologic grade (P=.01), estrogen receptor negativity (P<.001), progesterone receptor negativity (P<.001), EGFR positivity (P=.04), and high p53 expression (P<.001). Survival analysis demonstrated that patients with high EZH2 had a poorer overall survival, compared to those with low EZH2 (P=.03), and it retained its significance as an independent prognostic factor (P=.02). In addition, EZH2 gene silencing resulted in significant reduction in tumor growth (P<.01) in the orthotopic MB-231 mouse model of breast carcinoma. Our results show that high EZH2 expression is significantly associated with triple-negative breast cancer and decreased survival. EZH2 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation. PMID:22436627

  13. Clinicopathological Characteristics of Triple-negative Breast Cancers in the Northeast Region of Turkey

    Directory of Open Access Journals (Sweden)

    Bülent Yıldız

    2014-06-01

    Full Text Available Background: Triple-negative (TN breast cancer is a subtype of breast cancer characterised by a loss of estrogen receptor (ER, progesterone receptor (PR expression, and the absence of human epidermal growth factor (HER2 overexpression. Aims: To identify the relationships between clinicopathological characteristics of TN breast cancers in the northeast region of Turkey and disease free survival (DFS and overall survival (OS. Study Design: Retrospective clinical study. Methods: Seven hundred and eighty non-metastatic breast cancer patients were enrolled in this study. The relationships between TN breast cancer and other breast cancers with respect to clinicopathological characteristics, as well as DFS and OS, were studied. Results: The triple-negative phenotype was detected in 204 patients (27.1%. Patients with triple-negative breast cancer had more grade 2-3 tumours compared to those with other types of breast cancer (92.5% versus 84.3%, p=0.004. Invasive ductal carcinoma histology, on the other hand, was less prevalent in patients with TN breast cancer (77% versus 84.5%, p=0.016. No significant differences were identified between the groups in other clinicopathological variables. Relapse and mortality rates were higher in the TN group during the follow-up of both groups [57 (27.9% versus 89 (16.2%, p<0.001 for relapse; 27 (13.2% versus 37 (6.8%, p=0.005 for mortality]. The univariate analysis demonstrated shorter DFS and OS for patients with TN breast cancer compared to those with other types of breast cancer. In the multivariate analysis, patients with TN breast cancer were 2.21 times more likely to develop relapse, while the likelihood of death increased 3.21-fold (p<0.001 and p<0.001. Conclusion: Triple-negative breast cancers demonstrate a more aggressive clinical course compared to other breast cancers. More effective strategies should be developed for the treatment of this subgroup of breast cancer.

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

    Science.gov (United States)

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

    2012-07-01

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

  15. Deep Sequencing Reveals a MicroRNA Expression Signature in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Chang, Yao-Yin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Chuang, Eric Y

    2018-01-01

    Deep sequencing is an advanced technology in genomic biology to detect the precise order of nucleotides in a strand of DNA/RNA molecule. The analysis of deep sequencing data also requires sophisticated knowledge in both computational software and bioinformatics. In this chapter, the procedures of deep sequencing analysis of microRNA (miRNA) transcriptome in triple-negative breast cancer and adjacent normal tissue are described in detail. As miRNAs are critical regulators of gene expression and many of them were previously reported to be associated with the malignant progression of human cancer, the analytical method that accurately identifies deregulated miRNAs in a specific type of cancer is thus important for the understanding of its tumor behavior. We obtained raw sequence reads of miRNA expression from 24 triple-negative breast cancers and 14 adjacent normal tissues using deep sequencing technology in this work. Expression data of miRNA reads were normalized with the quantile-quantile scaling method and were analyzed statistically. A miRNA expression signature composed of 25 differentially expressed miRNAs showed to be an effective classifier between triple-negative breast cancers and adjacent normal tissues in a hierarchical clustering analysis.

  16. The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer

    International Nuclear Information System (INIS)

    Rhee, Jiyoung; Kim, Tae-You; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Im, Seock-Ah; Han, Wonshik; Ae Park, In; Noh, Dong-Young; Bang, Yung-Jue

    2008-01-01

    Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic 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 Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic 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 y, p = 0.003), and higher histologic 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 Ki67 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 (4-year RFS rate 85.5% vs. 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 higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer

  17. Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers.

    Science.gov (United States)

    Anantaraju, Hasitha Shilpa; Battu, Madhu Babu; Viswanadha, Srikant; Sriram, Dharmarajan; Yogeeswari, Perumal

    2016-05-01

    The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast cancers (TPBC & TNBC). The crystal structure of CatD at 2.5 Å resolution (PDB: 1LYB), which was complexed with Pepstatin A, was selected for computer-aided molecular modeling. The methods used in our study were pharmacophore modeling and molecular docking. Virtual screening was performed to identify small molecules from an in-house database and a large commercial chemical library. Cytotoxicity studies were performed on human normal cell line HEK293T and growth inhibition studies on breast adenocarcinoma cell lines, namely MCF-7, MDA-MB-231, SK-BR-3, and MDA-MB-468. Furthermore, RT-PCR analysis, in vitro enzyme assay, and cell cycle analysis ascertained the validity of the selected molecules. A set of 28 molecules was subjected to an in vitro fluorescence-based inhibitory activity assay, and among them six molecules exhibited >50 % inhibition at 25μM. These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules 1 and 17 showed single-digit micromolar GI50 values against MCF-7 and MDA-MB-231 cell lines.

  18. Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers.

    Science.gov (United States)

    Tung, Nadine; Gaughan, Elizabeth; Hacker, Michele R; Lee, Larissa J; Alexander, Brian; Poles, Emily; Schnitt, Stuart J; Garber, Judy E

    2014-07-01

    The majority of breast cancers developing in BRCA1 mutation carriers are triple negative breast cancers (TNBC), an aggressive subtype that accounts for 15-20 % of sporadic breast cancer. We compare the clinical outcome and sites of relapse of TNBC in BRCA1 mutation carriers and non-carriers who received adjuvant chemotherapy. Women with stage I-III TNBC who had BRCA1 testing within 36 months of diagnosis and received adjuvant chemotherapy were identified from clinical databases at two academic institutions. Sites of relapse, freedom from distant metastasis (FFDM), and breast cancer-specific survival (BCSS) were determined. RCA1 carriers (n = 89) were significantly younger at diagnosis (P < 0.0001) than non-carriers (n = 175). FFDM at 5 years was 80.5 % for carriers and 76.9 % for non-carriers; with median follow-up of 55 months, hazard ratio (HR) was 0.90, P = 0.71. Sites of recurrence, including brain, did not differ significantly. BCSS at 5 years was 88.1 % for carriers and 81.4 % for non-carriers; HR 0.60; P = 0.15 at 55 months follow-up. BRCA1 carriers who underwent oophorectomy had a significantly lower rate of death from TNBC, with an adjusted HR of 0.30 (95 % CI 0.10-0.94). Adjusting for age, oophorectomy, and prophylactic mastectomy, BRCA1 mutation status was not an independent predictor of survival (HR 2.1; P = 0.13). BRCA1 mutation carriers with TNBC had similar survival rates and sites of recurrence to non-carriers after treatment with conventional chemotherapy. Carriers who underwent oophorectomy had a significantly lower rate of breast cancer-related death; this finding should be studied further in all women with TNBC.

  19. Salicylate •Phenanthroline copper (II) complex induces apoptosis in triple-negative breast cancer cells.

    Science.gov (United States)

    Fan, Limei; Tian, Muyou; Liu, Yunyi; Deng, Ying; Liao, Zhengkai; Xu, Jinhua

    2017-05-02

    In this study, we investigated anti-tumor activity and associated molecular mechanism of action of Salicylate ●Phenanthroline Copper (II) Complex in triple-negative breast cancer. Salicylate ●Phenanthroline Copper (II) Complex inhibited the growth of four breast cancer cell lines (MCF-7, T47D, MDA-MB-231 and BT-20) and induced apoptosis in a concentration-dependent manner. The effect was more profound in MDA-MB-231 and BT-20 triple-negative breast cancer cell lines. Western blot showed that the expression of the apoptosis-related protein Bcl-2, Bcl-xl and survivin was significantly reduced in MDA-MB-231 after treatment with Salicylate ●Phenanthroline Copper (II) Complex. In vivo, Salicylate ●Phenanthroline Copper (II) Complex administration significantly attenuated tumor growth of MDA-MB-231 xenografts, and the expression levels of Bcl-2, Bcl-xL and survivin were reduced as measured by immunohistochemical staining. These data suggest that Salicylate ●Phenanthroline Copper (II) Complex is a promising novel therapeutic drug for triple-negative breast cancer and warrants further study.

  20. Does Lactation Mitigate Triple Negative/Basal Breast Cancer Progression

    Science.gov (United States)

    2013-11-01

    development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 1994, 54(16):4334-4341. 31. Stuelten CH, Barbul A, Busch JI...Briefly, on the day of sacrifice , 2 µCi of [14C]-sucrose (Amersham, Buckinghamshire, United Kingdom) was lyophilized and dissolved in sterile Trypan blue... chickens infected with Rous sarcoma virus. Cancer Res 1994, 54(16):4334-4341. 47. Stuelten CH, Barbul A, Busch JI, Sutton E, Katz R, Sato M

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

    Science.gov (United States)

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

    2012-01-01

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

  2. Targeting histone abnormality in triple negative breast cancer

    Science.gov (United States)

    2017-08-01

    important epigenetic modifiers such as LSD1, HDAC5, etc., promoted cellular proliferation and augmented formation of larger colonies in soft agar. We... cellular proliferation; and augments colony formation in soft agar; while attenuating motility and invasion (Fig. 4A-D). We found that overexpression...working on this project to advance their career goal in breast cancer and transition to an independent investigator. One postdoc fellow has completed his

  3. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2015-08-01

    negative tumors sensitized to tamoxifen by epigenetic therapy. The 58th ASMS Conference on Mass Spectrometry conference, Salt City, UT, May 23-27, 2010...and breast cancer: exploding the box, or unraveling the chromatin” 2013.9. The 24th Annual Vascular Biology and Hypertension Symposium...University of South Carolina 2013 Poster judge, 3rd Annual WCRC retreat, UPCI 2013 Poster judge, 24th Annual Vascular Biology and Hypertension Symposium

  4. Targeting Histone Abnormality in Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-08-01

    Sparano JA, Wang M, Zhao F, Stearns V, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge W Jr, Wood WC, Fetting J, Davidson NE. Obesity ...23264682 30. Sharma D, Davidson NE. Obesity and breast cancer: a multipartite connection. J Mammary Gland Biol Neoplasia. 18(3-4):253-5, 2013. PMID:24190309...American Fertility Society, New Orleans, LA Visiting Professor, Department of Medicine, Hahnemann University School of Medicine, Philadelphia, PA 1993

  5. Validation of a CFD model with a synchronized triple-lidar system in the wind turbine induction zone

    DEFF Research Database (Denmark)

    Meyer Forsting, Alexander Raul; Troldborg, Niels; Murcia Leon, Juan Pablo

    2017-01-01

    A novel validation methodology allows verifying a CFD model over the entire wind turbine induction zone using measurements from three synchronized lidars. The validation procedure relies on spatially discretizing the probability density function of the measured free-stream wind speed. The resulting...... distributions are reproduced numerically by weighting steady-state Reynolds averaged Navier-Stokes simulations accordingly. The only input varying between these computations is the velocity at the inlet boundary. The rotor is modelled using an actuator disc. So as to compare lidar and simulations, the spatial...... and temporal uncertainty of the measurements is quantified and propagated through the data processing. For all velocity components the maximal difference between measurements and model are below 4.5% relative to the average wind speed for most of the validation space. This applies to both mean and standard...

  6. Ferritin heavy chain in triple negative breast cancer

    DEFF Research Database (Denmark)

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

    2014-01-01

    to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part...... of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells...

  7. Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jeff C. Liu

    2018-04-01

    Full Text Available Summary: CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC, RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs. : Liu et al. report that inhibition of the protein phosphatase CDC25 kills diverse triple-negative breast cancer (TNBC cells. Moreover, CDC25 antagonists cooperate with other drugs, such as PI3K inhibitors, to efficiently suppress growth of human TNBC engrafted into mice. Keywords: triple negative breast cancer, basal-like breast cancer, therapy, RB1, PTEN, TP53, CDC25, WEE1, CHK1, checkpoint control

  8. 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

  9. A Liposome Encapsulated Ruthenium Polypyridine Complex as a Theranostic Platform for Triple-Negative Breast Cancer.

    Science.gov (United States)

    Shen, Jianliang; Kim, Han-Cheon; Wolfram, Joy; Mu, Chaofeng; Zhang, Wei; Liu, Haoran; Xie, Yan; Mai, Junhua; Zhang, Hang; Li, Zhi; Guevara, Maria; Mao, Zong-Wan; Shen, Haifa

    2017-05-10

    Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen) 2 dppz](ClO 4 ) 2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer.

  10. Is sunlight a predisposing factor for triple negative breast cancer in Turkey?

    Science.gov (United States)

    Mutlu, Hasan; Buyukcelik, Abdullah; Colak, Taner; Ozdogan, Mustafa; Erden, Abdulsamet; Aslan, Tuncay; Akca, Zeki

    2013-01-01

    INTRADUCTION: There is known to be a relationship between vitamin D level and more aggresive breast cancer subtypes, especially triple-negative breast cancer (TNBC). It was reported that sunlight exposure has an effect on the prognosis of patients with cancer, possibly related to the conversion of vitamin D to its active form with sunlight. We aimed to evaluate the effect of sunlight exposure on patients with TNBC. A total of 1,167 patients with breast cancer from two different regions of Turkey (Antalya and Kayseri, regions having different climate and sunlight exposure intensity over the year) were analysed retrospectively. The ratio of patients with TNBC was identified in those two regions. The ratio of patients with TNBC was 8% and 12% for Kayseri and Antalya regions, respectively, and this difference between the two groups was statistically significant (p=0.021). Sunlight exposure may be associated with more prevalent TNBC. This finding should be investigated with a prospective study.

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

    Science.gov (United States)

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

    2010-01-01

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

  12. The treatment and survival of patients with triple negative breast cancer in a London population.

    Science.gov (United States)

    Pal, Shrestha; Lüchtenborg, Margreet; Davies, Elizabeth A; Jack, Ruth H

    2014-01-01

    Triple negative breast cancer (TNBC) constitutes 10-15% of female breast cancers, and clinical guidelines recommend treatment with chemotherapy and surgery. We examined the recorded treatment and survival of women with TNBC in a population-based sample within the UK. Cancer registration data for North East London women diagnosed between 2005 and 2007 were supplemented with pathology data on hormone receptor status to determine triple negative status. Receipt of surgery, chemotherapy, radiotherapy, hormone therapy, or surgery plus chemotherapy according to TNBC status was assessed using logistic regression, and adjusted for age, stage of disease and socioeconomic deprivation. Five-year survival according to TNBC status and treatment was estimated using the Kaplan-Meier method and Cox regression analysis examined adjusted all-cause mortality. Triple negative status could be determined for 1228 of 2394 women with breast cancer and 128 (10%) had TNBC. Compared to patients without TNBC, patients with TNBC were more likely to receive chemotherapy (fully adjusted odds ratio (OR) =4.21, 95% confidence interval (CI) 2.63-6.75) or surgery plus chemotherapy (fully adjusted OR = 2.52, 95% CI 1.61-3.93). Of patients with TNBC, those who received surgery plus chemotherapy had the greatest 5-year survival estimate (0.74, 95% CI 0.60-0.83). Overall, patients with TNBC had a higher risk of death (fully adjusted hazard ratio (HR) =1.69, 95% CI 1.24-2.30) compared to those without TNBC. This population-based study found that despite women with TNBC being more likely to receive chemotherapy, or surgery plus chemotherapy, they had a poorer overall survival than with those without TNBC.

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

    Directory of Open Access Journals (Sweden)

    Rajeshwari Mehta

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

  14. Molecular heterogeneity in adjacent cells in triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Huebschman ML

    2015-08-01

    Full Text Available Michael L Huebschman,1 Nancy L Lane,1 Huaying Liu,1 Venetia R Sarode,2 Judith L Devlin,1 Eugene P Frenkel1,3 1Harold C Simmons Comprehensive Cancer Center, 2Department of Pathology, 3Division of Hematology-Medical Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA Purpose: This study interrogates the molecular status of individual cells in patients with triple-negative breast cancers and explores the molecular identification and characterization of these tumors to consider the exploitation of a potential-targeted therapeutic approach. Patients and methods: Hyperspectral immunologic cell by cell analysis was applied to touch imprint smears obtained from fresh tumors of breast cancer patients. Results: Cell by cell analysis confirms significant intratumoral molecular heterogeneity in cancer markers with differences from polymerase chain reaction marker reporting. The individual cell heterogeneity was recognized in adjacent cells examined with panels of ten molecular markers in each single cell and included some markers that are considered to express “stem-cell” character. In addition, heterogeneity did not relate either to the size or stage of the primary tumor or to the site from within the cancer. Conclusion: There is a very significant molecular heterogeneity when “adjacent cells” are examined in triple-negative breast cancer, thereby making a successful targeted approach unlikely. In addition, it is not reasonable to consider that these changes will provide an answer to tumor dormancy. Keywords: hyperspectral, cancer stem cells, CSC, CD44, CD24, ALDH1, uPAR, CD133, Her-2

  15. Insulin-like Growth Factor-Dependent Proliferation and Survival of Triple-Negative Breast Cancer Cells: Implications for Therapy

    Directory of Open Access Journals (Sweden)

    Zoë Davison

    2011-06-01

    Full Text Available Triple-negative breast cancers have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The prevailing view is that targeting the insulin-like growth factor (IGF signal transduction pathway will not be beneficial for triple-negative breast cancers because their growth is not IGF-responsive. The present study investigates the importance of IGFs in the proliferation and survival of triple-negative breast cancer cells. Estrogen and progesterone receptors, HER2, type I IGF, and insulin receptors were measured by Western transfer analysis. The effects of IGF-1 on proliferation were assessed by DNA quantitation and on cell survival by poly (ADP-ribose polymerase cleavage. The effect of IGF-1 on phosphorylation of the IGF receptors, Akt and mitogen-activated protein kinase, was measured by Western transfer analysis. Seven cell lines were identified as models of triple-negative breast cancer and shown to express IGF receptors at levels similar to those present in estrogen-responsive cell lines known to respond to IGFs. IGF-1 increased the proliferation and cell survival of all triple-negative cell lines. Proliferation was attenuated after reduction of type I IGF receptor expression. Cells that express higher levels of receptor were more sensitive to subnanomolar IGF-1 concentrations, but the magnitude of the effects was not correlated simply with the absolute amount or phosphorylation of the IGF receptors, Akt or mitogen-activated protein kinase. These results show that IGFs stimulate cell proliferation and promote cell survival in triple-negative breast cancer cells and warrant investigation of the IGF signal transduction pathway as a therapeutic target for the treatment of triple-negative breast cancer.

  16. A perspective on anti-EGFR therapies targeting triple-negative breast cancer

    Science.gov (United States)

    Nakai, Katsuya; Hung, Mien-Chie; Yamaguchi, Hirohito

    2016-01-01

    Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC. PMID:27648353

  17. The protective effect of longer duration of breastfeeding against pregnancy-associated triple negative breast cancer.

    Science.gov (United States)

    ElShamy, Wael M

    2016-08-16

    Parity associated breast cancer (PABC) often diagnosed within the 2-5 years after a full term pregnancy. PABC is usually present with more advanced, poorly differentiated, high-grade cancers that show shorter time to progression and often of the triple negative breast cancer (TNBC) subtype. Data from around the world show that pregnancy-associated TNBC is independently associated with poor survival, underscoring the impact of the pregnant breast microenvironment on the biology and consequently the prognosis of these tumors. Although it is not yet clear, a link between pregnancy-associated TNBCs and lack or shorter duration of breastfeeding (not pregnancy per se) has been proposed. Here, we present epidemiological and experimental evidence for the protective effect of longer duration of lactation against pregnancy-associated TNBCs, and propose a putative molecular mechanism for this protective effect and its effect in eliminating any potential TNBC precursors from the breast by the end of the natural breast involution.

  18. Pre-menopausal triple-negative breast cancer at HAM hospital medan

    Science.gov (United States)

    Betty; Laksmi, L. I.; Siregar, K. B.

    2018-03-01

    Triple-negative breast cancers (TNBC) are a type of breast cancer that does not have any or lack expression of the three receptors of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2). This cross-sectional study was performed on patients TNBC in HAM hospital Medan from 2013 to 2016 by immunohistochemistry stained. A total 60 invasive breast cancer samples with TNBC. The more frequent in TNBC group were 51-60 years (19 cases, 31.66%) and pre-menopause (34 cases, 57%). Tumor size T3 and T4 with staging IIIA and IIIB, histology sub-type IC-NOS and ILC with grade 2 and grade 3 of histologic was more common in TNBC.

  19. A new triple system DNA-Nanosilver-Berberine for cancer therapy

    Science.gov (United States)

    Grebinyk, Anna; Yashchuk, Valeriy; Bashmakova, Nataliya; Gryn, Dmytro; Hagemann, Tobias; Naumenko, Antonina; Kutsevol, Nataliya; Dandekar, Thomas; Frohme, Marcus

    2018-03-01

    The isoquinoline quaternary alkaloid Berberine possesses a variety of pharmacological properties that suggests its promising application for an anticancer delivery system design utilizing its ability to intercalate DNA. In the current work, we have investigated the effects of Berberine on the human T cell leukemia cell line in vitro. Fluorescent microscopy of leukemic cells revealed Berberine nuclear localization. The results showed that Berberine inhibited leukemic cell growth in a time- and dose-dependent manner, that was associated with reactive oxygen species production intensification and caspase 3/7 activity increase with followed apoptosis induction. Berberine was used as a toxic and phototoxic agent for triple system synthesis along with DNA as a carrier and nanosilver as a plasmonic accelerator of Berberine electronic transitions and high energy emission absorbent centers. The proposed method allows to obtain the complex of DNA with Berberine molecules and silver nanoparticles. The optical properties of free components as well as their various combinations, including the final triple system DNA-Nanosilver-Berberine, were investigated. Obtained results support the possibility to use the triple system DNA-Nanosilver-Berberine as an alternative therapeutic agent for cancer treatment.

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

    Directory of Open Access Journals (Sweden)

    Mina A

    2017-09-01

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

  1. Metronomic Chemotherapy in Triple-Negative Metastatic Breast Cancer: The Future Is Now?

    Directory of Open Access Journals (Sweden)

    M. E. Cazzaniga

    2017-01-01

    Full Text Available Triple-negative breast cancer (TNBC shows a very bad prognosis, even in early stages of disease. Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. In the present article, we review preclinical and clinical data of metronomic administration of chemotherapy agents with or without biological agents in TNBC cell lines and patients, contextually reporting data from the VICTOR-2 study in the subgroup of patients with TNBC, in order to stimulate new ideas for the design of clinical trials in this subset of patients.

  2. 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.

  3. Synchronous bilateral breast cancer in a patient with Klinefelter?s syndrome

    OpenAIRE

    Hoque, H M R; Kothari, A; Hamed, H; Fentiman, I S

    2010-01-01

    Synchronous bilateral male breast cancer (MBC) is rare and only a few cases have been reported in the literature. The majority of MBC patients have no definable risk factors. We describe a case with Klinefelter?s syndrome, prior thymic irradiation, testicular surgery, and first degree family history in a 61-year-old male.

  4. Invasive adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp and synchronous transverse colon cancer.

    Science.gov (United States)

    Chen, Chuang-Wei; Hsiao, Koung-Hong; Yue, Chung-Tai; Wang, Chia-Chi

    2013-08-28

    An admixture of hyperplastic and adenomatous components within the same polyp is unusual. Adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp (MHAP) occurs even more rarely. We report the first case of a 59-year-old male who presented with invasive adenocarcinoma originating from a MHAP at a sigmoid colon and synchronous transverse colon cancer.

  5. Invasive adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp and synchronous transverse colon cancer

    OpenAIRE

    Chen, Chuang-Wei; Hsiao, Koung-Hong; Yue, Chung-Tai; Wang, Chia-Chi

    2013-01-01

    An admixture of hyperplastic and adenomatous components within the same polyp is unusual. Adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp (MHAP) occurs even more rarely. We report the first case of a 59-year-old male who presented with invasive adenocarcinoma originating from a MHAP at a sigmoid colon and synchronous transverse colon cancer.

  6. Cancers du sein bilatéraux synchrones et grossesse a l'institut Joliot ...

    African Journals Online (AJOL)

    Décrire notre stratégie diagnostique et thérapeutique dans les cancers du sein bilatéraux synchrones pendant la grossesse. L'âge gestationnel au moment du diagnostic du cancer était respectivement de 7; 21 et 25 semaines. Il s'agissait de stade IV et IIIA respectivement dans deux et un cas. Elles ont toutes bénéficié ...

  7. The exploration of contrasting pathways in Triple Negative Breast Cancer (TNBC).

    Science.gov (United States)

    Narrandes, Shavira; Huang, Shujun; Murphy, Leigh; Xu, Wayne

    2018-01-04

    Triple Negative Breast Cancers (TNBCs) lack the appropriate targets for currently used breast cancer therapies, conferring an aggressive phenotype, more frequent relapse and poorer survival rates. The biological heterogeneity of TNBC complicates the clinical treatment further. We have explored and compared the biological pathways in TNBC and other subtypes of breast cancers, using an in silico approach and the hypothesis that two opposing effects (Yin and Yang) pathways in cancer cells determine the fate of cancer cells. Identifying breast subgroup specific components of these opposing pathways may aid in selecting potential therapeutic targets as well as further classifying the heterogeneous TNBC subtype. Gene expression and patient clinical data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used for this study. Gene Set Enrichment Analysis (GSEA) was used to identify the more active pathways in cancer (Yin) than in normal and the more active pathways in normal (Yang) than in cancer. The clustering analysis was performed to compare pathways of TNBC with other types of breast cancers. The association of pathway classified TNBC sub-groups to clinical outcomes was tested using Cox regression model. Among 4729 curated canonical pathways in GSEA database, 133 Yin pathways (FDR pathways (p-value pathway while PPARα is the top Yang pathway in TNBC. The TNBC and other types of breast cancers showed different pathways enrichment significance profiles. Using top Yin and Yang pathways as classifier, the TNBC can be further subtyped into six sub-groups each having different clinical outcomes. We first reported that the FOMX1 pathway is the most upregulated and the PPARα pathway is the most downregulated pathway in TNBC. These two pathways could be simultaneously targeted in further studies. Also the pathway classifier we performed in this study provided insight into the TNBC heterogeneity.

  8. The synchronous prevalence of colorectal neoplasms in patients with stomach cancer.

    Science.gov (United States)

    Lee, Sang Su; Jung, Woon Tae; Kim, Cha Young; Ha, Chang Yoon; Min, Hyun Ju; Kim, Hyun Jin; Kim, Tae Hyo

    2011-10-01

    The association between stomach cancer and colorectal cancer is controversial. The purpose of this study was to determine the synchronous prevalence of colorectal neoplasms in patients with stomach cancer. A total of 123 patients with stomach cancer (86 male) and 246 consecutive, age- and sex-matched persons without stomach cancer were analyzed from July 2005 to June 2010. All of them underwent colonoscopy within 6 months after undergoing gastroscopy. The prevalence of colorectal neoplasms was significantly higher in the stomach cancer group (35.8%) than in the control group (17.9%) (P stomach cancer (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.71 to 5.63). In particular, the difference in the prevalence of colorectal neoplasms was more prominent in the patients above 50 years old (OR, 3.54; 95% CI, 1.80 to 6.98). The results showed that the synchronous prevalence of colorectal neoplasms was higher in patients with stomach cancer than in those without stomach cancer. Therefore, patients with stomach cancer should be regarded as a high-risk group for colorectal neoplasms, and colonoscopy should be recommended for screening.

  9. Pretreatment Hematocrit Is Superior to Hemoglobin as a Prognostic Factor for Triple Negative Breast Cancer.

    Science.gov (United States)

    Chen, Bo; Dai, Danian; Tang, Hailin; Ai, Xiaohong; Chen, Xi; Zhang, Xiaoyan; Li, Zhiyan; Xie, Xiaoming

    2016-01-01

    Anemia usually refers to low hemoglobin (Hb) levels. Previous studies indicated that anemia negatively influence the survival in various cancers. Hematocrit (HCT) is the volume percentage of red blood cells in blood, which could indicate anemia in both individuals and populations. This study compared the value of HCT with that of Hb for predicting outcomes of patients who underwent treatment for triple negative breast cancer (TNBC). A retrospective study of 293 triple negative breast cancer patients, accepting treatment from January 2004 to December 2009 at Sun Yat-sen University Cancer Center, was conducted. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate disease free survival (DFS) and overall survival (OS). The cut-off value of HCT was 35.9% determined by X-tile software analysis. The cut-off value of Hb was 12.0 g/dl based on the World Health Organization (WHO) criteria. In univariate analysis, low HCT and low Hb were both significantly associated with decreased DFS and OS. In multivariate analysis, HCT (HR: 0.570; 95% CI: 0.331-0.981, P = 0.042 for DFS; HR: 0.456; 95% CI: 0.256-0.813, P = 0.008 for OS) was still identified as independent predictor of outcome, but not Hb. Pretreatment low HCT is independently associated with poor prognosis in TNBC patients. However, HCT was found to be superior to Hb in terms of predicting breast cancer mortality. In the future, large-scale prospective studies or validation studies are needed to verify our findings.

  10. Interest of radiotherapy of rectal cancer with synchronous metastases

    International Nuclear Information System (INIS)

    Tournat, H.; Vendrely, V.; Smith, D.; Capdepont, M.; Maire, J.P.; Cherciu, B.; Laurent, C.; Kantor, G.

    2008-01-01

    Purpose: There is no consensus about the treatment of rectal tumour when there are synchronous metastases. The interest of radiotherapy is debated. Patients and methods: Thirty-seven patients with rectal tumour and synchronous metastases were treated with radiotherapy first between September 1994 and December 2004. We analysed the tolerance, local control, resectability, overall survival of such a therapeutic strategy. Results: The mean follow-up was 30 months. Twenty-four tumors were resectable for both the primary site and the metastases. Thirteen were unresectable at the time of diagnosis. Thirty-three patients were treated with radio chemotherapy, ten with radiotherapy alone. Eighty-six decimal five percent of them had no pelvic symptom six weeks after the treatment. Twenty-one rectal tumours were finally resected. The disease progressed in six cases during the radiotherapy. Surgery of the metastases was possible for 12 patients with tumour initially resectable. Conclusion: Radio chemotherapy is a 'tolerable' treatment, in spite of more frequent urinary or digestive side-effects. But, if there is no surgery, palliative effect of radiotherapy is limited. (authors)

  11. {sup 18}F-FDG-PET/CT for systemic staging of newly diagnosed triple-negative breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ulaner, Gary A.; Castillo, Raychel; Riedl, Christopher C.; Jochelson, Maxine S. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Goldman, Debra A.; Goenen, Mithat [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Wills, Jonathan [Memorial Sloan Kettering Cancer Center, Department of Information Systems, New York, NY (United States); Pinker-Domenig, Katja [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States)

    2016-10-15

    National Comprehensive Cancer Network guidelines recommend {sup 18}F-FDG-PET/CT, in addition to standard staging procedures, for systemic staging of newly diagnosed stage III breast cancer patients. However, factors in addition to stage may influence PET/CT utility. As breast cancers that are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (triple-negative breast cancer, or TNBC) are more aggressive and metastasize earlier than other breast cancers, we hypothesized that receptor expression may be one such factor. This study assesses {sup 18}F-FDG-PET/CT for systemic staging of newly diagnosed TNBC. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with TNBC who underwent {sup 18}F-FDG-PET/CT in 2007-2013 prior to systemic or radiation therapy. Initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery, if performed prior to {sup 18}F-FDG-PET/CT. {sup 18}F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases, as well as unsuspected synchronous malignancies. Kaplan Meier survival estimates were calculated for initial stage IIB patients stratified by whether or not stage 4 disease was detected by {sup 18}F-FDG-PET/CT. A total of 232 patients with TNBC met inclusion criteria. {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 30 (13 %): 0/23 initial stage I, 4/82 (5 %) stage IIA, 13/87 (15 %) stage IIB, 4/23 (17 %) stage IIIA, 8/14 (57 %) stage IIIB, and 1/3 (33 %) stage IIIC. Twenty-six of 30 patients upstaged to IV by {sup 18}F-FDG-PET/CT were confirmed by pathology, with the remaining four patients confirmed by follow-up imaging. In addition, seven unsuspected synchronous malignancies were identified in six patients. Initial stage 2B patients who were upstaged to 4 by {sup 18}F-FDG-PET/CT had significantly shorter survival compared to

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

    Directory of Open Access Journals (Sweden)

    Balraj Singh

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

  13. Staged or simultaneous resection of synchronous liver metastases from colorectal cancer a systematic review

    DEFF Research Database (Denmark)

    Hillingso, J.G.; Wille-Jørgensen, Peer

    2009-01-01

    OBJECTIVE: A systematic review of the literature was undertaken to estimate the differences in length of hospital stay, morbidity, mortality and long-term survival between staged and simultaneous resection of synchronous liver metastases from colorectal cancer to determine the level of evidence......: For the reason of the heterogeneity of the observational studies, no odds ratios were calculated. In 11 studies, there was a tendency towards a shorter hospital stay in the synchronous resection group. Fourteen studies compared total perioperative morbidity and lower morbidity was observed in favour...

  14. Staged or simultaneous resection of synchronous liver metastases from colorectal cancer--a systematic review

    DEFF Research Database (Denmark)

    Hillingsø, J G; Wille-Jørgensen, P

    2008-01-01

    OBJECTIVE: A systematic review of the literature was undertaken to estimate the differences in length of hospital stay, morbidity, mortality and long-term survival between staged and simultaneous resection of synchronous liver metastases from colorectal cancer to determine the level of evidence......: For the reason of the heterogeneity of the observational studies, no odds ratios were calculated. In 11 studies, there was a tendency towards a shorter hospital stay in the synchronous resection group. Fourteen studies compared total perioperative morbidity and lower morbidity was observed in favour...

  15. Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Yusra Al Dhaheri

    Full Text Available In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer.We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2. Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol.In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration.

  16. Carnosol Induces ROS-Mediated Beclin1-Independent Autophagy and Apoptosis in Triple Negative Breast Cancer

    Science.gov (United States)

    Al Dhaheri, Yusra; Attoub, Samir; Ramadan, Gaber; Arafat, Kholoud; Bajbouj, Khuloud; Karuvantevida, Noushad; AbuQamar, Synan; Eid, Ali; Iratni, Rabah

    2014-01-01

    Background In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer. Results We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS) and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol. Conclusion In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration. PMID:25299698

  17. 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

  18. Prognostic aspects of dynamic contrast-enhanced magnetic resonance imaging in synchronous distant metastatic rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Jing; Xu, Qing; Song, Jia-Cheng; Li, Yan; Xu, Lu-Lu; Shi, Hai-Bin [First Affiliated Hospital of Nanjing Medical University, Department of Radiology, Nanjing (China); Huang, Dong-Ya [First Affiliated Hospital of Nanjing Medical University, Department of General Surgery, Nanjing (China)

    2017-05-15

    To explore the correlations between DCE-MRI quantitative parameters and synchronous distant metastasis and the clinicopathological factors in rectal cancers. Sixty-three patients with rectal cancer (synchronous distant metastasis, n = 31; non-metastasis, n = 32) were enrolled in this study. Student's t test and ANOVA were used to compare DCE-MRI parameters (K{sup trans}, K{sub ep} and V{sub e}). The receiver operating characteristic (ROC) analysis was used to find the reasonable threshold of DCE-MRI parameters to differentiate lesions with synchronous distant metastasis from those without metastasis. The K{sup trans}, K{sub ep}, and V{sub e} value were significantly higher in the lesions with distant metastasis than in the lesions without distant metastasis (0.536 ± 0.242 vs. 0.299 ± 0.118 min{sup -1}, p < 0.001; 1.598 ± 0.477 vs. 1.341 ± 0.390 min{sup -1}, p = 0.022; and 0.324 ± 0.173 vs. 0.249 ± 0.091, p = 0.034; respectively). The K{sup trans} showed the highest AUCs of 0.788 (p < 0.001), with sensitivity of 61.29 % and specificity of 87.5 %, respectively. DCE-MRI parameters may represent a prognostic indicator for synchronous distant metastases in patients with rectal cancer. (orig.)

  19. Synchronous Onset of Breast and Pancreatic Cancers: Results of Germline and Somatic Genetic Analysis

    Directory of Open Access Journals (Sweden)

    Michael Castro

    2016-07-01

    Full Text Available Background: Synchronous cancers have occasionally been detected at initial diagnosis among patients with breast and ovarian cancer. However, simultaneous coexistence and diagnosis of breast and pancreas cancer has not previously been reported. Case Report: Paternal transmission of a germline BRCA2 mutation to a patient who was diagnosed at age 40 with locally advanced breast and pancreas cancer is presented. Somatic genomic analysis of both cancers with next-generation DNA sequencing confirmed the germline result and reported a variety of variants of unknown significance alterations, of which two were present in both the breast and pancreas cancers. Discussion: The possibility that genomic alterations could have been responsible for modulating the phenotypic or clinical expression of this rare presentation is considered. The authors call attention to the practice of privatizing the clinicogenetic information gained from genetic testing and call for health policy that will facilitate sharing in order to advance the outcomes of patients diagnosed with hereditary cancers.

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

    Science.gov (United States)

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

    2017-01-03

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

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

    Science.gov (United States)

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

    2013-01-01

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

  2. Expression of ARs in triple negative breast cancer tumors: a potential prognostic factor?

    Directory of Open Access Journals (Sweden)

    Giannos A

    2015-07-01

    Full Text Available Aris Giannos,1 Martin Filipits,2 Flora Zagouri,2,3 Anita Brandstetter,2 Alexandra Tsigginou,1 Maria Sotiropoulou,4 Irene Papaspyrou,4 Theodoros N Sergentanis,5 Theodora Psaltopoulou,5 Alexandros Rodolakis,1 Aris Antsaklis,1 Meletios-Athanasios Dimopoulos,2 Constantine Dimitrakakis1 1Department of Obstetrics and Gynaecology, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece; 2Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 3Department of Clinical Therapeutics, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece; 4Department of Pathology, Alexandra General Hospital, Athens, Greece; 5Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece Background/aim: In light of the controversial published literature, this study aims to examine the potential prognostic role of AR immunohistochemical expression in triple negative breast cancer (TNBC.Patients and methods: Ninety patients with TNBC were included in this study; the associations between AR expression (Allred score, clinicopathological variables (stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression, and overall survival were evaluated.Results: AR expression was not associated with stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression. AR immunopositivity was not associated with overall survival either at the univariate or at the multivariate Cox regression analysis (multivariate hazard ratio =0.66, 95% confidence interval: 0.26–1.70, P=0.393.Conclusion: AR expression does not seem to play a prognostic role in TNBC. Keywords: biomarkers, prognosis, AR, triple negative breast cancer

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

    Science.gov (United States)

    Lindner, Robert; Sullivan, Catherine; Offor, Onyinye; Lezon-Geyda, Kimberly; Halligan, Kyle; Fischbach, Neal; Shah, Mansi; Bossuyt, Veerle; Schulz, Vincent; Tuck, David P; Harris, Lyndsay N

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Robert Lindner

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

  5. Down’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship

    Directory of Open Access Journals (Sweden)

    Nandini Dey

    2017-06-01

    Full Text Available Down’s syndrome (DS, the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21. Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001. A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982. A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015. Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance alteration(s were identified in ASXL1 (L1395V, NTRK1 (G18E, DDR2 (I159T, RUNX1 (amplification, ERG (amplification, SOX2 (T26A, FAM123B (G1031D, and HNF1A (A301T. Bonafide cancer-related genes of chromosome 21

  6. Down's Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship.

    Science.gov (United States)

    Dey, Nandini; Krie, Amy; Klein, Jessica; Williams, Kirstin; McMillan, Amanda; Elsey, Rachel; Sun, Yuliang; Williams, Casey; De, Pradip; Leyland-Jones, Brian

    2017-06-07

    Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1 . The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21

  7. Detection of miRNA regulatory effect on triple negative breast cancer transcriptome.

    Science.gov (United States)

    Martignetti, Loredana; Tesson, Bruno; Almeida, Anna; Zinovyev, Andrei; Tucker, Gordon C; Dubois, Thierry; Barillot, Emmanuel

    2015-01-01

    Identifying key microRNAs (miRNAs) contributing to the genesis and development of a particular disease is a focus of many recent studies. We introduce here a rank-based algorithm to detect miRNA regulatory activity in cancer-derived tissue samples which combines measurements of gene and miRNA expression levels and sequence-based target predictions. The method is designed to detect modest but coordinated changes in the expression of sequence-based predicted target genes. We applied our algorithm to a cohort of 129 tumour and healthy breast tissues and showed its effectiveness in identifying functional miRNAs possibly involved in the disease. These observations have been validated using an independent publicly available breast cancer dataset from The Cancer Genome Atlas. We focused on the triple negative breast cancer subtype to highlight potentially relevant miRNAs in this tumour subtype. For those miRNAs identified as potential regulators, we characterize the function of affected target genes by enrichment analysis. In the two independent datasets, the affected targets are not necessarily the same, but display similar enriched categories, including breast cancer related processes like cell substrate adherens junction, regulation of cell migration, nuclear pore complex and integrin pathway. The R script implementing our method together with the datasets used in the study can be downloaded here (http://bioinfo-out.curie.fr/projects/targetrunningsum).

  8. Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies.

    Science.gov (United States)

    Shaver, Timothy M; Lehmann, Brian D; Beeler, J Scott; Li, Chung-I; Li, Zhu; Jin, Hailing; Stricker, Thomas P; Shyr, Yu; Pietenpol, Jennifer A

    2016-08-15

    Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850-60. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer.

    Science.gov (United States)

    Lee, Soo Jung; Lee, Jeeyeon; Kim, Wan Wook; Jung, Jin Hyang; Park, Ho Yong; Park, Ji-Young; Chae, Yee Soo

    2018-01-01

    A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients. © 2018 S. Karger AG, Basel.

  10. Age-Related Frequency of Triple Negative Breast Cancer in Women

    International Nuclear Information System (INIS)

    Sajid, M. T.; Ahmad, M.; Mustafa, Q.; Shukr, I.; Azhar, M.

    2014-01-01

    Objective: To determine frequency of triple negative breast cancer (TNBC) in Pakistani women with respect to age. Study Design: Observational study. Place and Duration of Study: Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2005 to July 2010. Methodology: Pathological records of all specimens of breast cancer were reviewed and data was obtained for estrogen receptor (ER), progesterone receptor (PR) and HER-2 neu receptor proteins. Specimens having complete record of all three proteins were included for analysis. TNBC was defined as those who were ER, PR and HER-2 neu negative. Overall frequency as well as frequency with respect to age was calculated. Descriptive and categorical variables were analyzed using SPSS version 17. Results: Eight hundred and fifteen patients out of 4715 (17.28%) were found to be TNBC. Mean age of diagnosis of TNBC was found to be 46.26 A +- 12.22 years of age while other breast cancers had a mean age 52.90 A +- 9.78 years (p 50 years while majority of patients with other breast cancers were elderly females (p < 0.001). Conclusion: TNBC comprised 17.28% of the breast cancers in Pakistani women diagnosed at the studied centre. A higher frequency of TNBC was noted in significantly younger patients. (author)

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

    Science.gov (United States)

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

    2015-02-02

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

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Long-Term Complete Remission with nab-Paclitaxel, Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer

    Directory of Open Access Journals (Sweden)

    Alberto Montero

    2012-12-01

    Full Text Available This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2. In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m2, nab-paclitaxel 150 mg/m2, and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer.

  14. Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

    Science.gov (United States)

    vel Szic, Katarzyna Szarc; Declerck, Ken; Crans, René A.J; Diddens, Jolien; Scherf, David B.; Gerhäuser, Clarissa; Berghe, Wim Vanden

    2017-01-01

    Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment. PMID:28467815

  15. 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.

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

    International Nuclear Information System (INIS)

    Davis, A.A.; Kaklamani, V.G.

    2012-01-01

    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

  17. Update on the Treatment of Early-Stage Triple-Negative Breast Cancer.

    Science.gov (United States)

    Sharma, Priyanka

    2018-04-14

    Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared to other breast cancer subtypes. Currently, chemotherapy remains the main modality of treatment for early-stage TNBC, as there is no approved targeted therapy for this subtype. The biologic heterogeneity of TNBC has hindered the development and evaluation of novel agents, but recent advancements in subclassifying TNBC have paved the way for further investigation of more effective systemic therapies, including cytotoxic and targeted agents. TNBC is enriched for germline BRCA mutation and for somatic deficiencies in homologous recombination DNA repair, the so-called "BRCAness" phenotype. Together, germline BRCA mutations and BRCAness are promising biomarkers of susceptibility to DNA-damaging therapy. Various investigational approaches are consequently being investigated in early-stage TNBC, including immune checkpoint inhibitors, platinum compounds, PI3K pathway inhibitors, and androgen receptor inhibitors. Due to the biological diversity found within TNBC, patient selection based on molecular biomarkers could aid the design of early-phase clinical trials, ultimately accelerating the clinical application of effective new agents. TNBC is an aggressive breast cancer subtype, for which multiple targeted approaches will likely be required for patient outcomes to be substantially improved.

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

    Science.gov (United States)

    Parvani, Jenny G; Jackson, Mark W

    2017-04-01

    Over the past decade, RNA interference (RNAi) has been ubiquitously utilized to study biological function in vitro ; however, limitations were associated with its utility in vivo More recently, small interfering RNA (siRNA) nanoparticles with improved biocompatibility have gained prevalence as a potential therapeutic option for the treatment of various diseases. The adaptability of siRNA nanoparticles enables the delivery of virtually any siRNA, which is especially advantageous for therapeutic applications in heterogeneous diseases that lack unifying molecular features, such as triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast cancer that is stratified by the lack of estrogen receptor/progesterone receptor expression and HER2 amplification. There are currently no FDA-approved targeted therapies for the treatment of TNBCs, making cytotoxic chemotherapy the only treatment option available to these patients. In this review, we outline the current status of siRNA nanoparticles in clinical trials for cancer treatment and discuss the promising preclinical approaches that have utilized siRNA nanoparticles for TNBC treatment. Next, we address TNBC subtype-specific therapeutic interventions and highlight where and how siRNA nanoparticles fit into these strategies. Lastly, we point out ongoing challenges in the field of siRNA nanoparticle research that, if addressed, would significantly improve the efficacy of siRNA nanoparticles as a therapeutic option for cancer treatment. © 2017 Society for Endocrinology.

  19. 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.

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

    Science.gov (United States)

    Barbieri, Antonio; Quagliariello, Vincenzo; Del Vecchio, Vitale; Falco, Michela; Luciano, Antonio; Amruthraj, Nagoth Joseph; Nasti, Guglielmo; Ottaiano, Alessandro; Berretta, Massimiliano; Iaffaioli, Rosario Vincenzo; Arra, Claudio

    2017-02-28

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

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

    Directory of Open Access Journals (Sweden)

    Antonio Barbieri

    2017-02-01

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

  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. Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer

    NARCIS (Netherlands)

    Li, Bo; Chonghaile, Triona Ni; Fan, Yue; Madden, Stephen F.; Klinger, Rut; O'Connor, Aisling E.; Walsh, Louise; O'Hurley, Gillian; Udupi, Girish Mallya; Joseph, Jesuchristopher; Tarrant, Finbarr; Conroy, Emer; Gaber, Alexander; Chin, Suet-Feung; Bardwell, Helen A; Provenzano, Elena; Crown, John; Dubois, Thierry; Linn, Sabine; Jirstrom, Karin; Caldas, Carlos; O'Connor, Darran P; Gallagher, William M

    2017-01-01

    Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate

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

    Science.gov (United States)

    Zhao, Tiejun; Sun, Qiang; del Rincon, Sonia V; Lovato, Amanda; Marques, Maud; Witcher, Michael

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Tiejun Zhao

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

  6. Staged or simultaneous resection of synchronous liver metastases from colorectal cancer - a systematic review

    DEFF Research Database (Denmark)

    Hillingso, J.G.; Wille-Jørgensen, Peer

    2009-01-01

    A systematic review of the literature was undertaken to estimate the differences in length of hospital stay, morbidity, mortality and long-term survival between staged and simultaneous resection of synchronous liver metastases from colorectal cancer to determine the level of evidence for recommen......A systematic review of the literature was undertaken to estimate the differences in length of hospital stay, morbidity, mortality and long-term survival between staged and simultaneous resection of synchronous liver metastases from colorectal cancer to determine the level of evidence...... were retrospective and had a general bias, because the staged procedure was significantly more often undertaken in patients with left-sided primary tumours and larger, more numerous and bi-lobar metastases. Analyses of primary outcomes were performed using the random effects model. For the reason...

  7. [Synchronous bilateral breast cancer and pregnancy: about 3 cases at Joliot Curie institute of Dakar (Senegal)].

    Science.gov (United States)

    Zongo, Nayi; Sawadogo, Yobi Alexis; Some, Some Ollo Roland; Bagre, Sidpawalmdé Carine; Ka, Sidy; Diouf, Doudou; Dieng, Mamadou Moustapha; Gaye, Papa Macoumba; Dem, Ahmadou

    2016-01-01

    To describe our diagnostic and therapeutic strategy against synchronous, bilateral breast cancer during the pregnancy. Gestational age at diagnosis of cancer was 7; 21 and 25 weeks respectively. Patients had stage IV and IIIA of breast cancer in two and one case respectively. They all received chemotherapy, two cases during pregnancy (6TEC and 3AC) and one case after delivery. Bilateral mastectomy was performed in one case. One patient died. The others were alive but all metastatic. Fetal growth restriction was noted in one case. This association leads to delayed diagnosis of cancer. Surgery is feasible and the type of intervention is only determined by the cancer stage. Chemotherapy is feasible and is associated with less foetal complications in the last two quarters of pregnancy.

  8. Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle

    Science.gov (United States)

    Zhang, Li; Varma, Nadimpalli RS; Gang, Zhang Z.; Ewing, James R.; Arbab, Ali S; Ali, Meser M

    2016-01-01

    There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs. PMID:28018751

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Jeroen F Vermeulen

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

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

    Science.gov (United States)

    Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Shin-Cheh; Pang, Jong-Hwei S.; Yeh, Chun-Nan; Hsu, Jun-Te; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Kittaka, Atsushi; Chen, Tai C.; Sun, Chi-Chin; Juang, Horng-Heng

    2016-01-01

    Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), the newly-synthesized 1α,25(OH)2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC. PMID:27110769

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

    Directory of Open Access Journals (Sweden)

    Kun-Chun Chiang

    2016-04-01

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

  13. Ultra-microsecond pulsed curcumin for effective treatment of triple negative breast cancers.

    Science.gov (United States)

    Mittal, Lakshya; Raman, Vishak; Camarillo, Ignacio G; Sundararajan, Raji

    2017-09-30

    Triple negative breast cancer (TNBC) is difficult to treat due to lack of the three receptors, commonly used for treating breast cancers. Current standard of cure is either ineffective or refractive to many patients. Thus, there is a critical need for alternate, affordable therapies for TNBC cancers. Towards this, electrical pulse-mediated chemotherapy, known as electrochemotherapy is a viable option, because it uses the synergy of electrical pulses and the anticancer properties of chemo drug. Considering the cost and the harsh side effects of various commonly administered chemo drugs, in this study, low cost, yet effective, natural phytochemical curcumin is studied for its anticancer effect on MDA-MB-231, TNBC cells. We applied eight 10 μs, 2500 V/cm or 5000 V/cm pulses with 10 μM concentration of curcumin, and measured cell viability and cytotoxicity. Results indicate that cell survival, as low as 4% was induced by 5000 V/cm pulses, after 72 h, while it was 15% after 24 h. This demonstrates the potential of this treatment for TNBC and the transfer to clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry.

    Science.gov (United States)

    Brewster, Abenaa M; Chavez-MacGregor, Mariana; Brown, Powel

    2014-12-01

    Breast cancer incidence is increasing worldwide, and breast cancer-related mortality is highest in women of African ancestry, who are more likely to have basal-like or triple-negative breast cancer (TNBC) than are women of European ancestry. Identification of cultural, epidemiological, and genetic risk factors that predispose women of African ancestry to TNBC is an active area of research. Despite the aggressive behaviour of TNBC, achievement of a pathological complete response with chemotherapy is associated with good long-term survival outcomes, and sensitivity to chemotherapy does not seem to differ according to ethnic origin. Discovery of the molecular signalling molecules that define TNBC heterogeneity has led to the development of targeted agents such as inhibitors of poly (ADP-ribose) polymerase-1 and mTOR and immunomodulatory drugs that are in the early stages of clinical testing. First, we summarise the existing published work on the differences reported on the epidemiology, biology, and response to systemic treatment of TNBC between women of African ancestry and white women, and identify some gaps in knowledge. Second, we review the opportunities for development of new therapeutic agents in view of the potential high clinical relevance for patients with TNBC irrespective of race or ethnic origin. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Description of a clinical case of synchronous cancer in the native and graft kidneys

    Directory of Open Access Journals (Sweden)

    A. V. Khaylenko

    2017-01-01

    Full Text Available Kidney transplantation is the most frequently performed organ transplant procedure in the world. The occurrence of malignant tumors is one of the well-known late complications of organ transplantation, which is induced by immunosuppressive therapy. In the vast majority of patients, kidney cancer occurs in the native organs; however, in a small percentage of cases, malignancies are found in the graft organ. The article describes a rare clinical case of a patient with synchronous cancer in the native and graft kidneys.

  16. Colorectal cancer with synchronous hepatic metastases: Systematic review of reports comparing synchronous surgery with sequential bowel-first or liver-first approaches.

    Science.gov (United States)

    Baltatzis, M; Chan, A K C; Jegatheeswaran, S; Mason, J M; Siriwardena, A K

    2016-02-01

    The management of colorectal cancer with synchronous liver-limited metastases currently lacks randomised trial evidence to inform case selection for any of the bowel-first, liver-first or synchronous surgery routes. We examine the literature to report outcome data from reports utilising all three approaches. A systematic review was conducted using OvidSP (including Embase, EBM Reviews and MEDLINE databases) to find articles reporting discrete peri-operative and long-term outcomes for patients undergoing sequential bowel-first, liver-first surgery or synchronous liver and bowel surgery. Of 223 unique citations, 3 cohort studies were identified comprising a pooled population of 1203 patients who completed treatment protocols between 1982 and 2011. Patients were allocated to bowel-first surgery (748 patients, 62.2%), liver-first surgery (75, 6.2%) or synchronous liver/bowel surgery (380, 31.6%). Minor complications were similar between procedures. Major complications were consistent with a pooled fixed estimate of 9.1% (95%CI: 7.6%-10.8%, I(2) = 48%). Post-operative death was rare and consistent with a pooled fixed effect estimate of 3.1% (95%CI: 2.2%-4.3%, I(2) = 0%). Median follow-up ranged from 25.1 to 40.0 months, with a pooled underlying 5-year survival fixed effect estimate of 44% (I(2) = 39%). This review assesses outcomes of patients with colorectal cancer with synchronous liver metastases managed by either synchronous, sequential liver-first or bowel-first surgery. Overall treatment-related mortality is low and survival is similar among the three groups. These findings provide support for the continued use of all three pathways until better evidence to guide selection of an individual treatment option is available. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Fleisher B

    2016-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Nicholas C D'Amato

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

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

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

    2015-11-27

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

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

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    Danica L. Rowe

    2009-09-01

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

  1. Associations of two-pore domain potassium channels and triple negative breast cancer subtype in The Cancer Genome Atlas: systematic evaluation of gene expression and methylation.

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    Dookeran, Keith A; Zhang, Wei; Stayner, Leslie; Argos, Maria

    2017-09-12

    It is unclear whether 2-pore domain potassium channels are novel molecular markers with differential expression related to biologically aggressive triple-negative type breast tumors. Our objective was to systematically evaluate associations of 2-pore domain potassium channel gene expression and DNA methylation with triple-negative subtype in The Cancer Genome Atlas invasive breast cancer dataset. Methylation and expression data for all fifteen 2-pore domain potassium family genes were examined for 1040 women, and associations with triple-negative subtype (vs. luminal A) were evaluated using age/race adjusted generalized-linear models, with Bonferroni-corrected significance thresholds. Subtype associated CpG loci were evaluated for functionality related to expression using Spearman's correlation. Overexpression of KCNK5, KCNK9 and KCNK12, and underexpression of KCNK6 and KCNK15, were significantly associated with triple-negative subtype (Bonferroni-corrected p < 0.0033). A total of 195 (114 hypomethylated and 81 hypermethylated) CpG loci were found to be significantly associated with triple-negative subtype (Bonferroni-corrected p < 8.22 × 10 -8 ). Significantly negatively correlated expression patterns that were differentially observed in triple-negative vs. luminal A subtype were demonstrated for: KCNK2 (gene body: cg04923840, cg13916421), KCNK5 (gene body: cg05255811, cg18705155, cg09130674, cg21388745, cg00859574) and KCNK9 (TSS1500: cg21415530, cg12175729; KCNK9/TRAPPC9 intergenic region: cg17336929, cg25900813, cg03919980). CpG loci listed for KCNK5 and KCNK9 all showed relative hypomethylation for probability of triple-negative vs. luminal A subtype. Triple-negative subtype was associated with distinct 2-pore domain potassium channel expression patterns. Both KCNK5 and KCNK9 overexpression appeared to be functionally related to CpG loci hypomethylation.

  2. GINS2 regulates matrix metallopeptidase 9 expression and cancer stem cell property in human triple negative Breast cancer.

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    Peng, Liang; Song, Zhigang; Chen, Demeng; Linghu, Ruixia; Wang, Yingzhe; Zhang, Xingyang; Kou, Xiaoxue; Yang, Junlan; Jiao, Shunchang

    2016-12-01

    GINS2, a subunit of GINS complex, is critical for the initiation of DNA replication and DNA replication fork progression. The expression of GINS2 is misregulated in many malignant tumors, such as leukemia, breast cancer and melanoma. However, the role of GINS in breast cancer remains poorly characterized. We investigate the possible effect and particular mechanism of GINS in breast cancer cells. We showed that expression of GINS2 is enriched in triple negative breast cancer (TNBC) cell lines. Furthermore, GINS2 knockdown decreased the growth, invasive ability and stem-like property of TNBC cells. Mechanistically, silencing of GINS2 in TNBC cells caused dramatic decrease of matrix metalloproteinase-9 (MMP9). Finally, the abundance of GINS2 correlated with the advance stages of tumor in human TNBC patients. Our studies provided insight into the molecular regulation of TNBC progression and invasion. More importantly, our data suggest that GINS2 could be an outstanding therapeutic target for inhibiting invasive TNBC growth and metastasis. Copyright © 2016. Published by Elsevier Masson SAS.

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

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    Malathi Banda

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

  4. Lactoferrin- Endothelin-1 Axis Contributes to the Development and Invasiveness of Triple Negative Breast Cancer Phenotypes

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    Ha, Ngoc-Han; Nair, Vasudha; Reddy, Divijendra Natha Sirigiri; Mudvari, Prakriti; Ohshiro, Kazufumi; Ghanta, Krishna Sumanth; Pakala, Suresh B.; Li, Da-Qiang; Costa, Luis; Lipton, Allan; Badwe, Rajendra A.; Fuqua, Suzanne; Wallon, Margaretha; Prendergast, George C.; Kumar, Rakesh

    2013-01-01

    Triple-negative breast cancer (TNBC) is characterized by the lack of expression of ERα, PR and HER-2 receptors and the pathway(s) responsible for this downregulation and thus aggressiveness, remains unknown. Here we discovered that lactoferrin (Lf) efficiently downregulates the levels of ERα, PR and HER-2 receptors in a proteasome-dependent manner in breast cancer cells, and accounts for the loss of responsiveness to ER- or HER-2- targeted therapies. Further we found that Lf increases migration and invasiveness of both non-TNBC and TNBC cell lines. We discovered that Lf directly stimulates the transcription of endothelin-1 (ET-1), a secreted pro-invasive polypeptide that acts through a specific receptor ET(A)R, leading to secretion of bioactive ET-1 peptide. Interestingly, a therapeutic ET-1 receptor antagonist drug completely blocked Lf-dependent motility and invasiveness of breast cancer cells. Physiologic significance of this newly discovered Lf-ET-1 axis in the manifestation of TNBC phenotypes is revealed by elevated plasma and tissue Lf and ET-1 levels in TNBC patients as compared to those in ER+ cases. These findings describe the first physiologically relevant polypeptide as a functional determinant of downregulating all three therapeutic receptors in breast cancer which utilizes another secreted ET-1 system to confer invasiveness. Results presented here provide proof-of-principle evidence in support of therapeutic effectiveness of ET-1 receptor antagonist to completely block the Lf-induced motility and invasiveness of the TNBC as well as non-TBNC cells, and thus, opening a remarkable opportunity to treat TNBC by targeting the Lf-ET-1 axis using an approved developmental drug. PMID:22006997

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

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    Shuang Hao

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

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

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    Paolo Cossu-Rocca

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

  7. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer.

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    Grob, Tobias J; Heilenkötter, Uwe; Geist, Stefan; Paluchowski, Peter; Wilke, Christian; Jaenicke, Fritz; Quaas, Alexander; Wilczak, Waldemar; Choschzick, Matthias; Sauter, Guido; Lebeau, Annette

    2012-07-01

    Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population. We performed a comprehensive analysis of potential targetable genetic aberrations affecting the receptor tyrosine kinase/RAS/MAPK pathway, which are observed at higher frequencies in adenocarcinomas of other organs. Sixty-five individual TNBCs were studied by sequence analysis for HER2 (exon 18-23), EGFR (exon 18-21), KRAS (exon 2), and BRAF (exon 15) mutations. In addition, a tissue microarray was constructed to screen for EGFR gene copy gain and EML4-ALK fusion by FISH. Triple-negative status was confirmed by immunohistochemistry and FISH on tissue microarray sections. EGFR and CK5/6 immunohistochemical analyses were performed for identification of the basal-like phenotype. In addition, mutation analysis of TP53 (exon 5-8) was included. Sequence analysis revealed HER2 gene mutation in only one patient (heterozygous missense mutation in exon 19: p.L755S). No mutations were found in EGFR, KRAS, and BRAF. High polysomy of EGFR was detected in 5 of the 62 informative cases by FISH. True EGFR gene amplification accompanied by strong membranous EGFR protein expression was observed in only one case. No rearrangement of the ALK gene was detected. Basal-like phenotype was identified in 38 of the 65 TNBCs (58.5 %). TP53 gene mutation was found in 36/63 (57.1 %) tumors. We conclude that targetable genetic aberrations in the receptor tyrosine kinase/RAS/MAPK pathway occur rarely in TNBC.

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

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

    2017-01-01

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

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

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    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.

  10. Treatment of triple-negative breast cancer with Chinese herbal medicine: A prospective cohort study protocol.

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    Meng, Hui; Peng, Nan; Yu, Mingwei; Sun, Xu; Ma, Yunfei; Yang, Guowang; Wang, Xiaomin

    2017-11-01

    Triple-negative breast cancer (TNBC) is featured with the biological properties of strong aggressive behaviors, rapid disease progression, high risk of recurrence and metastasis, and low disease free survival. Patients with this tumor are insensitive to the endocrine therapy and target treatment for HER-2; therefore, chemotherapy is often used as routine treatment in clinical. Because of the fact that a considerable number of patients seek for Chinese herbal medicine (CHM) treatment after operation and chemotherapy and (or) radiotherapy, it is thus need to evaluate the correlation between Chinese herbal medicine treatment and prognosis. This is a multicenter, prospective cohort study started in March 2016 in Beijing. A simple of 220 participants diagnosed with TNBC were recruited from nine hospitals and are followed up every 3 to 6 months till March 2020. Detailed information of participants includes personal information, history of cancer, quality of life, symptoms of traditional Chinese medicine and fatigue status is taken face-to-face at baseline. The study has received ethical approval from the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University (No.2016BL-014-01). Articles summarizing the primary results and ancillary analyses will be published in peer-reviewed journals. Chinese Clinical Trial Registry: ChiCTR-OOC-16008246.

  11. Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems.

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    Nagaria, Teddy S; Shi, Changnian; Leduc, Charles; Hoskin, Victoria; Sikdar, Soma; Sangrar, Waheed; Greer, Peter A

    2017-10-06

    Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB-468 human TNBC cell lines, and in vitro effects on signaling and cytotoxicity, as well as in vivo effects on xenograft tumor growth and metastasis were assessed. The dual EGFR/HER2 inhibitor lapatinib (LPN) displayed greater cytotoxic potency and MAPK signaling inhibition than the EGFR inhibitor erlotinib, suggesting both EGFR and HER2 contribute to MAPK signaling in this TNBC model. The Raf inhibitor sorafenib (SFN) or the Mek inhibitor U0126 suppressed MAPK signaling to a greater extent than LPN; which correlated with greater cytotoxic potency of SFN, but not U0126. However, U0126 potentiated the cytotoxic efficacy of LPN and SFN in an additive and synergistic manner, respectively. This in-series Raf-Mek co-targeting synergy was recapitulated in orthotopic mouse xenografts, where SFN and the Mek inhibitor selumitinib (AZD6244) inhibited primary tumor growth and pulmonary metastasis. Raf and Mek co-inhibition exhibits synergy in TNBC models and represent a promising combination therapy for this aggressive breast cancer type.

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

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

    2014-01-01

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

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

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    Ramesh Narayanan

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

  14. Male occult triple-negative breast cancer with dermatomyositis: a case report and review of the literature

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    Zhang L

    2017-11-01

    Full Text Available Le Zhang,1 Chenghua Zhang,2 Zhaoying Yang,1 Miao He,3 Lijuan Zhang,1 Shereen Ezzat,4 Xi Liang5 1Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China; 2Endoscopy Department, Jilin Cancer Hospital, Changchun, Jilin,China; 3Department of Anesthesia, The Second Hospital of Jilin University, Changchun, Jilin, China; 4Ontario Cancer Institute and The Endocrine Oncology Site Group, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; 5Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China Abstract: Occult breast cancer is defined by the presence of axillary metastases without an identifiable primary breast tumor. Here, we report a rare case of a male occult breast cancer with dermatomyositis. We performed a modified radical mastectomy consisting of whole breast mastectomy and axillary lymph node dissection. Immunohistochemistry and fluorescent in situ hybridization analyses demonstrated an adenocarcinoma likely of breast origin, which was an occult triple-negative breast cancer. Interestingly, the patient’s previously noted periorbital dermatomyositis resolved promptly following surgical excision. Keywords: male breast cancer, occult breast cancer, triple-negative breast cancer, dermato­myositis 

  15. Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

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    Cecília P Popolin

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1 [Ru(SO4(dppb(bipy], (2 [Ru(CO3(dppb(bipy], (3 [Ru(C2O4(dppb(bipy] and (4 [Ru(CH3CO2(dppb(bipy]PF6 [where dppb = 1,4-bis(diphenylphosphinobutane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231, estrogen-dependent breast tumor cells (MCF-7 and a non-tumor breast cell line (MCF-10A. Complex (4 was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4 was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4 was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4 should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

  16. Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

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    Popolin, Cecília P; Reis, João P B; Becceneri, Amanda B; Graminha, Angélica E; Almeida, Márcio A P; Corrêa, Rodrigo S; Colina-Vegas, Legna A; Ellena, Javier; Batista, Alzir A; Cominetti, Márcia R

    2017-01-01

    Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

  17. Positive predictive value of additional synchronous breast lesions in whole-breast ultrasonography at the diagnosis of breast cancer: clinical and imaging factors

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    Ah Hyun Kim

    2014-07-01

    Conclusion: BWBU can detect additional synchronous malignancy at the diagnosis of breast cancer with a relatively high PPV, especially when mammography findings are correlated with ultrasonographic findings.

  18. Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells.

    Science.gov (United States)

    Burnett, Joseph P; Lim, Gi; Li, Yanyan; Shah, Ronak B; Lim, Rebekah; Paholak, Hayley J; McDermott, Sean P; Sun, Lichao; Tsume, Yasuhiro; Bai, Shuhua; Wicha, Max S; Sun, Duxin; Zhang, Tao

    2017-05-28

    Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs. Published by Elsevier B.V.

  19. Synchronous Diagnosis of Multiple Myeloma, Breast Cancer, and Monoclonal B-Cell Lymphocytosis on Initial Presentation

    Directory of Open Access Journals (Sweden)

    A. Vennepureddy

    2016-01-01

    Full Text Available The cooccurrence of more than one oncologic illness in a patient can present a diagnostic challenge. Here we report an unusual case of concomitant existence of multiple myeloma, breast cancer, and monoclonal B-cell lymphocytosis on initial presentation. The challenge was to accurately diagnose each disease and stage in order to maximize the therapeutic regimen to achieve cure/remission. Successful management of the patient and increased life expectancy can be achieved by multidisciplinary management and patient-oriented approach in multiple primary malignant synchronous tumors.

  20. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

    OpenAIRE

    Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi

    2016-01-01

    Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and...

  1. Breast cancer cells synchronous labeling and separation based on aptamer and fluorescence-magnetic silica nanoparticles

    Science.gov (United States)

    Wang, Qiu-Yue; Huang, Wei; Jiang, Xing-Lin; Kang, Yan-Jun

    2018-01-01

    In this work, an efficient method based on biotin-labeled aptamer and streptavidin-conjugated fluorescence-magnetic silica nanoprobes (FITC@Fe3O4@SiNPs-SA) has been established for human breast carcinoma MCF-7 cells synchronous labeling and separation. Carboxyl-modified fluorescence-magnetic silica nanoparticles (FITC@Fe3O4@SiNPs-COOH) were first synthesized using the Stöber method. Streptavidin (SA) was then conjugated to the surface of FITC@Fe3O4@SiNPs-COOH. The MCF-7 cell suspension was incubated with biotin-labeled MUC-1 aptamer. After centrifugation and washing, the cells were then treated with FITC@Fe3O4@SiNPs-SA. Afterwards, the mixtures were separated by a magnet. The cell-probe conjugates were then imaged using fluorescent microscopy. The results show that the MUC-1 aptamer could recognize and bind to the targeted cells with high affinity and specificity, indicating the prepared FITC@Fe3O4@SiNPs-SA with great photostability and superparamagnetism could be applied effectively in labeling and separation for MCF-7 cell in suspension synchronously. In addition, the feasibility of MCF-7 cells detection in peripheral blood was assessed. The results indicate that the method above is also applicable for cancer cells synchronous labeling and separation in complex biological system.

  2. Targeting Breast Cancer Stem Cells in Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-10-01

    overweight Fact Sheet. 2015. 3) Gonzalez-Perez RR, Lanier V, Newman G. Leptin’s Pro-Angiogenic Signature in Breast Cancer. Cancers ( Basel ) 2013;5:1140-1162...G. (2013) Leptin’s Pro-Angiogenic Signature in Breast Cancer. Cancers ( Basel ) 5: 1140-1162. 30) Gonzalez-Perez RR, Xu Y, Guo S, Watters A, Zhou W...12.47) 48.67 (± 11.15) 48.69 (± 11 Grade I 0 (0) 1 (3.03) 0 (0) II 6 (28.57) 10 (30.3) 3 (23.08) III 15 (71.43) 22 (66.67) 10 (76.92 Stage 1 1 (4.76) 1

  3. Pre-operative prognostic nutritional index predicts the outcomes for triple-negative breast cancer.

    Science.gov (United States)

    Yang, Zhengjun; Zhang, Bin; Hou, Likun; Xie, Yegong; Cao, Xuchen

    2014-12-01

    The purpose of this study was to investigate whether pre-operative prognostic nutritional index (PNI), an indicator of nutritional and immunological status, has an impact on the long-term outcomes in triple-negative breast cancer (TNBC) patients. This retrospective study reviewed the medical records of 382 TNBC patients who had suffered from mastectomy. Pre-operative PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm(3)). The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff value of PNI. The correlations of PNI value with clinicopathological features were analyzed and the univariate and multivariate analysis were applied to identify the prognostic factors. The results showed that pre-operative PNI value was significantly related to advanced tumor status such as N stage (p = 0.011), T stage (p = 0.015), and recurrence incidents (p = 0.001). Survival analysis identified PNI as an independent prognostic factor for TNBC. Patients with higher PNI value had better 5-year disease-free survival (DFS) and 5-year overall survival (OS) than those with lower PNI value (DFS, p = 0.007; OS, p = 0.011). Taken together, our results suggest that the pre-operative PNI can be used as a simple and useful marker for predicting the long-term outcomes of TNBC patients.

  4. Prognostic Value of E-Cadherin and β-Catenin in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Shen, Tiansheng; Zhang, Kui; Siegal, Gene P; Wei, Shi

    2016-11-01

    To analyze the expression of E-cadherin and β-catenin in triple-negative breast cancer (TNBC) to assess their prognostic significance. The expression of E-cadherin and β-catenin was examined semiquantitatively and correlated with other pathologic factors and survival outcomes. Of 72 consecutive TNBCs, 56% showed reduced membranous expression of E-cadherin or β-catenin, with a strong correlation to each other. Of the clinicopathologic factors analyzed, tumor size and nodal status were significantly associated with overall survival and disease-specific survival, while the latter remained an independent factor by multivariate analysis. Reduced E-cadherin and β-catenin were both significantly associated with a poor overall survival and disease-specific survival by univariate and multivariate analyses. E-cadherin and β-catenin expression provides discriminative prognostic power independent of conventional pathologic factors, thus further reinforcing the important role of cell adhesion molecules in the process of tumor metastasis, especially in TNBC. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer.

    Science.gov (United States)

    Chen, Zhong; Lan, Xun; Wu, Dayong; Sunkel, Benjamin; Ye, Zhenqing; Huang, Jiaoti; Liu, Zhihua; Clinton, Steven K; Jin, Victor X; Wang, Qianben

    2015-09-16

    Glucocorticoids (GCs) have been widely used as coadjuvants in the treatment of solid tumours, but GC treatment may be associated with poor pharmacotherapeutic response or prognosis. The genomic action of GC in these tumours is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC)-regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and are associated with unfavourable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR.

  7. Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy

    Science.gov (United States)

    López-Ozuna, Vanessa M.; Hachim, Ibrahim Y.; Hachim, Mahmood Y.; Lebrun, Jean-Jacques; Ali, Suhad

    2016-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. PMID:27480353

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

    Directory of Open Access Journals (Sweden)

    Zhang J

    2016-10-01

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

  9. Outcomes of Breast Cancer Patients With Triple Negative Receptor Status Treated With Accelerated Partial Breast Irradiation

    International Nuclear Information System (INIS)

    Wilkinson, J. Ben; Reid, Robert E.; Shaitelman, Simona F.; Chen, Peter Y.; Mitchell, Christine K.; Wallace, Michelle F.; Marvin, Kimberly S.; Grills, Inga S.; Margolis, Jeffrey M.; Vicini, Frank A.

    2011-01-01

    Purpose: Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). Methods and Materials: We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Results: Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). Conclusions: In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer.

  10. 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.

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Ye J

    2016-08-01

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

  13. Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from {sup 18}F-FDG PET/CT in operable triple-negative breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yong-il [CHA University, Department of Nuclear Medicine, CHA Bundang Medical Center, Seongnam (Korea, Republic of); Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Yong Joong [Veterans Health Service Medical Center, Seoul (Korea, Republic of); Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Chung, June-Key [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of)

    2017-10-15

    Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. A total of 228 patients with triple-negative breast cancer (mean age 47.0 ± 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P < 0.001), T stage (P = 0.010), N stage (P < 0.001), and TNM stage (P < 0.001) were significant parameters. In a multivariate survival analysis, SUVmax-N (P = 0.005), MTV (P = 0.008), and TLG (P = 0.006) with TNM stage (all P < 0.001) were significant parameters. Lymph node metabolic and volumetric parameters were significant predictors of recurrence in patients with triple-negative breast cancer after surgery. Lymph node metabolic and volumetric parameters were useful parameters for evaluating prognosis in patients with triple-negative breast cancer by {sup 18}F-FDG PET/CT, rather than tumor parameters. (orig.)

  14. 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.

  15. Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer.

    Science.gov (United States)

    Traina, Tiffany A; Miller, Kathy; Yardley, Denise A; Eakle, Janice; Schwartzberg, Lee S; O'Shaughnessy, Joyce; Gradishar, William; Schmid, Peter; Winer, Eric; Kelly, Catherine; Nanda, Rita; Gucalp, Ayca; Awada, Ahmad; Garcia-Estevez, Laura; Trudeau, Maureen E; Steinberg, Joyce; Uppal, Hirdesh; Tudor, Iulia Cristina; Peterson, Amy; Cortes, Javier

    2018-03-20

    Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

  16. 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.

  17. 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.

  18. Caveolin-1 expression as a prognostic marker in triple negative breast cancers of Asian women.

    Science.gov (United States)

    Yeong, Joe; Thike, Aye Aye; Ikeda, Murasaki; Lim, Jeffrey Chun Tatt; Lee, Bernett; Nakamura, Seigo; Iqbal, Jabed; Tan, Puay Hoon

    2018-02-01

    Triple-negative breast cancers (TNBCs) are defined by their lack of oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2. Although heterogeneous, the majority are aggressive and treatment options are limited. Caveolin acts as tumour suppressor or promoter depending on the cancer type. In this study, we aimed to determine if the expression levels of the candidate biomarker caveolin-1 on stromal or tumour cells were associated with clinicopathological parameters and disease outcomes in TNBCs from an ethnically diverse cohort of Asian women. Tumour specimens from 699 women with TNBC were subjected to immunohistochemical analysis of the frequency and intensity of caveolin-1 expression in tumour and stromal cells. A subset of 141 tumour samples also underwent Nanostring measurement of CAV1 mRNA. Results were correlated with clinicopathological parameters and disease outcomes. Expression of caveolin-1 in stromal cells was observed in 14.4% of TNBC cases. TNBCs of the basal-like phenotype (85% of samples) were significantly more likely to exhibit stromal cell caveolin-1 expression (p=0.028), as were those with a trabecular growth pattern (p=0.007). Lack of stromal caveolin-1 expression in both TNBCs and those with the basal-like phenotype was significantly associated with worse overall survival (p=0.009 and p=0.026, respectively): accordingly, increasing mRNA levels of CAV1 in TNBC samples predicted better overall survival. Caveolin-1 expression on TNBC tumour cells was not associated with clinical outcome. Stromal, but not tumoural, caveolin-1 expression is significantly associated with survival in Asian women with TNBC. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer.

    Science.gov (United States)

    Hunter, Francis W; Hsu, Huai-Ling; Su, Jiechuang; Pullen, Susan M; Wilson, William R; Wang, Jingli

    2014-11-01

    Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor clinical outcome and few validated drug targets. Two prevalent features of TNBC, tumor hypoxia and derangement of homologous recombination (HR) repair, are potentially exploitable for therapy. This study investigated whether hypoxia-activated prodrugs (HAP) of DNA-damaging cytotoxins may inhibit growth of TNBC by simultaneously addressing these two targets. We measured in vitro activity of HAP of DNA breakers (tirapazamine, SN30000) and alkylators (TH-302, PR-104, SN30548) in TNBC cell lines and isogenic models, and related this to measures of HR repair and expression of prodrug-activating enzymes. Antitumor activity of HAP was examined in isogenic BRCA2-knockout xenograft models and compared with platinum chemotherapy. All five HAP selectively inhibited growth of TNBC cell lines under hypoxia. Sensitivity to HAP was not strongly associated with BRCA1 genotype. However, HAP sensitivity was enhanced by suppression of HR (assessed by radiation-induced RAD51 focus formation) when BRCA1 and PALB2 were knocked down in a common (MDA-MB-231) background. Furthermore, knockout of BRCA2 markedly sensitized DLD-1 cells to the clinical nitrogen mustard prodrugs TH-302 and PR-104 and significantly augmented sterilization of clonogens by these agents in xenografts, both as monotherapy and in combination with radiotherapy, but had less effect on activity of the benzotriazine di-N-oxide SN30000. PR-104 monotherapy was more effective than cisplatin at inhibiting growth of BRCA2-knockout tumors at equitoxic doses. This study demonstrates the potential for HAP of nitrogen mustards to simultaneously exploit hypoxia and HR defects in tumors, with translational implications for TNBC and other HR-deficient malignancies. ©2014 American Association for Cancer Research.

  20. Theranostics of Triple-Negative Breast Cancer Based on Conjugated Polymer Nanoparticles.

    Science.gov (United States)

    Jin, Guorui; He, Rongyan; Liu, Qian; Dong, Yuqing; Lin, Min; Li, Wenfang; Xu, Feng

    2018-04-04

    Triple-negative breast cancer (TNBC) does not respond to many targeted drugs due to the lack of three receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2), which makes it difficult for TNBC detection and treatment. As compared to traditional breast cancer treatments such as surgery and chemotherapy, photodynamic therapy (PDT) has emerged as a promising approach for treating TNBC due to its precise controllability, high spatiotemporal accuracy, and minimal invasive nature. However, traditional photosensitizers used in PDT are associated with limitations of aggregation-caused quenching (ACQ), and the ACQ induced a significant decrease in reactive oxygen species (ROS) generation. To address these, we synthesized a cyclic arginine-glycine-aspartic acid (cRGD) peptide-decorated conjugated polymer (CP) nanoparticles with poly[2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylenevinylene] (MEH-PPV) as the photosensitizer for the theranostics of TNBC. The synthesized CP nanoparticles show bright fluorescence with high stability and could effectively produce ROS under light irradiation. Cell viability studies showed that the CP nanoparticles have negligible dark cytotoxicity and could efficiently kill the α v β 3 integrin-overexpressed MDA-MB-231 cells (one subtype of TNBC cells) in a selective way. With the use of cRGD-modified MEH-PPV nanoparticles as the theranostic agent, it permits targeted imaging and PDT of TNBC both in the in vitro 3D tumor model and in living mice. The application of CP nanoparticles in the successful theranostics of TNBC could pave the way for future development of CP-based photosensitizers for clinical applications.

  1. Triple negative breast cancer: looking for the missing link between biology and treatments

    Science.gov (United States)

    Frasci, Giuseppe; Chirico, Andrea; Esposito, Emanuela; Siani, Claudio; Saturnino, Carmela; Arra, Claudio; Ciliberto, Gennaro; Giordano, Antonio

    2015-01-01

    The so called “Triple Negative Breast Cancer” (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new “clever drugs” able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the

  2. Impact of BRCA Mutation Status on Survival of Women With Triple-negative Breast Cancer.

    Science.gov (United States)

    Yadav, Siddhartha; Ladkany, Rand; Yadav, Dhiraj; Alhalabi, Omar; Khaddam, Sinan; Isaac, Daniel; Cardenas, Paola Yumpo; Zakalik, Dana

    2017-12-30

    The effect of germline BRCA mutations on the outcomes of patients with triple-negative breast cancer (TNBC) is not well understood. The present retrospective study included women with newly diagnosed TNBC from January 1, 2004 to December 30, 2013. The demographic and tumor characteristics, genetic testing results, and outcomes were collected by a review of the patients' medical records. The outcomes were compared between the BRCA + and BRCA - women. Kaplan-Meier curves were plotted for survival analysis, and Cox proportional hazard regression was used to determine the predictors of recurrence-free survival. A total of 266 TNBC patients who had undergone BRCA testing were included in the final analysis. Of the 266 patients, 72 (27.0%) tested positive for a pathogenic BRCA mutation and 194 (73.0%) tested negative. BRCA + women were more likely to be diagnosed with breast cancer at a younger age than were the BRCA - women. Mutation carriers were also more likely to undergo bilateral mastectomy and less likely to receive radiation. The 2- and 5-year overall survival in BRCA + women was 97.1% and 83.1% and was 97.3% and 89.7% in the BRCA - women, respectively. No statistically significant difference was found in overall survival between the BRCA + and BRCA - group. No statistically significant difference was noted in the rate of locoregional recurrence, distant recurrence, or recurrence-free survival between the BRCA + and BRCA - women. Our study has demonstrated that BRCA mutation carrier status does not affect overall survival or recurrence-free survival in patients with TNBC. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2015-02-10

    Triple negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer (BC). Over the recent years, miRNA expression studies have been providing certain detailed overview that aberrant expression of miRNAs is associated with TNBC. Although TNBC tumors are strongly connected with loss of function of BRCA genes, there is no knowledge about the effect of BRCA mutation status on miRNA expressions in TNBC cases. The aims of this study were to evaluate the expression profile of miRNAs that plays role in TNBC progression and the role of BRCA mutations in their regulation. The expression level of BC associated 13 miRNAs was analyzed in 7 BRCA mutations positive, 6 BRCA mutations negative TNBC cases and 20 non-tumoral tissues using RT-PCR. According to RT2 Profiler PCR Array Data Analysis, let-7a expression was 4.67 fold reduced in TNBCs as compared to normal tissues (P=0.031). In addition, miR-200c expression was 5.75 fold reduced in BRCA mutation positive TNBC tumors (P=0.005). Analysis revealed a negative correlation between miR-200c and VEGFA expressions (r=-468). Thus, miR-200c may be involved in invasion and metastasis in TNBC cases with BRCA mutation. In this study we provide the knowledge on the first report of association between microRNA-200c and BRCA mutations in TNBC. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for TNBC treatment and new directions for the development of anticancer drugs. Copyright © 2014. Published by Elsevier B.V.

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

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    Thomas Karn

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

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  7. Laparoscopy-assisted combined resection for synchronous gastrointestinal multiple primary cancers.

    Science.gov (United States)

    Fang, Jia-feng; Zheng, Zong-heng; Huang, Yong; Wei, Bo; Huang, Jiang-long; Lei, Pu-run; Wei, Hong-bo

    2015-03-01

    Synchronous gastrointestinal multiple primary cancers (SGMPC) is infrequent. This study aimed to investigate the feasibility and outcomes of laparoscopy-assisted combined resection for SGMPC. We retrospectively reviewed 16 cases of SGMPC underwent either open or laparoscopy-assisted combined resection in the Third Affiliated Hospital of Sun Yat-sen University from Jan. 2005 to Jan. 2014. Sixteen cases contained synchronous colon cancers (n = 10), gastric and rectal cancer (n = 5), gastric and duodenal cancer (n = 1). Either laparoscopy-assisted or open procedure was performed. Compared with the open group, the laparoscopy group presented less blood loss (77.1 ± 46.3 ml vs. 145.0 ± 75.9 ml, P = 0.047) and shorter incision length (5.2 ± 0.7 cm vs. 16.4 ± 1.9 cm, P = 0.000), while no differences in operative time (228.3 ± 38.8 min vs. 188.8 ± 47.7 min, P > 0.05) and postoperative hospital stay (10.0 ± 3.4 days vs. 12.0 ± 4.8 days, P > 0.05). Two cases of postoperative complications occurred in the open group and one case of incision infection occurred in the laparoscopy one. Upon follow-up, 2 cases of open group (50.0%) and 8 cases of laparoscopy group (66.7%) were under status of disease free survival. Laparoscopy-assisted combined resection for SGMPC is feasible, safe and effective. Copyright © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  8. Treatment strategy for rectal cancer with synchronous metastasis: 65 consecutive Italian cases from the Bologna Multidisciplinary Rectal Cancer Group.

    Science.gov (United States)

    Pinto, Carmine; Pini, Sara; Di Fabio, Francesca; Cuicchi, Dajana; Iacopino, Bruno; Lecce, Ferdinando; Ercolani, Giorgio; Rojas Llimpe, Fabiola Lorena; De Raffele, Emilio; Stella, Franco; Di Tullio, PierGiorgio; Giaquinta, Stefania; Pinna, Antonio Daniele; Cola, Bruno

    2014-01-01

    Twenty percent of rectal cancer patients have synchronous distant metastasis at diagnosis. At present, the treatment strategy in this patient setting is not well defined. This study in one institution evaluates the treatment strategy of three different patient groups. Between January 2000 and July 2011, 65 patients with M1 rectal cancer were evaluated. Three different groups were defined: rectal cancer with resectable metastatic disease (group A); rectal cancer with potentially resectable metastatic disease (group B), and rectal cancer with unresectable metastatic disease (group C). Group A included 11 patients (16.9%), group B 28 patients (43.1%) and group C 26 patients (40%). Forty-three (66.2%) patients underwent surgery for primary rectal cancer, and 30 (46.2%) patients for metastasis resection (23 liver, 4 lung and 3 ovary). Median overall survival (OS) by group was: 51 (5-86; group A), 32 (24-40; group B) and 16 (7-26; group C) months. Patients undergoing metastasis resection have higher median OS than unresected patients (44 vs. 15 months; p cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach.

  9. A study of triple negative breast cancer at a tertiary cancer care ...

    African Journals Online (AJOL)

    Case files of all breast cancer patients were reviewed from the hospital database registered in 1 year and TNBC patients were selected for the study. Patient's characteristic, treatment, and histological features were analyzed. Results: A total of 322 patients were registered during the period of 1 year and 26% (84/322) of total ...

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

    Science.gov (United States)

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

    2015-11-01

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

  11. Synchronous uterine carcinosarcoma and contralateral breast cancer after tamoxifen therapy: a case report.

    Science.gov (United States)

    Shen, Ling; Hong, Liangli; Zhang, Guohong; Mai, Ruiqin

    2014-01-01

    Uterine carcinosarcoma (malignant mixed Müllerian tumor, MMMT) is a rare aggressive malignant tumor, which demonstrates both malignant epithelial (carcinoma) and mesenchymal (sarcoma) components. Synchronous uterine carcinosarcoma and contralateral breast cancer in patient received tamoxifen treatment had not been reported. We present a case of uterine carcinosarcoma co-occurrenced with contralateral breast cancer in a 56-year-old nulliparous, obese breast cancer patient, who had been treated with tamoxifen for 5 years. The patient presented with palpable pelvic mass and vaginal bleeding. Histopathological evidence revealed that the tumor was comprised of an admixture of malignant epithelial and mesenchymal components. The epithelial component was endometrioid type adenocarcinoma, while sarcomatous component had heterologous elements including fusiform cell sarcoma and a prominent component of cartilage. The infiltrating ductal carcinoma has been diagnosed on her right breast. The patient died of disease 8 months after diagnosis. Postmenopausal patients, with adjuvant tamoxifen treatment for breast cancer, are at increased risk for the development of uterine carcinosarcoma and less benefit for contralateral breast cancer.

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

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    Tingting Jiang

    2016-12-01

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

  13. 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

  14. 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

  15. 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

  16. Immunohistochemical, genetic and epigenetic profiles of hereditary and triple negative breast cancers. Relevance in personalized medicine.

    Science.gov (United States)

    Murria, Rosa; Palanca, Sarai; de Juan, Inmaculada; Alenda, Cristina; Egoavil, Cecilia; Seguí, Francisco J; García-Casado, Zaida; Juan, María J; Sánchez, Ana B; Segura, Ángel; Santaballa, Ana; Chirivella, Isabel; Llop, Marta; Pérez, Gema; Barragán, Eva; Salas, Dolores; Bolufer, Pascual

    2015-01-01

    This study aims to identify the profile of immunohistochemical (IHC) parameters, copy number aberrations (CNAs) and epigenetic alterations [promoter methylation (PM) and miR expression] related to hereditary (H) and triple negative (TN) breast cancer (BC). This profile could be of relevance for guiding tumor response to treatment with targeting therapy. The study comprises 278 formalin fixed paraffin-embedded BCs divided into two groups: H group, including 88 hereditary BC (HBC) and 190 non hereditary (NHBC), and TN group, containing 79 TNBC and 187 non TNBC (NTNBC). We assessed IHC parameters (Ki67, ER, PR, HER2, CK5/6, CK18 and Cadherin-E), CNA of 20 BC related genes, and PM of 24 tumor suppressor genes employing MLPA/MS-MLPA (MRC Holland, Amsterdam). MiR-4417, miR-423-3p, miR-590-5p and miR-187-3p expression was assessed by quantitative RT-PCR (Applied Biosystems). Binary logistic regression was applied to select the parameters that better differentiate the HBC or TN groups. For HBC we found that, ER expression, ERBB2 CNA and PM in RASSF1 and TIMP3 were associated with NHBC whereas; MYC and AURKA CNA were linked to HBC. For TNBC, we found that CDC6 CNA, GSTP1 and RASSF1 PM and miR-423-3p hyperexpression were characteristic of NTNBC, while MYC aberrations, BRCA1 hypermethylation and miR-590-5p and miR-4417 hyperexpression were more indicative of TNBC. The selected markers allow establishing BC subtypes, which are characterized by showing similar etiopathogenetic mechanisms, some of them being molecular targets for known drugs or possible molecular targets. These results could be the basis to implement a personalized therapy.

  17. Novel Model for Basaloid Triple-negative Breast Cancer: Behavior In Vivo and Response to Therapy

    Directory of Open Access Journals (Sweden)

    Lisa D Volk-Draper

    2012-10-01

    Full Text Available Introduction:The basaloid triple-negative breast cancer (B-TNBC is one of the most aggressive, therapy-resistant, and metastatic tumors. Current models do not recapitulate the basaloid phenotype of TNBC, thus limiting the understanding of its biology and designing new treatments. We identified HCC1806 as a line expressing typical B-TNBC markers, engineered a subline with traceable reporters, and determined growth, drug sensitivity, recurrence, and vascular and metastatic patterns of orthotopic xenografts in immunodeficient mice. Methods: mRNA and protein analyses showed that HCC1806 expresses basal but not luminal or mesenchymal markers. HCC1806-RR subline stably expressing red fluorescent protein and Renilla luciferase was generated and characterized for sensitivity to chemodrugs, orthotopic growth, vascular properties, recurrence, metastasis, and responsiveness in vivo. Results: The HCC1806 cells were highly sensitive to paclitaxel, but cytotoxicity was accompanied by pro-survival vascular endothelial growth factor-A loop. In vivo, HCC1806-RR tumors display linear growth, induce peritumoral lymphatics, and spontaneously metastasize to lymph nodes (LNs and lungs. Similarly to human B-TNBC, HCC1806-RR tumors were initially sensitive to taxane therapy but subsequently recur. Bevacizumab significantly suppressed recurrence by 50% and reduced the incidence of LN and pulmonary metastases by, respectively, 50% and 87%. Conclusions The HCC1806-RR is a new model that expresses bona fide markers of B-TNBC and traceable markers for quantifying metastases. Combination of bevacizumab with nab-paclitaxel significantly improved the outcome, suggesting that this approach can apply to human patients with B-TNBC. This model can be used for defining the metastatic mechanisms of B-TNBC and testing new therapies.

  18. Triple negative breast cancer: clinical characteristics in the different histological subtypes.

    Science.gov (United States)

    Dreyer, Geertje; Vandorpe, Thijs; Smeets, Ann; Forceville, Kathleen; Brouwers, Barbara; Neven, Patrick; Janssens, Hilde; Deraedt, Karen; Moerman, Philippe; Van Calster, Ben; Christiaens, Marie-Rose; Paridaens, Robert; Wildiers, Hans

    2013-10-01

    To investigate the clinical behavior of triple negative breast cancer (TNC), including age distribution, occurrence of LN (lymph node) invasion and prognosis in different histological subtypes. For this cohort study we used data on 476 patients with newly diagnosed TNC at the University Hospitals Leuven (Belgium) between 1999 and 2009. Of these, 395 received upfront surgery, 68 neoadjuvant chemotherapy and 21 had metastases at diagnosis. Apocrine and invasive lobular TNC occur more often in older patients compared to IDC-NOS. Of the primarily operated patients with TNC, 35.1% has pathological LN involvement. There were no significant differences in nodal invasion between different histological subtypes, but most subtypes contained few patients. In contrast to previous reports, 6/14 of apocrine TNC had LN involvement. Disease free survival (DFS) was different in different histological subtypes, but group sizes were insufficient to be able to draw firm conclusions. Within the histologically 'homogeneous' IDC-NOS group with primary surgery and outcome data (n = 300), DFS with 3.5 year median follow-up decreased with increasing age, but chemotherapy and radiotherapy were much less frequently given with increasing age. In multivariable analysis, lower age, presence of LN involvement, lack of administration of chemotherapy and radiotherapy were significant predictors of relapse. TNC is not a uniform disease. Different histological subtypes have different age distribution and behavior. The prognosis of the most common histological subgroup, IDC-NOS, is better in older patients, but this is counterbalanced by significantly decreased use of chemotherapy and radiotherapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer.

    Science.gov (United States)

    Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S; Ichihara, Shu; Ellis, Ian O; Reis-Filho, Jorge S; Weigelt, Britta

    2016-11-01

    Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Although the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intratumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by the MYB-NFIB fusion gene and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple

  20. Quantum-Dot-Based Theranostic Micelles Conjugated with an Anti-EGFR Nanobody for Triple-Negative Breast Cancer Therapy.

    Science.gov (United States)

    Wang, Yuyuan; Wang, Yidan; Chen, Guojun; Li, Yitong; Xu, Wei; Gong, Shaoqin

    2017-09-13

    A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs.

  1. Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.

    Science.gov (United States)

    Svec, Jiří; Schwarzová, Lucie; Janošíková, Bohumila; Stekrová, Jitka; Mandys, Václav; Kment, Milan; Vodička, Pavel

    2014-01-01

    Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points out the importance of sebaceous neoplasia, especially sebaceous adenocarcinoma, as cutaneous markers of MTS for timely implementation of cancer screening programs.

  2. Endoscopic hemostasis with endoscopic mucosal resection and multiple synchronous early gastric cancers: a case report

    Directory of Open Access Journals (Sweden)

    Fujihara Shintaro

    2012-08-01

    Full Text Available Abstract Introduction Endoscopic hemostasis for severe upper gastrointestinal bleeding due to tumors, such as gastrointestinal stromal tumors and malignant lymphoma, is temporarily effective. However, permanent hemostasis is difficult in many cases because of diffuse bleeding. Case presentation A 60-year-old Japanese woman was admitted to our hospital with hematemesis. Endoscopy revealed multiple gastric polyps and fresh blood in her stomach. One of the gastric polyps, which was associated with oozing bleeding, was found near the anterior wall of the lower gastric body. We initially applied hemostatic forceps and argon plasma coagulation over the tumor surface, but the bleeding persisted. After endoscopic mucosal resection, exposed vessels were seen at the base of the mucosal resection site with oozing bleeding. Coagulation of the bleeding vessels using hemostatic forceps allowed successful completion of the hemostatic procedure. Our patient also had eight synchronous gastric cancer lesions. Histological examination of the resected specimens showed various types of cancer. Conclusion This is a case report of gastric cancer associated with eight gastric cancer lesions, confirmed by histology, in which hemostasis was achieved through endoscopy.

  3. Results of immunohistochemistry diagnostics of breast cancer in the region of Grodno with consideration of the BRCA1 gene mutation in triple negative cancer

    OpenAIRE

    A. Yu. Krylov; M. G. Zubritsky; I. A. Kurstak; S. A. Lialikau; V. A. Basinski

    2017-01-01

    Background: The results of immunohistochemical (IHC) assessment in breast cancer may determine not only the outcome, but also the main directions of antitumor treatment.Aim: To study the results of IHC diagnosis of breast cancer in the Grodno region in 2010 to 2015, to determine the frequency of the BRCA1 gene mutations in triple-negative breast cancer.Materials and methods: 2008 cases of estrogen receptor and/or progesterone receptor positive and 2445 cases of HER2/neu expressing breast canc...

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

    International Nuclear Information System (INIS)

    Liu, Xianpeng; Gu, Xin; Sun, Limin; Flowers, Ashley B; Rademaker, Alfred W; Zhou, Yiran; Kiyokawa, Hiroaki

    2014-01-01

    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

  5. Pharmacological levels of Withaferin A (Withania somnifera trigger clinically relevant anticancer effects specific to triple negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Katarzyna Szarc vel Szic

    Full Text Available Withaferin A (WA isolated from Withania somnifera (Ashwagandha has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8, cell adhesion molecules (integrins, laminins, pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1. In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors

  6. Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells.

    Science.gov (United States)

    Szarc vel Szic, Katarzyna; Op de Beeck, Ken; Ratman, Dariusz; Wouters, An; Beck, Ilse M; Declerck, Ken; Heyninck, Karen; Fransen, Erik; Bracke, Marc; De Bosscher, Karolien; Lardon, Filip; Van Camp, Guy; Vanden Berghe, Wim

    2014-01-01

    Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy

  7. The prognostic value of the neoadjuvant response index in triple-negative breast cancer: validation and comparison with pathological complete response as outcome measure

    NARCIS (Netherlands)

    Jebbink, M.; van Werkhoven, E.; Mandjes, I. A. M.; Wesseling, J.; Lips, E. H.; Vrancken Peeters, M.-J. T. D. F.; Loo, C. E.; Sonke, G. S.; Linn, S. C.; Falo Zamora, C.; Rodenhuis, S.

    2015-01-01

    The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the

  8. The prognostic value of the neoadjuvant response index in triple-negative breast cancer : validation and comparison with pathological complete response as outcome measure

    NARCIS (Netherlands)

    Jebbink, M.; van Werkhoven, E.; Mandjes, I. A. M.; Wesseling, J.; Lips, E. H.; Peeters, M. -J. T. D. F. Vrancken; Loo, C. E.; Sonke, G. S.; Linn, S. C.; Falo Zamora, C.; Rodenhuis, S.

    The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the

  9. Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going

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    Omarini C

    2018-01-01

    Full Text Available Claudia Omarini, Giorgia Guaitoli, Stefania Pipitone, Luca Moscetti, Laura Cortesi, Stefano Cascinu, Federico Piacentini Department of Medical and Surgical Sciences for Children & Adults, Division of Medical Oncology, University Hospital of Modena, Modena, Italy Abstract: Triple-negative breast cancer (TNBC remains the poorest-prognosis breast cancer (BC subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile. Keywords: triple-negative breast cancer, neoadjuvant chemotherapy, BRCA, platinum, immunotherapy, PARP-1 inhibitors

  10. Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract.

    Science.gov (United States)

    Wang, Wen-Lun; Chang, Wei-Lun; Yang, Hsiao-Bai; Chang, I-Wei; Lee, Ching-Tai; Chang, Chi-Yang; Lin, Jaw-Town; Sheu, Bor-Shyang

    2015-07-01

    Patients with squamous cell carcinomas (SCC) of upper aerodigestive tract, either over head and neck (HNSCC) or esophagus (ESCC), frequently developed synchronous multiple cancers, leading to worse prognosis. This study validated whether suppression of host cancer immunosurveillance mediated by regulatory T cells (Treg) may predispose to the development of synchronous cancers. Tumor tissues of 200 patients (100 ESCC only, 50 HNSCC only, and 50 synchronous SCCs) were quantitatively accessed for the tumor infiltrating Treg by immunohistochemistry. The density of Treg was also correlated to the level of Treg-associated inhibitory cytokines (IL-10, IL-35 and TGF-β1), and chemokine (CCL22). The density of tumor infiltrating Treg in the index tumor (i.e. the first malignancy diagnosed) of synchronous SCC group was higher than those of HNSCC or ESCC only (prisk of synchronous cancer development to initiate a proper surveillance program. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. 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.

  12. Predictive Significance of Vascular Endothelial Growth Factor receptor VEGF-2 in triple-negative breast cancer patients

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    N. N. Babyshkina

    2016-01-01

    Full Text Available The identification of informative biomarkers that are able to predict prognosis and treatment response may be particularly important in triple negative breast cancer.The aim of the study was to investigate the relationship between vascular endothelial growth factor receptor VEGFR-2 expression and KDR gene polymorphisms with the efficacy of neoadjuvant chemotherapy (NAC in patients with triple negative breast cancer.Methods. The study included 70 patients with triple negative operable breast cancer (T1–3N0–3M0, who had received 2–4 cycles of FAC and CAX regimens. The pathologic complete response (pCR to treatment was determined by RECIST. VEGFR-2 expression level was evaluated using immunohistochemistry. Genotypes for KDR (rs2071559, rs2305948 were detected by a Real-time PCR.Results. The pCR rate was significantly associated with young age at diagnosis (≤50 years (p=0.0044, a high level of Ki67 expression (≥20 (p=0.0322 and with CAX regimen (p=0.0246. Additionally, all patients with pCR had the lack of VEGFR-2 expression in tumor tissue after surgery (p=0.0000. The presence of the VEGFR-2 expression (negative or positive in tumor tissue before NAC was associated with KDR rs2071559 (r=−0.297; p=0.0273. A significant correlation between the KDR rs2071559 and VEGFR-2 expression level (less than 70, 70% or more in the tumor tissue before NAC was found (r=−0.314; p=0.0297. Multivariate logistic regression analysis showed that the young age of the patients (≤50 years, the lack of VEGFR-2 expression after surgery and CAX regimen were significant predictors of NAC.Conclusion. The VEGFR-2 expression level in tumor tissue and KDR gene polymorphism can be considered as new additional molecular predictive markers of pathologic complete response to NAC in triple negative breast cancer patients.

  13. Outcome of triple-negative breast cancer in patients with or without markers regulating cell cycle and cell death

    OpenAIRE

    Ryu, Dong Won; Lee, Chung Han

    2012-01-01

    Purpose The genes p53 and B-cell lymphoma (bcl)-2 play an important role in regulating the mechanisms of apoptosis. In this paper, we retrospectively applied these factors to our series of triple negative breast cancer (TNBC) patients, in conjunction with an evaluation of the prognostic significance of these factors' influence on TNBC survival rate. Particular focus was placed on the role of bcl-2, p53, Ki-67. Methods The study subjects, 94 women with TNBC, were a subset of patients operated ...

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

    Science.gov (United States)

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

    2016-01-01

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

  15. Results of immunohistochemistry diagnostics of breast cancer in the region of Grodno with consideration of the BRCA1 gene mutation in triple negative cancer

    Directory of Open Access Journals (Sweden)

    A. Yu. Krylov

    2017-01-01

    Full Text Available Background: The results of immunohistochemical (IHC assessment in breast cancer may determine not only the outcome, but also the main directions of antitumor treatment.Aim: To study the results of IHC diagnosis of breast cancer in the Grodno region in 2010 to 2015, to determine the frequency of the BRCA1 gene mutations in triple-negative breast cancer.Materials and methods: 2008 cases of estrogen receptor and/or progesterone receptor positive and 2445 cases of HER2/neu expressing breast cancer were extracted from the database and IHC laboratory journals of the Grodno Regional Clinical Bureau for Pathological Anatomy. Standard DAKO kits (Denmark were used for IHC. Molecular genetic studies of DNA samples for the presence of the BRCA genes mutations were done by polymerase chain reaction in 449 women with breast cancer. BRCA1 mutation was assessed in 39 cases of triple-negative breast cancer.Results: HER2/neu overexpression (3+ was found in 25.5% (622/2445 of all breast cancer cases, whereas of estrogen receptor and progesterone receptor positive tumors in 50.05% (1105/2008 of cases. Triple negative breast cancer was diagnosed in 19.8% (398/2008 of cases, and the mean age of the patients at the diagnosis was 56.2 years. The BRCA1 gene mutations were identified in 5 of 39 (12.8% cases of triple negative breast cancer, which is significantly more often than in women with breast cancer without consideration of their hereditary predisposition (17/449, or 3.8%; χ2 = 4.87, p = 0.0274. Histological examination showed that among the tumors with the BRCA1 mutations, there were 3 cases with invasive ductal cancer (one G2 and two G3, one with medullary and one with undifferentiated G3 cancer. One patient had a metachronous bilateral lesion.Conclusion: In the region of Grodno, 50% of breast cancer patients would need hormonal therapy, 25% would need treatment with trastuzumab, and 20% with cytostatic agents. The

  16. Triple negative breast cancer in Moroccan women: clinicopathological and therapeutic study at the National Institute of Oncology

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    Rais Ghizlane

    2012-10-01

    Full Text Available Abstract Background Triple-negative breast cancer (TNBC is defined by the lack of estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER-2 expression. This is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. The aim of this study is to determine the clinicopathological, therapeutic features and outcomes associated with this type of breast cancer. Methods This is a retrospective study of confirmed triple negative breast cancer females collected at the National institute of oncology of Rabat in Morocco, between January 2007 and December 2008. Epidemiological, clinical, histological, therapeutic and evolutive data were analyzed. OS and DFS rates were estimated by Kaplan-Meier analysis. Results A total of one 152 patients with breast cancer, were identified as having triple-negative breast cancer (16,5%. The median age at diagnosis was 46 years. 130 patients (86% had infiltrating ductal carcinoma and thirteen had medullar carcinoma (9%. 84 cases (55% were grade III Scarff-Bloom-Richardson (SBR. 48 % had positive lymph nodes, and 5 % had distant metastases at diagnosis. According TNM staging, 12 patients (8% had stage I, 90 patients (60% had stage II and the 43(28% had stage III. 145 patients received surgery. 41 (28% had conservative surgery and 104 (72% received radical mastectomy with axillary lymph nodes dissection. 14 patients with advanced tumors or inflammatory breast cancer have received neoadjuvant chemotherapy and four patients (28% had complete pathologic response. From 131 patients how received adjuvant chemotherapy, 99 patients (75,5% had Anthracycline based chemotherapy and 27 patients (20,6% had sequential Anthracycline and docetaxel,. Seven patients with metastatic disease received anthracycline-based regimen in the first line metastatic chemotherapy. The median follow-up time was 46 months (range 6,1 -60 months. Overall survival at 5 years

  17. Breast cancer patient delay in Fukushima, Japan following the 2011 triple disaster: a long-term retrospective study.

    Science.gov (United States)

    Ozaki, Akihiko; Nomura, Shuhei; Leppold, Claire; Tsubokura, Masaharu; Tanimoto, Tetsuya; Yokota, Takeru; Saji, Shigehira; Sawano, Toyoaki; Tsukada, Manabu; Morita, Tomohiro; Ochi, Sae; Kato, Shigeaki; Kami, Masahiro; Nemoto, Tsuyoshi; Kanazawa, Yukio; Ohira, Hiromichi

    2017-06-19

    Little information is available concerning how patient delay may be affected by mass disasters. The main objectives of the present study are to identify whether there was a post-disaster increase in the risk of experiencing patient delay among breast cancer patients in an area affected by the 2011 triple disaster in Fukushima, Japan, and to elucidate factors associated with post-disaster patient delay. Sociodemographic factors (age, employment status, cohabitant status and evacuation status), health characteristics, and health access- and disaster-related factors were specifically considered. Records of symptomatic breast cancer patients diagnosed from 2005 to 2016 were retrospectively reviewed to calculate risk ratios (RRs) for patient delay in every year post-disaster compared with the pre-disaster baseline. Total and excessive patient delays were respectively defined as three months or more and twelve months or more from symptom recognition to first medical consultation. Logistic regression analysis was conducted for pre- and post-disaster patient delay in order to reveal any factors potentially associated with patient delay, and changes after the disaster. Two hundred nineteen breast cancer patients (122 pre-disaster and 97 post-disaster) were included. After adjustments for age, significant post-disaster increases in RRs of experiencing both total (RR: 1.66, 95% Confidence Interval (CI): 1.02-2.70, p disaster, and significant increases in the risk of excessive patient delay were observed in the second, fourth, and fifth years post-disaster, with more than five times the risk observed pre-disaster. A family history of any cancer was the only factor significantly associated with total patient delay post-disaster (odds ratio: 0.38, 95% CI: 0.15-0.95, p disaster. The triple disaster in Fukushima appears to have led to an increased risk of patient delay among breast cancer patients, and this trend has continued for five years following the disaster.

  18. Oromandibular reconstruction with chimeric double-skin paddle flap based on peroneal vessel axis for synchronous opposite double oral cancer.

    Science.gov (United States)

    Huang, Shih-Tsai; Liu, Wen-Chung; Chen, Lee-Wei; Yang, Kuo-Chung

    2015-05-01

    Synchronous double oral cancer represents the minority of cases of head and neck cancer. After tumor ablation, 2 separate oromandibular defects, even combined with a through-and-through oral defect, pose a serious reconstructive challenge. The ideal method for reconstruction remains controversial. Based on the peroneal vessel axis, a chimeric double-skin paddle peroneal fasciocutaneous or fibular osteomyocutaneous flap could be designed to accomplish the difficult reconstruction. Six male patients, each with 2 separate oromandibular defects after tumor ablation of synchronous double oral cancer, received double-skin paddle flap reconstruction with 3 peroneal fasciocutaneous and 3 fibular osteomyocutaneous flaps. All 6 flaps survived; however, complications included 1 skin paddle lost due to insufficient perfusion of a visible perforator, and 1 superficial necrosis occurring over the tip of a longer skin paddle. One postoperative intraoral infection and 1 donor site infection were also reported. During follow-up, 3 months later, 1 patient succumbed to local recurrence and bony metastasis. One patient developed a new cancer in the maxillary gingiva, and another had osteoradionecrosis 8 months later. Four patients gained acceptable cosmesis with good oral competence. A chimeric flap based on the peroneal artery could provide a segment of fibular bone, 1 or 2 skin paddles, and a cuff of the flexor hallucis longus muscle simultaneously. For 1-stage reconstruction of separate oromandibular defects after tumor ablation of synchronous double oral cancer, this design could provide all components at 1 transfer.

  19. Imaging and histologic prognostic factors in triple-negative breast cancer and carcinoma in situ as a prognostic factor.

    Science.gov (United States)

    Sebastián Sebastián, C; García Mur, C; Cruz Ciria, S; Rosero Cuesta, D S; Gros Bañeres, B

    2016-01-01

    To analyze what factors in magnetic resonance imaging (MRI) and histological study of triple-negative breast cancers are related to tumor recurrence and to shorter disease-free survival. To analyze survival and recurrence in function of the presence of an in situ component. This was a retrospective study of MRI staging examinations in 122 women with triple-negative breast cancer done from 2007 through 2014. In the MRI, we evaluated morphological variables (size, margins, morphology, internal signal in T2-weighted sequences) and dynamic variables (perfusion and diffusion). In the histological study, we evaluated Ki67, p53, CK5/6, nuclear grade, and Scarff-Bloom grade, as well as the presence of an in situ component and tumor grade (high grade or not high grade). We compared the variables between patients with tumor recurrence and those without, and we conducted a survival analysis. Non-nodular enhancement was more common in patients with tumor recurrence (p=0.038) and was associated with shorter disease-free survival (p=0.023). Neither diffusion restriction (p=0.079) nor ki67 (p=0.052) was associated with a worse prognosis. An in situ component was detected in 44% of triple-negative tumors, and a greater proportion of patients in the group with tumor recurrence had an in situ component; however, the presence of an in situ component was not associated with shorter survival (p = 0.185). Non-nodular enhancement was associated with a worse prognosis. Diffusion restriction, ki67, and the presence of an in situ component were not associated with shorter disease-free survival. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

    Science.gov (United States)

    Couch, Fergus J; Hart, Steven N; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E; Godwin, Andrew K; Pankratz, V Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I; Beckmann, Matthias W; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B; Slamon, Dennis J; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M; Tapper, William J; Durcan, Lorraine; Cross, Simon S; Pilarski, Robert; Shapiro, Charles L; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L; Vachon, Celine M; Eccles, Diana M; Fasching, Peter A

    2015-02-01

    Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. © 2014 by American Society of Clinical Oncology.

  1. Bilateral synchronous parathyroids cancer and femoral neck fracture as the complications of tertiary hyperparathyroidism

    Directory of Open Access Journals (Sweden)

    A F Romanchishen

    2013-12-01

    Full Text Available In the paper has presented the first in Russia observation of bilateral synchronous parathyroids cancer in patient with urolithiasis complicated by chronic pyelonephritis, renal insufficiency with tertiary hyperparathyroidism and femoral neck fracture. During observation of the patient in our hospital were found hyperparathyroid osteodystrophy, medial right femoral neck fracture, very high level of parathormone (1969,0 pg/ml, tumorous of right (16,0 × 17,0 mm and left (23,0 × 17,0 mm parathyroid glands located behind of inferior thyroid poles during ultrasound research. Surgical exploration has found bilateral whitish parathyroid tumorous with invasion to right recurrent laryngeal nerve. Were performed right hemithyroidectomy, left thyroid lobe resection and central neck dissections. Parathormone level has decreased to 3.5 times (up to 582 pg/ml. 20 minutes later after bilateral inferior parathyroidectomies. The regular hemodialysis was restore and six months later was successfully undertaken the hip prosthetics. Two year later after the surgery signs of parathyroid cancer relapses were no found.

  2. Surgical treatment of lung cancer with synchronous adrenal metastases: Adrenalectomy first.

    Science.gov (United States)

    Pardo Aranda, Fernando; Larrañaga Blanc, Itziar; Rivero Déniz, Joaquín; Trujillo, Juan Carlos; Rada Palomino, Arantxa; García-Olivares, Esteban; Rami Porta, Ramón; Veloso, Enrique Veloso

    2017-02-01

    The aim of this study is to present our patients with lung cancer and synchronous adrenal metastases treated with a reversal approach: starting with adrenalectomy and doing the lung resection second. A total of 108 laparoscopic adrenalectomies were performed, and we analyze a consecutive serie of 10 patients with isolated adrenal synchronous metastases from the lung, surgically treated in a sequential way. All patients underwent staging mediastinoscopy, and patients with positive lymph nodes were primary treated with chemotherapy. We analyze: postoperative morbidity, length of stay, time between the 2surgeries, suvival free progression and global survival. Survival analysis was performed by the Kaplan-Meier method. Mean age: 56.8 (41-73) years old. Of the total, 8 patients were surgically performed by laparoscopy. Metastases average size: 5.9 (3-10) cm. Days between the 2surgeries were 28 (12-35) days. No morbidity after adrenalectomy. Length of stay was 4.3 (3-5) days. Disease-free survival at 2 years was 60%, the 5-year overall survival was 30%, with a median survival of 41.5 (0-98) months. Adrenalectomy involves no significant morbidity and can be performed safely without delaying lung surgery, and allows us to operate the primary lung tumor successfully as long as we ensure complete resection of the adrenal gland. A multidisciplinary oncology committee must individualize all cases and consider this therapeutic approach in all patients with resectable primary tumor and resectable adrenal metastases. Copyright © 2017 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. 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

  4. Mifepristone Suppresses Basal Triple-Negative Breast Cancer Stem Cells by Down-regulating KLF5 Expression.

    Science.gov (United States)

    Liu, Rong; Shi, Peiguo; Nie, Zhi; Liang, Huichun; Zhou, Zhongmei; Chen, Wenlin; Chen, Haijun; Dong, Chao; Yang, Runxiang; Liu, Suling; Chen, Ceshi

    2016-01-01

    Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancers without effective targeted therapies. Mifepristone (MIF), a drug regularly used for abortion, has been reported to have anti-tumor activity in multiple hormone-dependent cancers, including luminal type breast cancers. In this study, we showed that MIF suppressed tumor growth of the TNBC cell lines and patient-derived xenografts in NOD-SCID mice. Furthermore, MIF reduced the TNBC cancer stem cell (CSC) population through down-regulating KLF5 expression, a stem cell transcription factor over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Interestingly, MIF suppresses the expression of KLF5 through inducing the expression of miR-153. Consistently, miR-153 decreases CSC and miR-153 inhibitor rescued MIF-induced down-regulation of the KLF5 protein level and CSC ratio. Taken together, our findings suggest that MIF inhibits basal TNBC via the miR-153/KLF5 axis and MIF may be used for the treatment of TNBC.

  5. Synchronicity from Synchronized Chaos

    Directory of Open Access Journals (Sweden)

    Gregory S. Duane

    2015-03-01

    Full Text Available The synchronization of loosely-coupled chaotic oscillators, a phenomenon investigated intensively for the last two decades, may realize the philosophical concept of “synchronicity”—the commonplace notion that related eventsmysteriously occur at the same time. When extended to continuous media and/or large discrete arrays, and when general (non-identical correspondences are considered between states, intermittent synchronous relationships indeed become ubiquitous. Meaningful synchronicity follows naturally if meaningful events are identified with coherent structures, defined by internal synchronization between remote degrees of freedom; a condition that has been posited as necessary for synchronizability with an external system. The important case of synchronization between mind and matter is realized if mind is analogized to a computer model, synchronizing with a sporadically observed system, as in meteorological data assimilation. Evidence for the ubiquity of synchronization is reviewed along with recent proposals that: (1 synchronization of different models of the same objective process may be an expeditious route to improved computational modeling and may also describe the functioning of conscious brains; and (2 the nonlocality in quantum phenomena implied by Bell’s theorem may be explained in a variety of deterministic (hidden variable interpretations if the quantum world resides on a generalized synchronization “manifold”.

  6. Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

    Directory of Open Access Journals (Sweden)

    Rust Steven

    2013-02-01

    Full Text Available Abstract Background The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options. Methods The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Results All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated

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

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    Kristianto Yuli Yarso

    2012-01-01

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

  8. Systemic Delivery of Anti-miRNA for Suppression of Triple Negative Breast Cancer Utilizing RNA Nanotechnology.

    Science.gov (United States)

    Shu, Dan; Li, Hui; Shu, Yi; Xiong, Gaofeng; Carson, William E; Haque, Farzin; Xu, Ren; Guo, Peixuan

    2015-10-27

    MicroRNAs play important roles in regulating the gene expression and life cycle of cancer cells. In particular, miR-21, an oncogenic miRNA is a major player involved in tumor initiation, progression, invasion and metastasis in several cancers, including triple negative breast cancer (TNBC). However, delivery of therapeutic miRNA or anti-miRNA specifically into cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miR-21 to block the growth of TNBC in orthotopic mouse models. The 15 nm therapeutic RNA nanoparticles contains the 58-nucleotide (nt) phi29 pRNA-3WJ as a core, a 8-nt sequence complementary to the seed region of miR-21, and a 39-nt epidermal growth factor receptor (EGFR) targeting aptamer for internalizing RNA nanoparticles into cancer cells via receptor mediated endocytosis. The RNase resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection into mice and strongly bound to tumors with little or no accumulation in healthy organs 8 h postinjection, and subsequently repressed tumor growth at low doses. The observed specific cancer targeting and tumor regression is a result of several key attributes of RNA nanoparticles: anionic charge which disallows nonspecific passage across negatively charged cell membrane; "active" targeting using RNA aptamers which increases the homing of RNA nanoparticles to cancer cells; nanoscale size and shape which avoids rapid renal clearance and engulfment by lung macrophages and liver Kupffer cells; favorable biodistribution profiles with little accumulation in healthy organs, which minimizes nonspecific side effects; and favorable pharmacokinetic profiles with extended in vivo half-life. The results demonstrate the clinical potentials of RNA nanotechnology based platform to deliver miRNA based therapeutics for cancer treatment.

  9. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus

    DEFF Research Database (Denmark)

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

    2012-01-01

    The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone recepto...

  10. HIV-1 matrix protein p17 and its variants promote human triple negative breast cancer cell aggressiveness.

    Science.gov (United States)

    Caccuri, Francesca; Giordano, Francesca; Barone, Ines; Mazzuca, Pietro; Giagulli, Cinzia; Andò, Sebastiano; Caruso, Arnaldo; Marsico, Stefania

    2017-01-01

    The introduction of cART has changed the morbidity and mortality patterns affecting HIV-infected (HIV + ) individuals. The risk of breast cancer in HIV + patients has now approached the general population risk. However, breast cancer has a more aggressive clinical course and poorer outcome in HIV + patients than in general population, without correlation with the CD4 or virus particles count. These findings suggest a likely influence of HIV-1 proteins on breast cancer aggressiveness and progression. The HIV-1 matrix protein (p17) is expressed in different tissues and organs of successfully cART-treated patients and promotes migration of different cells. Variants of p17 (vp17s), characterized by mutations and amino acid insertions, differently from the prototype p17 (refp17), also promote B-cell proliferation and transformation. Wound-healing assay, matrigel-based invasion assay, and anchorage-independent proliferation assay were employed to compare the biological activity exerted by refp17 and three different vp17s on the triple-negative human breast cancer cell line MDA-MB 231. Intracellular signaling was investigated by western blot analysis. Motility and invasiveness increased in cells treated with both refp17 and vp17s compared to untreated cells. The effects of the viral proteins were mediated by binding to the chemokine receptor CXCR2 and activation of the ERK1/2 signaling pathway. However, vp17s promoted MDA-MB 231 cell growth and proliferation in contrast to refp17-treated or not treated cells. In the context of the emerging role of the microenvironment in promoting and supporting cancer cell growth and metastatic spreading, here we provide the first evidence that exogenous p17 may play a crucial role in sustaining breast cancer cell migration and invasiveness, whereas some p17 variants may also be involved in cancer cell growth and proliferation.

  11. ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Clément Chevalier

    Full Text Available The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.

  12. PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients.

    Science.gov (United States)

    Absmaier, Magdalena; Napieralski, Rudolf; Schuster, Tibor; Aubele, Michaela; Walch, Axel; Magdolen, Viktor; Dorn, Julia; Gross, Eva; Harbeck, Nadia; Noske, Aurelia; Kiechle, Marion; Schmitt, Manfred

    2018-03-01

    Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to

  13. The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer.

    Science.gov (United States)

    Huang, Shang-Pen; Liu, Pei-Yao; Kuo, Chih-Jung; Chen, Chi-Long; Lee, Wei-Jiunn; Tsai, Yu-Hui; Lin, Yuan-Feng

    2017-06-02

    Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells. Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression

  14. Comparison of Radiologic Features of Triple-Negative and Estrogen Receptor/Progesteron Receptor Positive Breast Cancer

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    Kim, Young Joong; Kim, Keum Won; Kim, Dae Ho; Cho, Yong Jun; Hwang, Cheol Mog; Seo, Jae Young; Kim, Jin Suk; Yoon, Dae Sung [Dept. of Konyang University College of Medicine, Konyang University Hospital, Daejeon (Korea, Republic of); Kim, Gyu Soon [Dept. of Radiology, Eulji University College of Medicine, Eulji University Hospital, Daejeon (Korea, Republic of)

    2013-06-15

    To retrospectively investigate the imaging [mammographic, ultrasonographic (US), magnetic resonance (MR) imaging] features and standardized uptake values (SUV) in positron emission tomography (PET)/computed tomography (CT) of triple-negative breast cancers (TNBC) and to compare them with breast cancers that are either estrogen receptor (ER) positive or progesteron receptor (PR) positive. 155 breast cancers cases were identified in 134 women (mean age, 51 years; range, 31-86 years). Surgically confirmed TNBC (n = 27) and ER-positive/PR-positive breast cancers (n = 81) were included among them. Cancers were investigated with mammography (n = 81), US (n = 106), MR imaging (n = 34) and PET-CT (n = 59). Mammographic findings are identified by detection of characteristic masses and microcalcifications. US findings included tumor size, margin, tumor shape, calcification and posterior shadowing. MR findings included tumor size, shape, margin, internal enhancement, intratumoral signal intensity and kinetics. Peak SUVs (p-SUV) of breast cancers were evaluated in PET/CT. These findings were compared with TNBC and ER/PR positive groups. Mammographic findings had no significant association with the TNBC. High pathological grade (p < 0.05), larger than 2 cm in size, well-marginal mass, and round or oval-shaped (p < 0.05) is US were significantly associated with TNBC. In MR imaging, round mass shape (p < 0.05), well-circumscribed mass margin (p < 0.05), rim enhancement (p < 0.05), were significantly associated with TNBC. The peak SUV of TNBC tend to be higher than that of ER-positive/PR-positive breast cancer (7.95 {+-} 5.50 vs. 4.91 {+-} 3.00, p < 0.05). TNBC tend to have high pathological grade, are of a large, round and smooth mass with rim enhancement on MR and US. In addition to above features, PET-CT with SUV estimation can improve the accuracy of test through the evaluation of TNBC.

  15. The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer.

    Science.gov (United States)

    Du, Yongli; Song, Lianhua; Zhang, Liudi; Ling, Hao; Zhang, Yanhui; Chen, Haifei; Qi, Huijie; Shi, Xiaojin; Li, Qunyi

    2017-08-18

    The estrogen-related receptor α (ERRα) is an orphan receptor and a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor micro environments. Here we describe the discovery of novel potent inverse agonists of ERRα. In vitro, compound 11 potently inhibits ERRα's transcriptional activity by preventing endogenous PGC-1α and ERRα binding and suppresses the proliferation of different human cancer cell lines and the migration of breast cancer cells (MDA-MB-231). In vivo, compound 11 demonstrates a strong inhibitory effect on the growth of human breast cancer xenografts (MDA-MB-231) and the tumor growth is inhibited by 40.9% after treating with compound 11 (30 mg/kg). The binding mode shows that compound 11 interacts with the binding pocket of ERRα through hydrogen interactions with the residue Gly397 and hydrophobic interactions with the hydrophobic residues. All these results suggest that compound 11 represents a novel potent ERRα inverse agonist and is promising in the discovery of antitumor compounds for the treatment of triple negative breast cancer. Copyright © 2017. Published by Elsevier Masson SAS.

  16. Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A.

    Science.gov (United States)

    Huang, Qiuyue; Qin, Shanshan; Yuan, Xiaoning; Zhang, Liang; Ji, Juanli; Liu, Xuewen; Ma, Wenjing; Zhang, Yunfei; Liu, Pengfei; Sun, Zhiting; Zhang, Jingxuan; Liu, Ying

    2017-07-01

    We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

  17. ERRα regulates the growth of triple-negative breast cancer cells via S6K1-dependent mechanism.

    Science.gov (United States)

    Berman, Adi Y; Manna, Subrata; Schwartz, Naomi S; Katz, Yardena E; Sun, Yang; Behrmann, Catherine A; Yu, Jane J; Plas, David R; Alayev, Anya; Holz, Marina K

    2017-01-01

    Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.

  18. Outcomes of aggressive treatment in esophageal cancer patients with synchronous solitary brain metastasis.

    Science.gov (United States)

    Onal, Cem; Akkus Yildirim, Berna; Guler, Ozan Cem

    2017-07-01

    The aim of the present study was to investigate the outcomes of esophageal cancer (EC) patients with isolated synchronous brain oligometastasis (oligo-BM) treated with chemoradiotherapy (CRT) of the primary site and localized treatment of the BM with surgery, radiotherapy (RT) or radiosurgery. Of 125 EC patients investigated, seven patients (6%) had solitary BM. Six patients were diagnosed prior to, and one patient was diagnosed during, treatment. All patients were treated with neoadjuvant chemotherapy and whole-brain RT (WBRT) for BM. All but one patient received definitive CRT with a median RT dose of 50.4 Gy using conventional fractionation RT. The median age at diagnosis was 59 years (range, 48-77 years). Six patients succumbed to mortality, and one continued to receive systemic chemotherapy at the last visit. The median survival time of the patients was 18.9 months (range, 10.0-27.2 months). Median time to progression after completion of the treatments was 8 months (range, 3-9 months). Two patients had progression of the primary tumor, and one patient had progression of the BM. The neurological status of three patients with BM who were identified during the staging work-up did not deteriorate as a consequence of WBRT. In conclusion, the present study has demonstrated that aggressive treatment of the primary tumor and oligo-BM in patients with EC may prolong the survival time.

  19. Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs

    Directory of Open Access Journals (Sweden)

    Ringnér Markus

    2008-07-01

    Full Text Available Abstract Background Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods 32 K tiling microarray-based comparative genomic hybridization (aCGH was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5 unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29 displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and

  20. Early stage cost-effectiveness analysis of a BRCA1-like test to detect triple negative breast cancers responsive to high dose alkylating chemotherapy

    NARCIS (Netherlands)

    Miquel-Cases, Anna; Steuten, Lotte Maria Gertruda; Retel, Valesca P.; van Harten, Willem H.

    2015-01-01

    Purpose Triple negative breast cancers (TNBC) with a BRCA1-like profile may benefit from high dose alkylating chemotherapy (HDAC). This study examines whether BRCA1-like testing to target effective HDAC in TNBC patients can be more cost-effective than treating all patients with standard

  1. Increased sensitivity of African American triple negative breast cancer cells to nitric oxide-induced mitochondria-mediated apoptosis

    International Nuclear Information System (INIS)

    Martinez, Luis; Thames, Easter; Kim, Jinna; Chaudhuri, Gautam; Singh, Rajan; Pervin, Shehla

    2016-01-01

    Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells. Breast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed. NO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin. Ethnic differences in breast

  2. Synchronous Oligometastatic Non-Small Cell Lung Cancer and Isolated Renal Cell Carcinoma: A Case Report and Literature Review.

    Science.gov (United States)

    Nguyen, Timothy K; Louie, Alexander V

    2015-10-27

    A 58-year-old gentleman presenting with a progressive headache, visual disturbance, decreased appetite, and weight loss was found to have a localized clear cell carcinoma of the kidney and synchronous Stage IV non-small cell lung cancer with a solitary brain metastasis. This case illustrates the challenges in distinguishing between primary and metastatic disease in a patient with both renal cell carcinoma and lung cancer. We highlight the uncertainties in the diagnosis and management of this unique clinical scenario and the potential implications on prognosis.

  3. 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 N(3)-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. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. 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.

  5. Evidence for the Existence of Triple-Negative Variants in the MCF-7 Breast Cancer Cell Population

    Directory of Open Access Journals (Sweden)

    Euphemia Leung

    2014-01-01

    Full Text Available The MCF-7 line, derived in 1973 from a malignant pleural effusion, is one of the most commonly used culture models for human breast cancer. Despite its long history, MCF-7 is a surprisingly heterogeneous line. We previously showed that if MCF-7 cells were cultured for a prolonged period either in the absence of estrogen or in the presence of the antiestrogen tamoxifen, sub-lines were selected that differed from the parental line in ploidy, mean cell volume, signaling pathway usage, and drug sensitivity. This suggests a process of selection of preexisting variants rather than of adaptation of the parental line. All the sublines were estrogen receptor (ER positive, raising the question of whether MCF-7 also contains ER negative variants. Here, we have looked for such variants by culturing for a prolonged period in the presence of fulvestrant, an estrogen antagonist that has no estrogen agonist activity. Three sublines were developed, each of which was ER negative, progesterone receptor (PR negative and expressed only a low level of HER2. Each of the variants differed from the original MCF-7 line in ploidy, modal cell volume, and signaling pathway usage. Control experiments in which cells were cultured for a prolonged period in the absence of estrogen selected for variants that were ER and PR positive. The properties of the triple-negative MCF-7 were compared with those of an existing triple-negative cell line, MDA-MB-231, and human epidermal growth factor receptor 2 (HER2+ SKBr3, as well as from those of the “immortalized” breast epithelial line MCF10A. The results suggest that new variants or phenotypes of MCF-7 might be generated continuously in culture, and by implication this might apply to breast cancer development and even normal breast epithelial development in vivo.

  6. Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.

    Science.gov (United States)

    Zhou, Yan; Lin, Shuchen; Tseng, Kuo-Fu; Han, Kun; Wang, Yaling; Gan, Zhi-Hua; Min, Da-Liu; Hu, Hai-Yan

    2016-10-21

    Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again. Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed. MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

  7. Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers.

    Science.gov (United States)

    Witkiewicz, Agnieszka K; Whitaker-Menezes, Diana; Dasgupta, Abhijit; Philp, Nancy J; Lin, Zhao; Gandara, Ricardo; Sneddon, Sharon; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2012-03-15

    We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT

  8. EGFR signaling enhances aerobic glycolysis in triple negative breast cancer cells to promote tumor growth and immune escape

    Science.gov (United States)

    Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya; Lee, Heng-Huan; Chang, Shih-Shin; Shen, Jia; Hsu, Jennifer L.; Raftery, Dan; Djukovic, Danijel; Gu, Haiwei; Chang, Wei-Chao; Wang, Hung-Ling; Chen, Mong-Liang; Huo, Longfei; Chen, Chung-Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M.; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. PMID:26759242

  9. Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT

    Directory of Open Access Journals (Sweden)

    Zhen-Yu He

    2017-02-01

    Full Text Available Triple-negative breast cancer (TNBC was regarded as the most aggressive and mortal subtype of breast cancer (BC since the molecular subtype system has been established. Abundant studies have revealed that epithelial-mesenchymal transition (EMT played a pivotal role during breast cancer metastasis and progression, especially in TNBC. Herein, we showed that inhibition the expression of replication factor C subunit 3 (RFC3 significantly attenuated TNBC metastasis and progression, which was associated with EMT signal pathway. In TNBC cells, knockdown of RFC3 can down-regulate mesenchymal markers and up-regulate epithelial markers, significantly attenuated cell proliferation, migration and invasion. Additionally, silencing RFC3 expression can decrease nude mice tumor volume, weight and relieve lung metastasis in vivo. Furthermore, we also demonstrated that overexpression of RFC3 in TNBC showed increased metastasis, progression and poor prognosis. We confirmed all of these results by immunohistochemistry analysis in 127 human TNBC tissues and found that RFC3 expression was significantly associated with poor prognosis in TNBC. Taken all these findings into consideration, we can conclude that up-regulation of RFC3 promotes TNBC progression through EMT signal pathway. Therefore, RFC3 could be an independent prognostic factor and therapeutic target for TNBC.

  10. ABO blood type/Rh factor and the incidence and outcomes for patients with triple-negative breast cancer.

    Science.gov (United States)

    Yu, Jennifer; Gao, Feng; Klimberg, V Suzanne; Margenthaler, Julie A

    2012-10-01

    Triple-negative breast cancer (TNBC) has a poorer prognosis; the factors that contribute to this remain unclear. We hypothesized that TNBC is associated with ABO blood type/Rh factors that account for differences in survival. We identified 468 patients with stage I-III TNBC [estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2 nonamplified]. Patient/tumor characteristics, treatments, and outcomes were obtained. Data were examined for associations with specific ABO blood type/Rh factors. Descriptive statistics and χ (2) analysis were utilized for data summary and comparisons. Of 468 TNBC patients, 283 had known ABO blood type [122 (43 %) O, 108 (38 %) A, 39 (14 %) B, and 14 (5 %) AB] and Rh factor [253 (89 %) positive and 30 (11 %) negative]. Mean patient age was 53.7 ± 12.5 years, and median follow-up was 30.2 ± 20.5 months. The incidence of each ABO blood type/Rh factor in our TNBC cohort was not different from the general population or a cohort of ER-positive breast cancers (P > 0.05). Compared with patients with blood type O, there was no difference in breast cancer-specific mortality for type A [hazard ratio (HR) 0.906; 95 % confidence interval (CI) 0.554-1.481], type B (HR 1.534; 95 % CI 0.792-2.972), or type AB (HR 0.488; 95 % CI 0.113-2.106). Compared with women with negative Rh, there was no difference in breast cancer-specific mortality for women with positive Rh (HR 1.161; 95 % CI 0.568-2.374). TNBC was not associated with a specific ABO blood type or Rh factor. Our results failed to demonstrate an association between ABO blood type/Rh factor and breast cancer mortality in patients with TNBC.

  11. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells.

    Science.gov (United States)

    Pizato, Nathalia; Luzete, Beatriz Christina; Kiffer, Larissa Fernanda Melo Vasconcelos; Corrêa, Luís Henrique; de Oliveira Santos, Igor; Assumpção, José Antônio Fagundes; Ito, Marina Kiyomi; Magalhães, Kelly Grace

    2018-01-31

    The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA-MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1β secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA-induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment.

  12. Upper Gastrointestinal Endoscopy Detection of Synchronous Multiple Primary Cancers in Esophagus and Stomach: Single Center Experience from China

    Directory of Open Access Journals (Sweden)

    Rui Wang

    2012-01-01

    Full Text Available The present study was undertaken to clarify the prevalence and clinicopathological features of synchronous multiple primary cancers (SMPCs under upper gastrointestinal endoscopic examination. We enrolled 45,032 consecutive patients who underwent upper gastrointestinal endoscopic examination for digestive disease from January 2006 to December 2007 in our hospital and analyzed the clinicopathological features of SMPCs in esophagus and stomach. SMPCs are defined as two or over two different cancerous lesions developing in the same or other organs within 6 months. SMPCs were identified in 46 patients (0.1%. The gender ratio was 5.6 : 1 (male/female and the mean age was 59.4 years. Synchronous esophageal and gastric cancers were the most frequent, being seen in 32 patients (0.07%. The most common histological types of SMPCs were squamous cell carcinoma in esophagus and adenocarcinoma in stomach, respectively. There were 27 (59% SMPCs patients who had the history of simultaneous exposure to tobacco smoking and alcohol drinking. Additionally, 32 (78% esophageal squamous cell cancers were associated with tobacco use. And 23 adenocarcinomas of the stomach were associated with Helicobacter pylori infection.

  13. LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.

    Science.gov (United States)

    Choi, Sul Ki; Kim, Hoe Suk; Jin, Tiefeng; Moon, Woo Kyung

    2017-02-14

    Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.

  14. Synchronous sigmoid and caecal cancers together with a primary renal cell carcinoma.

    LENUS (Irish Health Repository)

    Bhargava, A

    2012-06-01

    Multiple primary neoplasms, a common clinical entity, can be classified as synchronous or metachronous. Renal cell carcinoma, in particular, is associated with a high rate of multiple primary neoplasms.

  15. [Synchronous Double Cancer Involving Gastric Cancer Resembling a Submucosal Tumor with Stenosis in the Pylorus and Ascending Colon Cancer - A Case Report].

    Science.gov (United States)

    Miyauchi, Tatsuomi; Miyaki, Akira; Ida, Arika; Kishibe, Saki; Yamaguchi, Kentaro; Shiozawa, Shunichi; Usui, Takebumi; Kuhara, Kotaro; Kono, Teppei; Naritaka, Yoshihiko

    2016-11-01

    An 82-year-old woman presented to our hospital with a complaint of frequent vomiting. She was admitted for intensive examination and treatment. Abdominal computed tomography revealed that her stomach was severely expanded, and the wall of the ascending colon was thickened throughout its circumference. Upper gastrointestinal endoscopy uncovered severe stenosis in the pylorus and an elevated lesion resembling a submucosal tumor on the posterior wall of the pylorus. Biopsies of the lesion revealed that it was of Group 1. On colonoscopy, type 2 cancer was found in the ascending colon throughout the circumference, and the biopsies revealed that it was of Group 5. Upper gastrointestinal endoscopy was repeated, and the same result was obtained. The possibility of malignancy could not be excluded; therefore, distal gastrectomy and right colectomy were performed. In terms of histopathology, both resected specimens displayed poorly differentiated adenocarcinoma; however, immunohistochemical studies revealed differences in staining at the two sites. The case was diagnosed as synchronous double cancer involving gastric cancer resembling a submucosal tumor with stenosis in the pylorus and ascending colon cancer. Gastric cancer resembling a submucosal tumor is usually difficult to diagnose on biopsy. If the endoscopic findings reveal an elevated lesion resembling a submucosal tumor with stenosis, then the possibility of carcinoma should be considered, and the most suitable treatment should be selected.

  16. Simultaneous resection for colorectal cancer with synchronous liver metastases is a safe procedure: Outcomes at a single center in Turkey.

    Science.gov (United States)

    Dulundu, Ender; Attaallah, Wafi; Tilki, Metin; Yegen, Cumhur; Coskun, Safak; Coskun, Mumin; Erdim, Aylin; Tanrikulu, Eda; Yardimci, Samet; Gunal, Omer

    2017-05-23

    The optimal surgical strategy for treating colorectal cancer with synchronous liver metastases is subject to debate. The current study sought to evaluate the outcomes of simultaneous colorectal cancer and liver metastases resection in a single center. Prospectively collected data on all patients with synchronous colorectal liver metastases who underwent simultaneous resection with curative intent were analyzed retrospectively. Patient outcomes were compared depending on the primary tumor location and type of liver resection (major or minor). Between January 2005 and August 2016, 108 patients underwent simultaneous resection of primary colorectal cancer and liver metastases. The tumor was localized to the right side of the colon in 24 patients (22%), to the left side in 40 (37%), and to the rectum in 44 (41%). Perioperative mortality occurred in 3 patients (3%). Postoperative complications were noted in 32 patients (30%), and most of these complications (75%) were grade 1 to 3 according to the Clavien-Dindo classification. Neither perioperative mortality nor the rate of postoperative complications after simultaneous resection differed among patients with cancer of the right side of the colon, those with cancer of the left side of the colon, and those with rectal cancer (4%, 2.5%, and 2%, respectively, p = 0.89) and (17%, 33%, and 34%, respectively; p = 0.29)]. The 5-year overall survival of the entire sample was 54% and the 3-year overall survival was 67 %. In conclusion, simultaneous resection for primary colorectal cancer and liver metastases is a safe procedure and can be performed without excess morbidity in carefully selected patients regardless of the location of the primary tumor and type of hepatectomy.

  17. Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study).

    Science.gov (United States)

    Rao, Roshni; Rivers, Aeisha; Rahimi, Asal; Wooldridge, Rachel; Rao, Madhu; Leitch, Marilyn; Euhus, David; Haley, Barbara B

    2017-01-01

    Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; Pancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry). Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society. © 2016 American Cancer

  18. Silencing β3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple Negative Breast Cancer

    Science.gov (United States)

    Mack, Margaret A.; Schiemann, William P.; Lu, Zheng-Rong

    2015-01-01

    Metastatic breast cancer is the second leading cause of cancer-related deaths amongst women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Since previous studies coupled β3 integrin to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/siβ3). Treatment of TNBC cells with ECO/siβ3 was sufficient to effectively silence β3 integrin expression, attenuate TGF-β-mediated EMT and invasion, restore TGF-β-mediated cytostasis, and inhibit 3-dimensional organoid growth. Modification of ECO/siβ3 nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/siβ3 nanoparticles in vivo alleviated primary tumor burden, and more importantly, significantly inhibited metastasis. Mice bearing orthotopic, TGF-β-pre-stimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/siβ3 nanoparticles were free of metastases and relapse after primary tumor resection and 4 weeks after release from the treatment, in comparison to untreated mice. Collectively, these results highlight ECO/siβ3 nanoparticles as a promising therapeutic regimen to combat TNBC. PMID:25858145

  19. Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype.

    Science.gov (United States)

    Jeong, Hoiseon; Ryu, Young-joon; An, Jungsuk; Lee, Youngseok; Kim, Aeree

    2012-05-01

      Epithelial-mesenchymal transition (EMT) is characterized by a loss of epithelial nature and the acquisition of a mesenchymal form. The aim of this study was to assess the role of EMT in human mammary carcinogenesis, by performing immunohistochemical studies of EMT markers with tissue microarrays.   A total of 492 cases were evaluated and classified as hormone receptor (HR)-positive type, HER2 type and triple-negative (TN) type by the use of immunohistochemistry and in-situ hybridization. We compared these groups in terms of epithelial and mesenchymal marker expression patterns. Of the 102 cases of TN-type breast cancer, 24.5% expressed vimentin, 13.7% expressed N-cadherin, and 9.8% expressed smooth muscle actin (SMA). Of the 221 cases of HR-type breast cancer, 4.1% expressed vimentin, 5.9% expressed N-cadherin, and 0.4% expressed SMA. Regarding epithelial markers, decreased expression was seen in 16.7% of cases for E-cadherin, in 45.1% for cytokeratin (CK)19 and in 60.8% for CK8 and CK18 (CAM5.2) in TN-type breast cancer cases. Decreased expression was seen in 11.8% of cases for E-cadherin, in 6.8% for CK19 and in 3.2% for CAM5.2 in HR-type cases.   EMT features were particularly seen in TN-type breast cancer (P grade (P < 0.001). © 2012 Blackwell Publishing Ltd.

  20. 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.)

  1. Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances.

    Science.gov (United States)

    Miller-Kleinhenz, Jasmine M; Bozeman, Erica N; Yang, Lily

    2015-01-01

    Effective treatment of triple-negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle-based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor-associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in-depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. © 2015 Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    Sartika Nurwenda

    2016-09-01

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

  3. Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nalo Hamilton

    2015-01-01

    Full Text Available Triple-negative breast cancer (TNBC occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2, along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

  4. 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.

  5. PKCα and ERβ Are Associated with Triple-Negative Breast Cancers in African American and Caucasian Patients

    Directory of Open Access Journals (Sweden)

    Debra A. Tonetti

    2012-01-01

    Full Text Available Although the incidence of breast cancer in the United States is higher in Caucasian women compared with African American women, African-American patients have more aggressive disease as characterized by a higher percentage of triple-negative breast cancers (TNBCs, high-grade tumors, and a higher mortality rate. PKCα is a biomarker associated with endocrine resistance and poor prognosis and ERβ is emerging as a protective biomarker. Immunohistochemical analysis of ERβ and PKCα expression was performed on 198 formalin-fixed paraffin-embedded primary infiltrating ductal carcinomas from 105 African-American and 93 Caucasian patients. PKCα is positively correlated with TNBC in patients of both races and with high tumor grade in African-American patients. Patients with TNBC express less nuclear ERβ compared with all other subtypes. We find no difference in frequency or intensity of PKCα or ERβ expression between African-American and Caucasian patients. PKCα and ERβ are discussed as potential therapeutic targets for the treatment of patients with TNBC.

  6. 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)

    Sturtz, Lori A; Melley, Jen; Mamula, Kim; Shriver, Craig D; Ellsworth, Rachel E

    2014-01-01

    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

  7. Molecular analysis driven video-assisted thoracic surgery resections in bilateral synchronous lung cancers: from the test tube to the operatory room.

    Science.gov (United States)

    Forti Parri, Sergio Nicola; Bonfanti, Barbara; Cancellieri, Alessandra; De Biase, Dario; Trisolini, Rocco; Zoboli, Stefania; Bertolaccini, Luca; Solli, Piergiorgio; Tallini, Giovanni

    2017-10-01

    Synchronous cancers are not such rare clinical conditions. Nevertheless, even after the 8th edition of the TNM classification of the lung cancer, the surgical approach for patients presenting with synchronous bilateral lung cancer is still under debate. The resection of both lesions in the case of synchronous bilateral lung cancer is reasonable, but, on the other hand, is the lobectomy the correct choice in the event of the single primary with a contralateral metastatic lesion? In this case report, we describe how the molecular analysis and the detection of the EGFR, KRAS and TP53 mutations in both tumours have determined in a patient the two tumours as primary and both the right surgical approach. We also discuss how molecular analysis found differences in all the three genes examined in the two lesions and allowed to exclude the clonal nature of the two tumours. In conclusion, genetic studies help to offer a more radical surgical treatment to this patient.

  8. Biological characteristics and clinical outcome of triple negative primary breast cancer in older women - comparison with their younger counterparts.

    Directory of Open Access Journals (Sweden)

    Binafsha M Syed

    Full Text Available Triple negative (ER, PgR and HER2 negative breast cancers (TNBCs are often considered as a poor prognostic phenotype. There is dearth of evidence showing the prevalence and biological behaviour of TNBCs in older women. This study aimed to analyse their biological characteristics in comparison with a well characterised younger series from a single centre with long term clinical follow-up. Over 37 years (1973-2010, 1,758 older (≥70 years women with early operable (<5 cm primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. A total of 127 patients (22.1% had TNBCs and full biological analysis of 15 biomarkers was performed. The results were compared with those of their younger (<70 years counterparts 342 (18.9% from a previously characterised, consecutive series of primary breast cancer treated in the same unit (1986-1998. The 127 older patients with TNBCs showed lower rates of Ki67 and CK 7/8 positivity and high rates of bcl2 and CK18 positivity when compared with their younger counterparts (p<0.05. There was no significant difference in the long term clinical outcome between the two age groups, despite the fact that 47% of the younger patients had adjuvant chemotherapy, while none in the older cohort received such treatment. EGFR, axillary stage and pathological size showed prognostic significance in older women with TNBCs on univariate analysis. Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of whom had chemotherapy. This appears to be related to other biomarkers (in addition to ER/PgR/HER2 eg Ki67, bcl2 and cytokeratins which have different expression patterns influencing prognosis.

  9. Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Dávila-González, Daniel; Choi, Dong Soon; Rosato, Roberto R; Granados-Principal, Sergio M; Kuhn, John G; Li, Wen-Feng; Qian, Wei; Chen, Wen; Kozielski, Anthony J; Wong, Helen; Dave, Bhuvanesh; Chang, Jenny C

    2018-03-01

    Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC. Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay. Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9. Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy. Clin Cancer Res; 24(5); 1152-62. ©2018 AACR . ©2018 American Association for Cancer Research.

  10. Cisplatin Induces Apoptosis Through the Endoplasmic Reticulum-mediated, Calpain 1 Pathway in Triple-negative Breast Cancer Cells.

    Science.gov (United States)

    Al-Bahlani, Shadia M; Al-Bulushi, Khadija H; Al-Alawi, Zaina M; Al-Abri, Nadia Y; Al-Hadidi, Zuweina R; Al-Rawahi, Shaikha S

    2017-06-01

    Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive type that can be treated using platinum-based chemotherapy such as cisplatin (cis-diamminedichloroplatinum II). Although the calpain protein is essential in many cellular processes, including apoptosis, cell signaling, and proliferation, its role in cisplatin-induced apoptosis in TNBC cells is not fully understood. The present study assessed calpain 1-dependent, cisplatin-induced apoptosis in TNBC cells. MDA-MB231 cells were treated with different concentrations of cisplatin (0, 20, and 40 μM). The cisplatin deposit and its effect on endoplasmic reticulum and, subsequently, calcium release were detected using transmission electron microscopy and Von Koss staining, respectively. Calpain 1 messenger RNA, protein content, and apoptosis was measured using reverse transcriptase-polymerase chain reaction, Western blotting, and Hoechst stain, respectively. In addition, calpain modulation, by either activation or inhibition, and its effect on cisplatin-induced apoptosis were assessed. Our results showed that cisplatin induced endoplasmic reticulum stress, indicated by an increase in calcium staining and protein expression of glucose-regulated protein 78 and calmodulin, followed by cleavage of α-fodrin and caspase-12 and, eventually, apoptosis. Cyclopiazonic acid showed a similar effect and enhanced the sensitivity of these cells to cisplatin treatment. In contrast, calpain 1 inhibition by both specific small interfering RNA and exogenous inhibitor (calpeptin) attenuated cisplatin-induced apoptosis in these cells. Altogether, these findings suggest, for the first time, that calpain 1 activation by endoplasmic reticulum plays an essential role in sensitizing TNBC cells to cisplatin-induced apoptosis. This finding will allow exploration of new insights for the treatment of TNBC by overcoming its resistance to apoptosis. Copyright © 2016 Elsevier Inc. All

  11. 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...... cancer between 2008 and 2012 was retrieved from the Danish Breast Cancer Cooperative Group database. The associations between clinical and pathological variables and ALN involvement at the time of diagnosis were evaluated in univariate and multivariate regression analyses, as well as the significance...... of tumor subtypes in ALN involvement. The risk of ALN metastases at the time of diagnosis was significantly reduced in HR-negative patients compared to HR-positive patients [adjusted odds ratio (OR) 0.69; 95 % CI 0.63-0.76; P = 0.0009]. A HER2-positive status was associated with an increased risk of ALN...

  12. Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer.

    Science.gov (United States)

    Liu, Junjun; Chen, Xiaosong; Ward, Toby; Pegram, Mark; Shen, Kunwei

    2016-07-01

    Women with triple-negative breast cancer have worse prognosis compared to other breast cancer subtypes. Acquired drug resistance remains to be an important reason influencing triple-negative breast cancer treatment efficacy. A prevailing theory postulates that the cancer resistance and recurrence results from a subpopulation of tumor cells with stemness program, which are often insensitive to cytotoxic drugs such as cisplatin. Recent studies suggested that niclosamide, an anti-helminthic drug, has potential therapeutic activities against breast cancer stem cells, which prompts us to determine its roles on eliminating cisplatin-resistant cancer cells. Hence, we established a stable cisplatin-resistant MDA-MB-231 cell line (231-CR) through continuously exposure to increasing concentrations of cisplatin (5-20 μmol/l). Interestingly, 231-CR exhibited properties associated to epithelial-mesenchymal transition with enhanced invasion, preserved proliferation, increased mammosphere formation, and reduced apoptosis compared to naive MDA-MB-231 sensitive cells (231-CS). Importantly, niclosamide or combination with cisplatin inhibited both 231-CS and 231-CR cell proliferation in vitro. In addition, niclosamide reversed the EMT phenotype of 231-CR by downregulation of snail and vimentin. Mechanistically, niclosamide treatment in combination with or without cisplatin significantly inhibited Akt, ERK, and Src signaling pathways. In vivo study showed that niclosamide or combination with cisplatin could repress the growth of xenografts originated from either 231-CS or 231-CR cells, with prominent suppression of Ki67 expression. These findings suggested that niclosamide might serve as a novel therapeutic strategy, either alone or in combination with cisplatin, for triple-negative breast cancer treatment, especially those resistant to cisplatin.

  13. Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sangmin Kim

    2018-01-01

    Full Text Available Background/Aims: Transforming growth factor-beta proteins (TGF-βs are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR on tumor growth and metastasis of triple negative breast cancer (TNBC cells via suppression of TGF-β1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1–induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.

  14. Targeting MUC1-Mediated Tumor-Stromal Metabolic Interaction in Triple-Negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 µg/ml streptomycin ... resistance to platinum-based chemotherapy in patients with ovarian cancer. Oncol Rep, 2004. 12(6): p. 1177-82. 5. Schroeder, J.A., et al., MUC1 alters beta

  15. Targeting MUC1 mediated tumor stromal metabolic interaction in Triple negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 µg/ml streptomycin ... resistance to platinum-based chemotherapy in patients with ovarian cancer. Oncol Rep, 2004. 12(6): p. 1177-82. 5. Schroeder, J.A., et al., MUC1 alters beta

  16. Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS - a randomised controlled multicentre trial (ISRCTN30964555)

    International Nuclear Information System (INIS)

    Rahbari, Nuh N; Koch, Moritz; Büchler, Markus W; Kieser, Meinhard; Weitz, Jürgen; Lordick, Florian; Fink, Christine; Bork, Ulrich; Stange, Annika; Jäger, Dirk; Luntz, Steffen P; Englert, Stefan; Rossion, Inga

    2012-01-01

    Currently, it remains unclear, if patients with colon cancer and synchronous unresectable metastases who present without severe symptoms should undergo resection of the primary tumour prior to systemic chemotherapy. Resection of the primary tumour may be associated with significant morbidity and delays the beginning of chemotherapy. However, it may prevent local symptoms and may, moreover, prolong survival as has been demonstrated in patients with metastatic renal cell carcinoma. It is the aim of the present randomised controlled trial to evaluate the efficacy of primary tumour resection prior to systemic chemotherapy to prolong survival in patients with newly diagnosed colon cancer who are not amenable to curative therapy. The SYNCHRONOUS trial is a multicentre, randomised, controlled, superiority trial with a two-group parallel design. Colon cancer patients with synchronous unresectable metastases are eligible for inclusion. Exclusion criteria are primary tumour-related symptoms, inability to tolerate surgery and/or systemic chemotherapy and history of another primary cancer. Resection of the primary tumour as well as systemic chemotherapy is provided according to the standards of the participating institution. The primary endpoint is overall survival that is assessed with a minimum follow-up of 36 months. Furthermore, it is the objective of the trial to assess the safety of both treatment strategies as well as quality of life. The SYNCHRONOUS trial is a multicentre, randomised, controlled trial to assess the efficacy and safety of primary tumour resection before beginning of systemic chemotherapy in patients with metastatic colon cancer not amenable to curative therapy. http://www.controlled-trials.com/ISRCTN30964555

  17. [A Comparative Study of Acute and Chronic Pain between Single Port and Triple Port Video-assisted Thoracic Surgery for Lung Cancer].

    Science.gov (United States)

    Li, Caiwei; Xu, Meiqing; Xu, Guangwen; Xiong, Ran; Wu, Hanran; Xie, Mingran

    2018-04-20

    Through the comparative analysis of the acute and chronic pain postoperative between the single port and triple port video-assisted thoracic surgery to seek the better method which can reduce the incidence of acute and chronic pain in patients with lung cancer. Data of 232 patients who underwent single port -VATS (n=131) or triple port VATS (n=101) for non-small cell lung cancer (NSCLC) on January 1, 2016 to June 30, 2017 in our hospital were analyzed. The clinical and operative data were assessed, numeric rating scale (NRS) was used to evaluate the mean pain score on the 1th, 2th, 3th, 7th, 14th days, 3th months and 6th months postoperative. Both groups were similar in clinical characteristics, there were no perioperative death in two groups. In the 1th, 2th, 7th, 14th days and 3th, 6th months postoperative, the NRS score of the single port group was superior, and the difference was significant compared with the triple port (P0.05). Univariate and multivariate analysis of the occurrence on the chronic pain showed that the operation time, surgical procedure and the 14th NRS score were risk factors for chronic pain (Pport thoracoscopic surgery has an advantage in the incidence of acute and chronic pain in patients with non-small cell lung cancer. Shorter operative time can reduce the occurrence of chronic pain. The 14th day NRS score is a risk factor for chronic pain postoperative.

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

    Science.gov (United States)

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

    2016-12-01

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

  19. Knock-out transmembrane prostate androgen-induced protein gene suppressed triple-negative breast cancer cell proliferation

    Directory of Open Access Journals (Sweden)

    Bantari W.K. Wardhani

    2017-11-01

    Full Text Available Background: Triple negative breast cancer (TNBC tends to grow more rapidly and has poorer prognosis compared to others. High expression of transmembrane prostate androgen-induced protein (TMEPAI correlates with poor prognosis in TNBC patients. However, the mechanistic role of TMEPAI in tumorigenic remains unknown. This study aimed to knock-out TMEPAI in TNBC cell line to determine its function further in cells proliferation.Methods: CRISPR-Cas9 has been used previously to knock-out TMEPAI in Hs857T TNBC cell line. Hs587T TNBC parental cell line (wild-type/WT and TMEPAI knock out Hs 586T cell lines were cultured in Dulbecco’s modified eagle medium (DMEM supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin and amphotericin B. Both cell lines were seeded in 24-well plates and counted every two days, then proliferation rates were plotted. Afterwards, total RNA were isolated from the cells and Ki-67, and TGF-β mRNA expression levels as proliferation markers were determined.Results: Cell proliferation rates as displayed in growth curve plots showed that WT-TMEPAI cell line grew more rapidly than KO-TMEPAI. In accordance, mRNA expression levels of  Ki-67 and TGF-β  were significantly decreased KO-TMEPAI as compare to TMEPAI-WT.Conclusion: Knock-out of TMEPAI attenuates cell proliferation in TNBC.

  20. MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Wanqin Wang

    2017-01-01

    Full Text Available AXL receptor tyrosine kinase is overexpressed in a number of solid tumor types including triple-negative breast cancer (TNBC. AXL is considered an important regulator of epithelial-to-mesenchymal transition (EMT and a potential therapeutic target for TNBC. In this work, we used microPET/CT with 64Cu-labeled anti-human AXL antibody (64Cu-anti-hAXL to noninvasively interrogate the degradation of AXL in vivo in response to 17-allylamino-17-demethoxygeldanamycin (17-AAG, a potent inhibitor of HSP90. 17-AAG treatment caused significant decline in AXL expression in orthotopic TNBC MDA-MB-231 tumors, inhibited EMT, and delayed tumor growth in vivo, resulting in significant reduction in tumor uptake of 64Cu-anti-hAXL as clearly visualized by microPET/CT. Our data indicate that 64Cu-anti-hAXL can be useful for monitoring anti-AXL therapies and for assessing inhibition of HSP90 molecular chaperone using AXL as a molecular surrogate.

  1. "Triple negative breast cancer": Translational research and the (re)assembling of diseases in post-genomic medicine.

    Science.gov (United States)

    Keating, Peter; Cambrosio, Alberto; Nelson, Nicole C

    2016-10-01

    The paper examines the debate about the nature and status of "Triple-negative breast cancer", a controversial biomedical entity whose existence illustrates a number of features of post-genomic translational research. The emergence of TNBC is intimately linked to the rise of molecular oncology, and, more generally, to the changing configuration of the life sciences at the turn of the new century. An unprecedented degree of integration of biological and clinical practices has led to the proliferation of bio-clinical entities emerging from translational research. These translations take place between platforms rather than between clinical and laboratory settings. The complexity and heterogeneity of TNBC, its epistemic and technical, biological and clinical dualities, result from its multiple instantiations via different platforms, and from the uneven distribution of biological materials, techniques, and objects across clinical research settings. The fact that TNBC comes in multiple forms, some of which seem to be incompatible or, at least, only partially overlapping, appears to be less a threat to the whole endeavor, than an aspect of an ongoing translational research project. Discussions of translational research that rest on a distinction between basic research and its applications fail to capture the dynamics of this new domain of activity, insofar as application is built-in from the very beginning in the bio-clinical entities that emerge from the translational research domain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. 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)

    Ikonomov, Ognian C.; Filios, Catherine; Sbrissa, Diego; Chen, Xuequn; Shisheva, Assia

    2013-01-01

    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 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 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 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 indirectly the

  3. 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

  4. Synchronous development of breast cancer and chest wall fibrosarcoma after previous mantle radiation for Hodgkin's disease

    International Nuclear Information System (INIS)

    Patlas, Michael; McCready, David; Kulkarni, Supriya; Dill-Macky, Marcus J.

    2005-01-01

    Survivors of Hodgkin's disease are at increased risk of developing a second malignant neoplasm, including breast carcinoma and sarcoma. We report the first case of synchronous development of chest wall fibrosarcoma and breast carcinoma after mantle radiotherapy for Hodgkin's disease. Mammographic, sonographic and MR features are demonstrated. (orig.)

  5. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

    Science.gov (United States)

    Cereda, Matteo; Gambardella, Gennaro; Benedetti, Lorena; Iannelli, Fabio; Patel, Dominic; Basso, Gianluca; Guerra, Rosalinda F.; Mourikis, Thanos P.; Puccio, Ignazio; Sinha, Shruti; Laghi, Luigi; Spencer, Jo; Rodriguez-Justo, Manuel; Ciccarelli, Francesca D.

    2016-01-01

    Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation. PMID:27377421

  6. MRI-detected extramural vascular invasion is an independent prognostic factor for synchronous metastasis in patients with rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Beomseok; Lim, Joon-seok; Kim, Honsoul; Kim, Myeong-Jin [Yonsei University, College of Medicine, Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Seoul (Korea, Republic of); Myoung, Sungmin [Jungwon University, Department of Medical Information, Goesan (Korea, Republic of); Choi, Junjeong [Yonsei University Wonju College of Medicine, Department of Pathology, Wonju (Korea, Republic of); Kim, Nam Kyu [Yonsei University, College of Medicine, Department of Surgery, Severance Hospital, Seoul (Korea, Republic of)

    2015-05-01

    To determine whether magnetic resonance imaging (MRI)-detected extramural vascular invasion (EMVI) could predict synchronous distant metastases in rectal cancer. Patients who underwent rectal MRI between July 2011 and December 2012 were screened. This study included 447 patients with pathologically confirmed rectal adenocarcinoma who had undergone MRI without previous treatment. Distant metastases were recorded at the initial work-up and over a 6-month follow-up. Univariate/multivariate logistic regression models were used to determine the risk of metastasis. The diagnostic performance was calculated using pathologic lymphovascular invasion (LVI) as a gold standard. Among 447 patients, 79 patients (17.7 %) were confirmed to have distant metastases. Three MRI features are significantly associated with a high risk of distant metastasis: positive EMVI (odds ratio 3.02), high T stage (odds ratio 2.10) and positive regional lymph node metastasis (odds ratio 6.01). EMVI in a large vessel (≥3 mm) had a higher risk for metastasis than EMVI in a small vessel (<3 mm). Sensitivity, specificity and accuracy of MRI-detected EMVI were 28.2 %, 94.0 % and 80.3 %, respectively. MRI-detected EMVI is an independent risk factor for synchronous metastasis in rectal cancer. EMVI in large vessels is a stronger risk factor for distant metastasis than EMVI in small vessels. (orig.)

  7. The prognostic value of the proliferation marker phosphohistone H3 (PPH3) in luminal, basal-like and triple negative phenotype invasive lymph node-negative breast cancer.

    Science.gov (United States)

    Skaland, Ivar; Janssen, Emiel A M; Gudlaugsson, Einar; Hui Ru Guo, Lydia; Baak, Jan P A

    2009-01-01

    Prognostic comparison of phosphohistone-H3 (PPH3) with Cytokeratin 5/6 and/or 14 positive (=basal-CK), triple (ER, PR, HER2)-negative (=TNP) and basal-like (=TNP and basal-CK positive) phenotype in invasive breast cancers. Classical variables, PPH3, ER, PR, basal-CK and HER2 in 240 T1-2N0M0 patients under 71 years. TNP and basal-like cancers had higher PPH3 expression than the other cancers (mean 48 versus 11, Pbasal-like cancers recurred. With multivariate analysis, PPH3or=13 (n=84=35% of all cases) was the strongest and only prognosticator (10-year survival 96% and 64%, Pbasal-like T1-2N0M0 invasive breast cancers.

  8. Lipid rafts disruption induces apoptosis by attenuating expression of LRP6 and survivin in triple negative breast cancer.

    Science.gov (United States)

    Badana, Anil Kumar; Chintala, Madhuri; Gavara, Murali Mohan; Naik, Shailender; Kumari, Seema; Kappala, Vijaya Rachel; Iska, Bhaskar Reddy; Malla, Rama Rao

    2018-01-01

    Triple negative breast cancer is a clinically challenging subtype due to lack of biomarker for rational targeted therapy. Lipid rafts are cholesterol enriched rigid platforms, which colocalize signalling molecules of cancer progression. This study explores the effect of lipid rafts disruption by cholesterol depleting agent, MβCD on induction of apoptosis and expression of WNT receptor LRP6, survivin and common apoptotic markers in TNBC cell lines. The in vitro effect of lipid rafts disruption on viability, single cell reproductive ability, proliferation and migration were evaluated by MTT, clonogenic, BrdU incorporation and wound scratch assays, respectively. The morphological changes were assessed by tryphan blue, Wright and Giemsa staining; nuclear changes by Hoechst staining. The induction of apoptosis was evaluated by AO/EtBr staining, DNA damage and DNA fragmentation assays. Expression of Caveolin-1, LRP6, β-Catenin, Survivin, Bcl2, BAX, Caspase-3, Ki67 and c-myc were analyzed by PCR and Western blotting techniques. The lipid raft disruption resulted in reduction of the proliferation of MDA-MB 231 and MDA-MB 468 cells by 56.3 and 42.0%; survival fraction by 54.7 and 59.4%; migration by 44.3 and 48.4%, respectively. It also induced apoptosis by causing cell shrinkage, membrane blebbing, nuclear condensation, chromatin cleavage, oligonucleotide fragmentation with an apoptotic index of 59.1 and 46.6% in MDA-MB 231 and 468 cells, respectively. Further, it downregulated the expression of caveolin-1, LRP6, β-catenin, survivin, Bcl2, ki67, c-myc and upregulated BAX, caspase-3. The cholesterol supplementation enhanced the clonogenic potential and upregulated the expression of caveolin-1 and LRP6. The results underline a potential effect of lipid rafts disruption on induction of apoptosis in TNBC cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

    Science.gov (United States)

    Panayotopoulou, Effrosini G; Müller, Anna-Katharina; Börries, Melanie; Busch, Hauke; Hu, Guohong; Lev, Sima

    2017-07-11

    Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

  10. 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. ©2015 American Association for Cancer Research.

  11. Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA.

    Science.gov (United States)

    Piechocki, Marie P; Wu, Gen Sheng; Jones, Richard F; Jacob, Jennifer B; Gibson, Heather; Ethier, Stephen P; Abrams, Judith; Yagita, Hideo; Venuprasad, K; Wei, Wei-Zen

    2012-12-01

    TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies. We tested the hypothesis that DR5 DNA vaccination will induce proapoptotic antibody to trigger apoptosis of tumor cells. BALB/c mice were electrovaccinated with DNA-encoding wild-type human DR5 (phDR5) or its derivatives. Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. The proapoptotic activity of immune serum at dilutions of 0.5-2% was comparable to that of 1-2 μg/ml of TRAIL. Apoptotic activity of immune serum was enhanced by antibody crosslinking. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In contrast, immune serum had no effect on the proliferation of activated human T cells, which expressed low levels of DR5. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. DR5-specific IFN-γ-secreting T cells were also induced by DNA vaccination. Furthermore, the feasibility to overcome immune tolerance to self DR5 was shown by the induction of mouse DR5-binding antibody after electrovaccination of BALB/c mice with pmDR5ectm-Td1 encoding a fusion protein of mouse DR5 and an immunogenic fragment of tetanus toxin. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers. Copyright © 2012 UICC.

  12. Social isolation and cancer management after the 2011 triple disaster in Fukushima, Japan

    Science.gov (United States)

    Ozaki, Akihiko; Leppold, Claire; Tsubokura, Masaharu; Tanimoto, Tetsuya; Saji, Shigehira; Kato, Shigeaki; Kami, Masahiro; Tsukada, Manabu; Ohira, Hiromichi

    2016-01-01

    Abstract Breast cancer patients may present with patient delay or experience provider delay—2 factors which can lead to a late-stage diagnosis and poor prognosis. Mass disasters drastically change social structures, and have the potential to contribute to these delays. However, there is little information available on patient and provider delay related to cancer after disasters. In March 2011, an earthquake, followed by a tsunami and nuclear accident struck Fukushima, Japan. In July 2014, a 59 year-old Japanese widow, living alone, presented to our hospital with a lump and pain in her right breast, which had originally appeared in April 2011 and continuously deteriorated for 3 years and 3 months. She was diagnosed with stage IIIB right breast cancer. Detailed history revealed that she was exposed to social isolation in the aftermath of the disasters due to evacuation of her friends and daughter. Although she regularly saw her general practitioner, she did not disclose her breast symptoms for 1 year and 5 months, at which time she was falsely diagnosed with intercostal neuralgia. She did not seek further medical attention for the breast symptoms for another 1 year and 10 months, despite multiple clinic visits for unrelated reasons. The present disasters, particularly the nuclear disaster, seem to have led to the social isolation of local residents, reducing their opportunities to discuss health concerns with others and seek subsequent medical attention. This case highlights that social isolation may contribute to patient and provider delay in breast cancer patients, as accentuated in this disaster setting. PMID:27368025

  13. Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple negative breast cancer therapy.

    Science.gov (United States)

    Fan, Yang; Wang, Qingjie; Lin, Guimei; Shi, Yanbin; Gu, Zili; Ding, Tingting

    2017-10-15

    In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (∼200nm) and distribution (PDIapoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy. The Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes

  14. Social isolation and cancer management - advanced rectal cancer with patient delay following the 2011 triple disaster in Fukushima, Japan: a case report.

    Science.gov (United States)

    Ozaki, Akihiko; Leppold, Claire; Sawano, Toyoaki; Tsubokura, Masaharu; Tsukada, Manabu; Tanimoto, Tetsuya; Kami, Masahiro; Ohira, Hiromichi

    2017-05-16

    Little is known about the effects of social isolation in the elderly on their process of gaining health information and seeking health care. In March 2011, Fukushima, Japan experienced an earthquake, tsunami, and nuclear disaster, also known as Japan's triple disaster. In June 2016, an 80-year-old Japanese man, who lived alone after divorce at the age of 42, presented to our hospital with bloody stools and dizziness. Although his bloody stools initially occurred in May 2015, a year earlier, he did not pursue the possibility of malignancy. He was diagnosed as having stage IIIA rectal cancer. Detailed history taking revealed that he experienced social isolation after the disaster, due to the evacuation of his friends, losing his regular opportunities for socialization. He additionally reported that the current diagnosis of rectal cancer made him feel he had lost his health in addition to his social relationships. Although radical surgery was attempted, it failed to resect the lesion completely, and thereafter his disease gradually progressed. As support from family or friends was not available, he was not able to receive palliative radiation therapy or home-based care in his end-of-life period. He died at a long-term care facility in February 2017. This case suggests that intense social isolation after the Fukushima disaster was a likely contributor to the patient delay, poor treatment course, and poor outcome of an elderly patient with rectal cancer. Direct communication with family and friends may play an indispensable role in increasing health awareness and promoting health-seeking behaviors, and in the midst of social isolation, elderly patients with cancer may lose these opportunities and experience increased risk of patient delay. Although health care providers may be able to alleviate isolation-induced delay by promoting cancer knowledge and awareness widely among local residents, policy-led interventions at the community level may be essential to reducing

  15. Important predictors of response determined by surgical staging prior to triple modality therapy for esophageal cancer

    International Nuclear Information System (INIS)

    Suntharalingam, M.; Vines, E.; Slawson, R.; Doyle, A.; Schuetz, J.; Greenwald, B.; Sonnet, J.; Krasna, M.

    1997-01-01

    Purpose/Objective: Since 1992, the University of Maryland has routinely performed preoperative surgical staging including thoracoscopy and laparoscopy on patients undergoing concurrent chemoradiation followed by surgical resection for esophageal carcinoma. We have performed an analysis of the pathologic pretreatment data in an attempt to identify possible predictors of response and outcome. Materials: Patients underwent thoracoscopy and laparoscopy in order to determine resectability of the primary lesion and pathologic nodal status prior to therapy. To date, 32 patients have completed triple modality therapy (28 men, 4 women, median age 59). Patients received 50.4 Gy in 1.8 Gy fractions in conjunction with two cycles of 5-FU (1 gm/m2) and Cisplatin (100 mg/m2) on days 1 and 28. Radiotherapy fields were determined by the extent of disease discovered at time of surgical staging. Ivor Lewis esophagectomy was performed 4 to 6 weeks after completion of chemo/RT. The median follow up is 24.8 months (range 4-49 mo.) Sixteen patients had squamous cell ca and 16 had adenocarcinoma. Univariate and multivariate analysis was performed in order to determine the influence of age, KPS, T stage, Lymph Nodes status and histology, on the likelihood of achieving a pathologic complete response and disease free survival. Results: Twenty-eight have undergone preoperative staging (2 refused, 2 medical contraindications.) All 32 patients are valuable for response to therapy and are included in the analysis. The three year cause specific and disease free survival is 46% and 41% respectively with a median CSS of 23 months and DFS of 19 months. The overall complete response rate assessed by histologic and immunohistologic evaluation at the time of esophagectomy is 31%. The DFS at 32 months is 72% (median not reached) for these patients versus 24% for those with residual disease at the time of surgery. The most significant predictor for the likelihood of achieving a pathologic CR was the

  16. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer.

    Science.gov (United States)

    Mehner, Christine; Hockla, Alexandra; Miller, Erin; Ran, Sophia; Radisky, Derek C; Radisky, Evette S

    2014-05-15

    Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.

  17. Synchronous malignant renal mass in patient with a Lung cancer: case report and literature review

    OpenAIRE

    Mazouz, Aicha; Amaadour, Lamiae; Souaf, Ihsane; El Fatemi, Hinde; Amarti, Afaf; Erraisse, Mohamed Ait; Oubelkacem, Essaadia; Bouhafa, Touria; Tahiri, Yassir; Tazi, Mohammed Fadl; Mellas, Soufiane; Arifi, Samia; Mellas, Nawfel

    2015-01-01

    The finding on imaging (computed tomography scan or magnetic resonance imaging) of synchronous malignant renal mass in patient with an active nonrenal malignancy without renal specific symptoms is not frequent and diagnostic evaluation can be challenging. We describe a 54-year-old Moroccan male former chronic smoker who presented to our hospital with dry cough and impairment of the performance status. The imaging found a tumor mass in the left upper lobe of the lung associated to mediastinal ...

  18. Segmental neurofibromatosis and cancer: report of triple malignancy in a woman with mosaic Neurofibromatosis 1 and review of neoplasms in segmental neurofibromatosis.

    Science.gov (United States)

    Cohen, Philip R

    2016-07-15

    BackgroundSegmental neurofibromatosis, referred to as mosaic neurofibromatosis 1, patients present with neurofibromas or café au lait macules or both in a unilateral segment of the body.PurposeA woman with segmental neurofibromatosis and triple cancer (renal cell carcinoma, mixed thyroid carcinoma, and lentigo maligna) is described and cancers observed in patients with segmental neurofibromatosis are reviewed.MethodsPubMed was used to search the following terms, separately and in combination: cancer, malignancy, mosaic, neoplasm, neurofibroma, neurofibromatosis, segment, segmental, tumor.ResultsMalignancy (13 cancers) has been observed in 11 segmental neurofibromatosis patients; one patient had three different cancers. The most common neoplasms were of neural crest origin {malignant peripheral nerve sheath tumor (3 patients) and melanoma (3 patients)] and gastrointestinal tract origin [colon (1 patient) and gastric (1 patient)]. Breast cancer, Hodgkin lymphoma, lung cancer, kidney cancer, and thyroid cancer each occurred in one patient.ConclusionsSimilar to patients with von Recklinghausen neurofibromatosis 1, individuals with segmental neurofibromatosis also have a genodermatosis-associated increased risk of developing cancer.

  19. Triple Therapy of HER2+ Cancer Using Radiolabeled Multifunctional Iron Oxide Nanoparticles and Alternating Magnetic Field.

    Science.gov (United States)

    Zolata, Hamidreza; Afarideh, Hossein; Davani, Fereydoun Abbasi

    2016-11-01

    By using radio-labeled multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) and an alternating magnetic field (AMF), we carried out targeted hyperthermia, drug delivery, radio-immunotherapy (RIT), and controlled chemotherapy of cancer tumors. We synthesized and characterized Indium-111-labeled, Trastuzumab and Doxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs in our previous work. Then, we evaluated their capability in SPECT/MRI (single photon emission computed tomography/magnetic resonance imaging) dual modal molecular imaging, targeting, and controlled release. In this research, AMF was introduced to evaluate therapeutic effects of magnetic hyperthermia on radionuclide-chemo therapy of HER2 + cells and tumor (HER2 + )-bearing mice. In vitro and in vivo experiments using synthesized complex were repeated under an AMF (f: 100 KHz, H: 280 Gs). Instead of an intra-tumor injection in most hyperthermia experiments, SPIONs were injected to the tail vein, based on our delivery strategies. For magnetic delivery, we held a permanent Nd-B-Fe magnet near the tumor region. The results showed that simultaneous magnetic hyperthermia enhanced SKBR3 cancer cells, killing by 24%, 28%, 33%, and 80% at 48 hours post-treatment for treated cells with (1) bare SPIONs; (2) antibody-conjugated, DOX-free, surface-modified SPIONs; (3) 111 In-labeled, antibody-conjugated surface-modified SPIONs; and (4) 111 In-labeled, antibody- and DOX-conjugated surface-modified SPIONs, respectively. Moreover, tumor volume inhibitory rate was 85% after a 28 day period of treatment. By using this method, multimodal imaging-guided, targeted hyperthermia, RIT, and controlled chemotherapy could be achievable in the near future.

  20. [Development of Peptide Vaccines for Triple-Negative Breast Cancer Treatment].

    Science.gov (United States)

    Toh, Uhi; Saku, Shuko; Okabe, Mina; Iwakuma, Nobutaka; Kimitsuki, Yuko; Akashi, Momoko; Ogo, Etsuyo; Yamada, Akira; Shichijo, Shigeki; Itoh, Kyogo; Akagi, Yoshito

    2016-10-01

    Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.

  1. Expression of MAGE-A and NY-ESO-1 cancer-testis antigens is enriched in triple-negative invasive breast cancers.

    Science.gov (United States)

    Raghavendra, Ashwini; Kalita-de Croft, Priyakshi; Vargas, Ana Cristina; Smart, Chanel E; Simpson, Peter T; Saunus, Jodi M; Lakhani, Sunil R

    2018-02-21

    A better understanding of the expression of cancer testis antigens (CTA) in breast cancer might identify new immunotherapy options, especially for triple-negative (TN) tumours, which lack expression of conventional therapeutic targets ER, PR and HER2 (receptors for Oestrogen, Progesterone and Human epidermal growth factor). The aim of this study was to quantify the expression of MAGE-A and NY-ESO-1 CTAs in breast cancer, and relate this to known clinicopathologic parameters. We surveyed MAGE-A and NY-ESO-1 protein expression in an unselected cohort of 367 breast tumours (out of which 65 tumours were TN), with accompanying clinical follow-up data, using immunohistochemistry (IHC) analysis of tissue microarrays. Relevant to their potential as vaccine targets in breast cancer, MAGE-A was expressed in 13% of cases, and NY-ESO-1 in 3.8%, with the majority of tumours exhibiting fairly homogeneous staining within individual tissue cores (~85% of cases with staining in >75% tumour cells). Most NY-ESO-1 positive cases also expressed MAGE-A (p=2.06x10 -9 ), and both were strongly associated with the TN phenotype (pESO-1 are frequently expressed in TNBC (~47% and 17% of TN cases, respectively), suggesting that targeting them could be feasible in this patient group. Expression is reasonably homogeneous in positive cases suggesting that IHC analysis of tissue biopsies would be a reliable companion biomarker. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  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. 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)

    Doyen, J.; Trastour, C.; Ettore, F.; Peyrottes, I.; Toussant, N.; Gal, J.; Ilc, K.; Roux, D.; Parks, S.K.; Ferrero, J.M.; Pouysségur, J.

    2014-01-01

    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: 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 + 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

  4. Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Julie L Boerner

    Full Text Available Patients with metastatic triple-negative breast cancer (TNBC have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose polymerase (PARP, a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.

  5. 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.

    2016-01-01

    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. MicroRNAs (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 were 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 re-introduction, while SRC overexpression rescued the anti-tumorigenic 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 anti-tumorigenic 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

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

    Directory of Open Access Journals (Sweden)

    Sugiura Hiroshi

    2008-10-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.

  7. Synchronous BI-RADS Category 3 Lesions on Preoperative Ultrasonography in Patients with Breast Cancer: Is Short-Term Follow-Up Appropriate?

    Science.gov (United States)

    Lee, Seokwon; Jung, Younglae

    2015-01-01

    Purpose Breast ultrasonography (US) has been widely used in the preoperative examination of patients with breast cancer. Breast Imaging Reporting and Data System (BI-RADS) category 3 (C3) lesions (probably benign) are regarded as having a low probability of malignancy (≤2%). The purposes of this study were to verify the malignancy rates for synchronous BI-RADS C3 lesions in patients with breast cancer and consider appropriate management strategies for these lesions. Methods Between January 2010 and January 2013, a total of 161 patients underwent surgery in our institute for breast cancer and synchronous BI-RADS C3 lesions. In the US reports, we found records of 219 synchronous BI-RADS C3 nodules in 161 patients. They were excised during surgery for breast cancer management. Stepwise logistic regression analysis was used to identify predictors of malignancy for synchronous BI-RADS C3 lesions. Results The rate of malignancy among the 219 BI-RADS C3 lesions was 9.6%. In simple logistic regression analysis, the size of the primary tumor (pBI-RADS C3 lesions identified on preoperative US when the primary tumor has the following risk factors: large size, high PR expression, and HER2 positivity. PMID:26155295

  8. Synchronous BI-RADS Category 3 Lesions on Preoperative Ultrasonography in Patients with Breast Cancer: Is Short-Term Follow-Up Appropriate?

    Science.gov (United States)

    Lee, Seokwon; Jung, Younglae; Bae, Youngtae

    2015-06-01

    Breast ultrasonography (US) has been widely used in the preoperative examination of patients with breast cancer. Breast Imaging Reporting and Data System (BI-RADS) category 3 (C3) lesions (probably benign) are regarded as having a low probability of malignancy (≤2%). The purposes of this study were to verify the malignancy rates for synchronous BI-RADS C3 lesions in patients with breast cancer and consider appropriate management strategies for these lesions. Between January 2010 and January 2013, a total of 161 patients underwent surgery in our institute for breast cancer and synchronous BI-RADS C3 lesions. In the US reports, we found records of 219 synchronous BI-RADS C3 nodules in 161 patients. They were excised during surgery for breast cancer management. Stepwise logistic regression analysis was used to identify predictors of malignancy for synchronous BI-RADS C3 lesions. The rate of malignancy among the 219 BI-RADS C3 lesions was 9.6%. In simple logistic regression analysis, the size of the primary tumor (pBI-RADS C3 lesions identified on preoperative US when the primary tumor has the following risk factors: large size, high PR expression, and HER2 positivity.

  9. Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile.

    Science.gov (United States)

    Swisher, Anne K; Abraham, Jame; Bonner, Daniel; Gilleland, Diana; Hobbs, Gerald; Kurian, Sobha; Yanosik, Mary Anne; Vona-Davis, Linda

    2015-10-01

    Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy-Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-α, IL-6), and adipokine profile (leptin, adiponectin, insulin). Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p quality of life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p quality of life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a

  10. STAT3/NF-κB-Regulated Lentiviral TK/GCV Suicide Gene Therapy for Cisplatin-Resistant Triple-Negative Breast Cancer.

    Science.gov (United States)

    Kuo, Wei-Ying; Hwu, Luen; Wu, Chun-Yi; Lee, Jhih-Shian; Chang, Chi-Wei; Liu, Ren-Shyan

    2017-01-01

    Triple-negative breast cancer (TNBC) represents approximately 20% of all breast cancers and appears resistance to conventional cytotoxic chemotherapy, demonstrating a particularly poor prognosis and a significantly worse clinical outcome than other types of cancer. Suicide gene therapy has been used for the in vivo treatment of various solid tumors in recent clinical trials. In tumor microenvironment, STAT3/NF-κB pathways are constitutively activated in stromal cells as well as in cancer stem cells (CSCs). In this study, we have cloned a novel STAT3/NF-κB-based reporter system to drive the expression of herpes simplex virus thymidine kinase (HSV-TK) against breast cancer. Lentiviral vector expressing HSV-TK under the regulation of STAT3/NF-κB fused response element was developed. In this setting, we exploited the constitutive STAT3/NF-κB activation in tumors to achieve higher transgene expression than that driven by a constitutively active CMV promotor in vivo . An orthotropic MDA-MB-231 triple negative breast cancer mouse model was used for evaluating the feasibility of STAT3-NF-κB-TK/GCV suicide gene therapy system. The basal promoter activity of Lenti-CMV-TK and Lenti-STAT3-NF-κB-TK in MDA-MB-231 cells was compared by 3 H-FEAU uptake assay. The Lenti-CMV-TK showed ~5 fold higher 3 H-FEAU uptake then Lenti -STAT3-NF-κB-TK. In clonogenic assay, cells expressing Lenti-CMV-TK were 2-fold more sensitive to GCV than Lenti-STAT3-NF-κB-TK transduced cells. In vitro effect of STAT3-NF-κB-induced transgene expression was determined by 10ng/mL TNF-α induction and confirmed by western blot analysis and DsRedm fluorescent microscopy. In vivo evaluation of therapeutic effect by bioluminescence and [ 18 F]FHBG microPET imaging indicated that Lenti-STAT3-NF-κB-TK showed more tumor growth retardation than Lenti-CMV-TK when GCV (20 mg/kg) was administered. The invasiveness and expression of cancer stem cell markers were both decreased after STAT3/NF-κB-regulated HSV

  11. The prognostic values of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastatic colorectal cancer

    International Nuclear Information System (INIS)

    Huang, Ching-Wen; Wang, Jaw-Yuan; Tsai, Hsiang-Lin; Chen, Yi-Ting; Huang, Chun-Ming; Ma, Cheng-Jen; Lu, Chien-Yu; Kuo, Chao-Hung; Wu, Deng-Chyang; Chai, Chee-Yin

    2013-01-01

    The epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway is an important pathway in the carcinogenesis, invasion and metastasis of colorectal cancers (CRCs). We conducted a retrospective study to determine the prognostic values of EGFR expression and KRAS mutation in patients with metastatic CRC (mCRC) based on synchronous or metachronous status. From October 2002 to March 2012, 205 patients with mCRC were retrospectively analyzed; 98 were found to have metachronous mCRC while 107 were found to have synchronous mCRC. The EGFR expressions were determinate by IHC (immunohistochemistry) analysis and categorized 1+ (weak intensity), 2+ (moderate intensity), and 3+ (strong intensity). Genomic DNA was isolated from frozen primary CRC tissues and direct sequencing of KRAS was performed. The clinicopathological features of these mCRC patients were retrospectively investigated according to EGFR expression and KRAS mutation status. Moreover, we analyzed the prognostic values of EGFR expression and KRAS mutation among these patients. Of the 205 patients with mCRC, EGFR expression was analyzed in 167 patients, and positive EGFR expression was noted in 140 of those patients (83.8%). KRAS mutation was investigated in 205 patients and mutations were noted in 88 of those patients (42.9%). In patients with metachronous mCRC, positive EGFR expression was significantly correlated with well-and moderately-differentiated tumors (P = 0.028), poorer disease-free survival (DFS) (P < 0.001), and overall survival (OS) (P < 0.001). Furthermore, positive EGFR expression was a significant independent prognostic factor of DFS (P = 0.006, HR: 4.012, 95% CI: 1.130–8.445) and OS (P = 0.028, HR: 3.090, 95% CI: 1.477–10.900) in metachronous mCRC patients. KRAS mutation status was not significantly related to DFS and OS of patients with metachronous mCRC; likewise, KRAS mutation status was not significantly different in the progression-free survival (PFS) and OS of patients with

  12. ER, HER2, and TOP2A expression in primary tumor, synchronous axillary nodes, and asynchronous metastases in breast cancer

    DEFF Research Database (Denmark)

    Jensen, Jeanette Dupont; Knoop, Ann; Ewertz, Marianne

    2011-01-01

    with the primary tumors with respect to ER, HER2, and TOP2A. In the prospective tissue-collection study, 81 patients had biopsy from a suspected relapse. Additional archived paired material was included, leaving a total of 119 patients with paired primary tumor, synchronous axillary nodes (available in 52 patients......At recurrence of breast cancer, the therapeutic target is the metastases. However, it is current practice to base the choice of systemic treatment on the biomarker profile of the primary tumor. In the present study, confirmatory biopsies were obtained from suspected metastatic lesions and compared......) and asyncronous metastases available for analysis. ER, HER2, and TOP2A expression of primary tumors, axillary nodes and metastases were re-analysed and determined centrally by immunohistochemistry, chromogenic in situ hybridization, and fluorescence in situ hybridization. Of the 81 patients with a biopsy from...

  13. Comparative effectiveness analysis of monotherapy with cytotoxic agents in triple-negative metastatic breast cancer in a community setting.

    Science.gov (United States)

    Dranitsaris, George; Gluck, Stefan; Faria, Claudio; Cox, David; Rugo, Hope

    2015-01-01

    There has been considerable progress in the treatment of metastatic breast cancer. However, the identification of optimal cytotoxic agents in patients with triple-negative breast cancer (TNBC) (negative for hormone receptors and human epidermal growth factor receptor 2) remains a therapeutic challenge. We conducted a comparative effectiveness analysis of 4 cytotoxic agents in patients with TNBC. We retrospectively identified patients who received single-agent chemotherapy with eribulin, capecitabine, gemcitabine, or vinorelbine from 19 community oncology clinics across the United States. Data collection included baseline patient and disease characteristics, prior therapies, performance status, duration of current therapy, growth-factor use and other supportive care, and dose-limiting toxicities and associated dose reductions or delays or skipped doses. Time to treatment failure (TTF) was measured from the first cycle of chemotherapy until disease progression, discontinuation due to toxicity, or death. TTF was estimated using the Kaplan-Meier method and Cox proportional hazards modeling adjusted for clustering on the practice site. To control for selection bias, which is inherent in observational studies, a propensity score-weighted TTF analysis was also conducted. Data from 225 patients were included in the analysis (eribulin, 47 patients; capecitabine, 69; gemcitabine, 56; and vinorelbine, 53). The median age of each group was exception of the gemcitabine group (63 years). The 4 groups were comparable with respect to age, performance status, duration of disease-free survival, presence of comorbidities, and hemoglobin level before the start of chemotherapy. Median lines of therapy of eribulin, capecitabine, gemcitabine, and vinorelbine and were 4th, 2nd, 3rd, and 3rd, respectively. The median durations of treatment were ~2 months with eribulin, capecitabine, and gemcitabine compared with 1.6 months with vinorelbine. Using eribulin as the reference drug, and with

  14. Synchronous BI-RADS Category 3 Lesions on Preoperative Ultrasonography in Patients with Breast Cancer: Is Short-Term Follow-Up Appropriate?

    OpenAIRE

    Lee, Seokwon; Jung, Younglae; Bae, Youngtae

    2015-01-01

    Purpose Breast ultrasonography (US) has been widely used in the preoperative examination of patients with breast cancer. Breast Imaging Reporting and Data System (BI-RADS) category 3 (C3) lesions (probably benign) are regarded as having a low probability of malignancy (?2%). The purposes of this study were to verify the malignancy rates for synchronous BI-RADS C3 lesions in patients with breast cancer and consider appropriate management strategies for these lesions. Methods Between January 20...

  15. Four synchronous cancers in a patient with tongue pain as the only symptom

    DEFF Research Database (Denmark)

    Nyhøj Heidemann, Lene; Johansen, Jørgen; Larsen, Stine Rosenkilde

    2016-01-01

    with three synchronous squamous cell carcinomas, two in the tongue and one in the aryepiglottic fold. Positron emission tomography CT (PET-CT) was required for the detection of the carcinomas as the initial MRI and CT scans were inconclusive due to artefacts. Furthermore, PET-CT also revealed increased...... metabolic activity in the lymph nodes of the neck, which subsequently led to detection of a low-grade follicular lymphoma in addition to the squamous cell carcinomas. These findings support a generous use of PET-CT in patients with HNSCC, at least in those with obvious risk factors....

  16. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing

    Science.gov (United States)

    Klemp, Jennifer R.; Kimler, Bruce F.; Mahnken, Jonathan D.; Geier, Larry J.; Khan, Qamar J.; Elia, Manana; Connor, Carol S.; McGinness, Marilee K.; Mammen, Joshua M. W.; Wagner, Jamie L.; Ward, Claire; Ranallo, Lori; Knight, Catherine J.; Stecklein, Shane R.; Jensen, Roy A.; Fabian, Carol J.; Godwin, Andrew K.

    2014-01-01

    NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I–IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African–American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51–60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC. PMID:24807107

  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

    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......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......-negative breast cancer. METHODS: We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple...

  18. Pretreatment magnetic resonance imaging of regional lymph nodes with carcinoembryonic antigen in prediction of synchronous distant metastasis in patients with rectal cancer.

    Science.gov (United States)

    Liu, Huanhuan; Cui, Yanfen; Shen, Wei; Fan, Xingwen; Cui, Long; Zhang, Caiyuan; Ren, Gang; Fu, Jihong; Wang, Dengbin

    2016-05-10

    Distant metastasis in patients with rectal cancer remains a problem influencing prognosis. Prediction of synchronous distant metastasis is important for the choice of personalized treatment strategies and postoperative follow-up protocol. So far, there are few studies about the predictive value of MRI features combined with clinical characteristics for synchronous distant metastasis in rectal cancer, especially for the lesions developed within 6 months after surgery. We retrospectively reviewed the pretreatment clinical characteristics and magnetic resonance imaging (MRI) features of 271 patients from January 2010 to December 2011with pathologically confirmed rectal adenocarcinoma and tried to identify independent risk factors for synchronous distant metastasis. Forty-nine patients (18.1%) were confirmed to have synchronous distant metastasis. Multivariate logistic regression model demonstrated that the elevated carcinoembryonic antigen (CEA), positive MRI-predicted lymph nodes staging (mrN), and MRI-predicted mesorectal fascia (mrMRF) involvement were independent risk factors. The odd ratios were 12.2 for elevated CEA, 5.4 for mrN1 and 7.6 for mrN2, and 3.8 for mrMRF involvement, respectively. The accuracy and specificity for predicting synchronous distant metastasis by evaluating the positive mrN combined with elevated CEA were improved to 87.8% and 94.6%, respectively. The accuracy, sensitivity and specificity of positive mrN assessment were 86.1%, 71.4% and 91.7%, respectively using the histopathologic results as the reference standard. Altogether, our findings suggest that pretreatment positive mrN and elevated CEA are independent risk factors for synchronous distant metastasis in rectal cancer and combination of both could help to recognize the patients with high risk for structuring personalized treatment protocol.

  19. Elucidation of epithelial-mesenchymal transition-related pathways in a triple-negative breast cancer cell line model by multi-omics interactome analysis

    DEFF Research Database (Denmark)

    Pauling, Josch K; Christensen, Anne G; Batra, Richa

    2014-01-01

    exhibiting epithelial-like and mesenchymal-like morphology, respectively. Here we identified altered protein signaling activity in a complex biologically relevant network, related to focal adhesion and migration of breast cancer cells. We found dysregulated functional network modules revealing altered...... obtained from a triple-negative breast cancer cell line model, combining data sets of gene and protein expression as well as protein phosphorylation. We focus on alterations associated with the phenotypical differences arising from epithelial-mesenchymal transition in two breast cancer cell lines...... with generation of biological networks. This allows identification of intrinsic patterns in the data and their linkage to a specific context such as cellular compartments, diseases or functions. Identification of aberrant pathways by traditional approaches is often limited to biological networks based on either...

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

    International Nuclear Information System (INIS)

    Fastner, Gerd; Zehentmayr, Franz; Kopp, Peter; Fussl, Christoph; Sedlmayer, Felix; Hauser-Kronberger, Cornelia; Moder, Angelika; Reitsamer, Roland; Fischer, Thorsten; Deutschmann, Heinrich

    2016-01-01

    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 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.) [de

  1. ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer.

    Science.gov (United States)

    Guo, Peng; Yang, Jiang; Jia, Di; Moses, Marsha A; Auguste, Debra T

    2016-01-01

    Lipocalin 2 (Lcn2) is a promising therapeutic target as well as a potential diagnostic biomarker for breast cancer. It has been previously shown to promote breast cancer progression by inducing the epithelial to mesenchymal transition in breast cancer cells as well as by enhancing angiogenesis. Lcn2 levels in urine and tissue samples of breast cancer patients has also been correlated with breast cancer status and poor patient prognosis. In this study, we have engineered a novel liposomal small interfering RNA (siRNA) delivery system to target triple negative breast cancer (TNBC) via a recently identified molecular target, intercellular adhesion molecule-1 (ICAM-1). This ICAM-1-targeted, Lcn2 siRNA- encapsulating liposome (ICAM-Lcn2-LP) binds human TNBC MDA-MB-231cells significantly stronger than non-neoplastic MCF-10A cells. Efficient Lcn2 knockdown by ICAM-Lcn2-LPs led to a significant reduction in the production of vascular endothelial growth factor (VEGF) from MDA-MB-231 cells, which, in turn, led to reduced angiogenesis both in vitro and in vivo. Angiogenesis (neovascularization) is a requirement for solid tumor growth and progression, and its inhibition is an important therapeutic strategy for human cancers. Our results indicate that a tumor-specific strategy such as the TNBC-targeted, anti-angiogenic therapeutic approach developed here, may be clinically useful in inhibiting TNBC progression.

  2. 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.)

  3. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

    Science.gov (United States)

    Adams, Sylvia; Gray, Robert J.; Demaria, Sandra; Goldstein, Lori; Perez, Edith A.; Shulman, Lawrence N.; Martino, Silvana; Wang, Molin; Jones, Vicky E.; Saphner, Thomas J.; Wolff, Antonio C.; Wood, William C.; Davidson, Nancy E.; Sledge, George W.; Sparano, Joseph A.; Badve, Sunil S.

    2014-01-01

    Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter. PMID:25071121

  4. Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Quéré, Gilles; Descourt, Renaud; Robinet, Gilles; Autret, Sandrine; Raguenes, Odile; Fercot, Brigitte; Alemany, Pierre; Uguen, Arnaud; Férec, Claude; Quintin-Roué, Isabelle; Le Gac, Gérald

    2016-01-01

    Despite reported discordance between the mutational status of primary lung cancers and their metastases, metastatic sites are rarely biopsied and targeted therapy is guided by genetic biomarkers detected in the primary tumor. This situation is mostly explained by the apparent stability of EGFR-activating mutations. Given the dramatic increase in the range of candidate drugs and high rates of drug resistance, rebiopsy or liquid biopsy may become widespread. The purpose of this study was to test genetic biomarkers used in clinical practice (EGFR, ALK) and candidate biomarkers identified by the French National Cancer Institute (KRAS, BRAF, PIK3CA, HER2) in patients with metastatic non-small-cell lung cancer for whom two tumor samples were available. A retrospective study identified 88 tumor samples collected synchronously or metachronously, from the same or two different sites, in 44 patients. Mutation analysis used SNaPshot (EGFR, KRAS, BRAF missense mutations), pyrosequencing (EGFR and PIK3CA missense mutations), sizing assays (EGFR and HER2 indels) and IHC and/or FISH (ALK rearrangements). About half the patients (52 %) harbored at least one mutation. Five patients had an activating mutation of EGFR in both the primary tumor and the metastasis. The T790M resistance mutation was detected in metastases in 3 patients with acquired resistance to EGFR tyrosine kinase inhibitors. FISH showed discordance in ALK status between a small biopsy sample and the surgical specimen. KRAS mutations were observed in 36 % of samples, six patients (14 %) having discordant genotypes; all discordances concerned sampling from different sites. Two patients (5 %) showed PI3KCA mutations. One metastasis harbored both PI3KCA and KRAS mutations, while the synchronously sampled primary tumor was mutation free. No mutations were detected in BRAF and HER2. This study highlighted noteworthy intra-individual discordance in KRAS mutational status, whereas EGFR status was stable. Intratumoral

  5. Effects of phenotype transformation of receptors of triple-negative breast cancer(TNBC on clinical prognosis of patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Xin ZHAO

    2012-04-01

    Full Text Available Objective To evaluate the expression of estrogen receptor (ER, progesterone receptor (PR and human epidermis growth-factor receptor 2(HER-2, to determine the phenotype transformation of these receptors before and after recurrence and/or metastasis, and to explore the effects of expression and phenotype transformation of receptors on the treatment efficacy and clinical prognosis of patients with breast cancer. Methods Based on the phenotype transformation of ER, PR, and HER-2 receptor, 211 breast cancer patients were assigned to 3 groups. Twenty patients of Group A were with primary triple-negative breast cancer (TNBC, defined as lacking expression of ER, PR and HER2 which transformed into non-TNBC after recurrence and/ or metastasis, 73 of Group B were with primary non-TNBC which transformed into TNBC after recurrence and/or metastasis, and 118 of Group C were with primary TNBC which was still TNBC after recurrence and/or metastasis. The phenotype transformation of receptors, recurrence/metastasis, and efficacy and clinical prognosis were analyzed following collection of general information of the patients. Results The median age of 211 recurrent patients was 52 years (range, 22 to 78 years. Most of the patients exhibited solitary metastasis. The most common locations of the initial metastasis were lymph node, bone and skin. The median disease-free survival for Groups A, B, and C was 34.0, 25.0, and 20.0 months, respectively. The clinical effect of Groups B and C was better than that of Group A for first-line, second-line, and third-line rescuing therapy (P=0.030, 0.003, 0.001. However, the clinical benefit rate of Group A was higher than those of Groups B and C for rescuing endocrine therapy. The median follow-up time of the 211 patients was 68 months (range, 20 to 127 months, and the median survival after recurrence for Groups A, B, and C was 63.1, 33.7, and 25.8 months respectively (P=0.000. The median overall survival for Groups A, B

  6. Serum starvation and thymidine double blocking achieved efficient cell cycle synchronization and altered the expression of p27, p53, bcl-2 in canine breast cancer cells.

    Science.gov (United States)

    Tong, Jinjin; Sun, Dongdong; Yang, Chao; Wang, Yingxue; Sun, Sichao; Li, Qing; Bao, Jun; Liu, Yun

    2016-04-01

    Cell synchronization is an approach to obtain cell populations of the same stage, which is a prerequisite to studying the regulation of cell cycle progression in vivo. Serum starvation and thymidine double blocking (TdR) are two important practices in studying cell cycle synchronization. However, their effects on canine cancer cells as well as the regulatory mechanisms by these two methods are poorly understood. In this study, we determined the optimum conditions of serum starvation and TdR and their effects on cell cycle synchronization. We further explored the involvement of PI3K/Akt signaling pathway in the cell cycle synchronization by investigating the expression of three key genes (p27, p53 and bcl-2). Serum starvation resulted in a reversible cell cycle arrest and synchronously progress through G0/G1. The highest percentage of CHMm cells (87.47%) in G0/G1 stage was obtained after 42 h incubation with 0.5% fetal bovine serum (FBS). TdR double blocking could arrest 98.9% of CHMm cells in G1/S phase (0 h of release), and could arrest 93.74% of CHMm cells in S phase after 4h of release. We also found that the p27, p53, bcl-2 genes were most highly expressed in G0/G1 phase. Our current work revealed that serum starvation and TdR methods could achieve sufficient synchronization of CHMm cells. Moreover, the expression of p27, p53 and bcl-2 genes was related to cyclical movements and apoptosis. Our results will provide a new insight into cell cycle regulation and reprogramming of canine cancer cells induced by serum starvation and TdR blocking. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.

    Science.gov (United States)

    İyikesici, Mehmet Salih; Slocum, Abdul Kadir; Slocum, Ayshe; Berkarda, Ferhan Bulent; Kalamian, Miriam; Seyfried, Thomas N

    2017-07-07

    Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC.

  8. MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells

    Directory of Open Access Journals (Sweden)

    Wang Chen

    2012-06-01

    Full Text Available Abstract Background This study was performed to investigate the effect of microRNA-203 (miR-203 on cell proliferation and migration in triple-negative breast cancer (TNBC. Methods Real-time PCR was performed to detect the expression of miR-203 in TNBC cell lines. miR-203 precursor and control microRNA (miRNA were transfected into triple-negative breast cancer (TNBC cell lines and the effects of miR-203 up-regulation on the proliferation and migration of cells were investigated. Meanwhile, the mRNA and protein levels of baculoviral IAP repeat-containing protein 5 (BIRC5 and Lim and SH3 domain protein 1 (LASP1 were measured. Luciferase assays were also performed to validate BIRC5 and LASP1 as miR-203 targets. Results Both miR-203 and BIRC5 siRNA signicantly inhibited cell proliferation in TNBC cells. Both miR-203 and LASP1 siRNA signicantly inhibited cell migration in TNBC cells, also. Moreover, up-regulated of BIRC5 and LASP1 was able to abrogate the effects induced by transfection with the miR-203 precursor. Conclusions These data suggest that miR-203 may function as a tumor suppressor in TNBC cells. Thus, miR-203 could be a potential therapeutic target for this disease.

  9. A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells

    Science.gov (United States)

    Petrocca, Fabio; Altschuler, Gabriel; Tan, Shen Mynn; Mendillo, Marc L.; Yan, Haoheng; Jerry, D. Joseph; Kung, Andrew L.; Hide, Winston; Ince, Tan A.; Lieberman, Judy

    2013-01-01

    Summary Basal-like triple negative breast cancers (TNBC) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes - basal-like BPLER and myoepithelial HMLER. Expression of the screen’s 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal and mesenchymal TNBC lines. Proteasome inhibition reduced growth of established basal-like TNBC tumors in mice and blocked tumor-initiating cell function and macrometastasis. Proteasome addiction in basal-like TNBCs was mediated by NOXA and linked to MCL-1 dependence. PMID:23948298

  10. 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

  11. DEGRO practical guidelines for radiotherapy of breast cancer V. Therapy for locally advanced and inflammatory breast cancer, as well as local therapy in cases with synchronous distant metastases

    Energy Technology Data Exchange (ETDEWEB)

    Budach, Wilfried; Matuschek, Christiane; Boelke, Edwin [University Hospital, Heinrich-Heine-University Duesseldorf, Klinik fuer Strahlentherapie und Radioonkologie, Duesseldorf (Germany); Dunst, Juergen [University Hospital Schleswig-Holstein, Luebeck (Germany); Feyer, Petra [Vivantes Hospital Neukoelln, Berlin (Germany); Fietkau, Rainer; Sauer, Rolf [University Hospital Erlangen, Erlangen (Germany); Harms, Wolfgang [St. Clara Hospital, Basel (Switzerland); Piroth, Marc D. [Helios Hospital, Wuppertal (Germany); Sautter-Bihl, Marie-Luise [Municipal Hospital, Karlsruhe (Germany); Sedlmayer, Felix [Paracelsus Medical University Hospital, Salzburg (Austria); Wenz, Frederick [Universitaetsmedizin Mannheim, Mannheim (Germany); Haase, Wulf; Souchon, Rainer; Collaboration: Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO)

    2015-08-15

    The purpose of this work is to give practical guidelines for radiotherapy of locally advanced, inflammatory and metastatic breast cancer at first presentation. A comprehensive survey of the literature using the search phrases ''locally advanced breast cancer'', ''inflammatory breast cancer'', ''breast cancer and synchronous metastases'', ''de novo stage IV and breast cancer'', and ''metastatic breast cancer'' and ''at first presentation'' restricted to ''clinical trials'', ''randomized trials'', ''meta-analysis'', ''systematic review'', and ''guideline'' was performed and supplemented by using references of the respective publications. Based on the German interdisciplinary S3 guidelines, updated in 2012, this publication addresses indications, sequence to other therapies, target volumes, dose, and fractionation of radiotherapy. International and national guidelines are in agreement that locally advanced, at least if regarded primarily unresectable and inflammatory breast cancer should receive neoadjuvant systemic therapy first, followed by surgery and radiotherapy. If surgery is not amenable after systemic therapy, radiotherapy is the treatment of choice followed by surgery, if possible. Surgery and radiotherapy should be administered independent of response to neoadjuvant systemic treatment. In patients with a de novo diagnosis of breast cancer with synchronous distant metastases, surgery and radiotherapy result in considerably better locoregional tumor control. An improvement in survival has not been consistently proven, but may exist in subgroups of patients. Radiotherapy is an important part in the treatment of locally advanced and inflammatory breast cancer that should be given to all patients regardless to the intensity and effect of

  12. Preoperative identification of synchronous ovarian and endometrial cancers: the importance of appropriate workup

    NARCIS (Netherlands)

    Broeders, F.M.; Wurff, A.A. van der; Pijnenborg, J.M.A.; Vos, M.C.

    2012-01-01

    OBJECTIVE: For treatment of patients with both endometrial and ovarian cancer, it is important to discriminate between 2 primary tumors and metastatic disease. Currently, criteria are based on postoperative findings. The aim of this study was to determine whether clinical parameters can discriminate

  13. Cytogenetic comparisons of synchronous carcinomas and polyps in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Bardi, G; Parada, L A; Bomme, L

    1997-01-01

    Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and cytogenetically analysed: 16 non-adenomatous polyps, six adenomas, seven carcinomas, including one in polyp, and one lymph node metastasis. Clonal chromosome aberrations were found in 20 samples in 100...

  14. Gomisin G Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing AKT Phosphorylation and Decreasing Cyclin D1.

    Science.gov (United States)

    Maharjan, Sony; Park, Byoung Kwon; Lee, Su In; Lim, Yoonho; Lee, Keunwook; Kwon, Hyung-Joo

    2018-03-28

    A type of breast cancer with a defect in three molecular markers such as the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor is called triple-negative breast cancer (TNBC). Many patients with TNBC have a lower survival rate than patients with other types due to a poor prognosis. In this study, we confirmed the anti-cancer effect of a natural compound, Gomisin G, in TNBC cancer cells. Treatment with Gomisin G suppressed the viability of two TNBC cell lines, MDA-MB-231 and MDA-MB-468 but not non-TNBC cell lines such as MCF-7, T47D, and ZR75-1. To investigate the molecular mechanism of this activity, we examined the signal transduction pathways after treatment with Gomisin G in MDA-MB-231 cells. Gomisin G did not induce apoptosis but drastically inhibited AKT phosphorylation and reduced the amount of retinoblastoma tumor suppressor protein (Rb) and phosphorylated Rb. Gomisin G induced in a proteasome-dependent manner a decrease in Cyclin D1. Consequently, Gomisin G causes cell cycle arrest in the G1 phase. In contrast, there was no significant change in T47D cells except for a mild decrease in AKT phosphorylation. These results show that Gomisin G has an anti-cancer activity by suppressing proliferation rather than inducing apoptosis in TNBC cells. Our study suggests that Gomisin G could be used as a therapeutic agent in the treatment of TNBC patients.

  15. Expression of NY-ESO-1 in Triple-Negative Breast Cancer Is Associated with Tumor-Infiltrating Lymphocytes and a Good Prognosis.

    Science.gov (United States)

    Lee, Hee Jin; Kim, Joo Young; Song, In Hye; Park, In Ah; Yu, Jong Han; Gong, Gyungyub

    2015-01-01

    Accumulating evidence suggests that immunotherapy has great potential for treating triple-negative breast cancer (TNBC). We analyzed the expression of NY-ESO-1, which is a potent immunogenic cancer testis antigen, and its association with clinicopathological factors in large cohorts of breast cancer patients. A total of 623 consecutive breast cancer patients who underwent surgery between 1993 and 1998 and 612 TNBC patients who underwent surgery between 2004 and 2010 at Asan Medical Center were included. Immunohistochemical staining for NY-ESO-1 was performed using tissue microarrays. NY-ESO-1 was expressed in 2.6% of consecutive breast cancers, all of which were TNBC (p ESO-1 expression was identified in 9.7% of the TNBC cohort and was significantly correlated with a higher level of tumor-infiltrating lymphocytes (TIL; p = 0.026). In survival analyses, a lower level of TIL (all, p ESO-1 expression (p = 0.024) were significantly associated with poor disease-free survival. Additionally, positive NY-ESO-1 expression was an independent favorable prognostic factor in TNBC patients (p = 0.046). NY-ESO-1 is specifically expressed in TNBC, and NY-ESO-1 expression is an independent good prognostic factor in TNBC. Evaluation of NY-ESO-1 expression in TNBC might be useful for selecting patients who may benefit from vaccination therapy and also has a prognostic significance in TNBC. © 2015 S. Karger AG, Basel.

  16. [Docetaxel plus carboplatin versus EC-T as adjuvant chemotherapy for triple-negative breast cancer: safety data from a phase III randomized open-label trial].

    Science.gov (United States)

    Yuan, Peng; Xu, Bing-he; Wang, Jia-yu; Ma, Fei; Li, Qing; Zhang, Pin; Fan, Ying; Li, Qiao; Wang, Wen-miao

    2012-06-01

    Triple-negative [estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] breast cancer (TNBC) accounts for ∼ 15% of overall breast cancer and associated with a poor prognosis. There is a short of standard adjuvant chemotherapy regimens for TNBC. A number of studies have shown that TNBC might be sensitive to cisplatin and carboplatin on the basis that dysfunction of BRCA1 and its pathway is associated with a specific DNA-repair defect, but data of adjuvant setting about this is limited. From January 2010 to September 2011, 95 early triple-negative breast cancer patients confirmed by pathology were randomly assigned to receive TP (docetaxel 75 mg/m², carboplatin AUC = 5, day 1, 21 days a cycle for 6 cycles) or EC-T (epirubicin 90 mg/m², cyclophosphamide 600 mg/m², d1, 21 days a cycle for 4 cycles, followed by docetaxel 80 mg/m², d1, 21 days a cycle for 4 cycles) chemotherapy. Adjuvant radiation therapy was given selectively after chemotherapy. Here we report a preliminary safety analysis with the chi-square test. Seventy-six out of the 95 patients had completed the chemotherapy and could be assessed for the safety profiles of the regimens. Thirty-seven of them were in the EC-T group with a median age of 47 years, and 21 out of these 37 patients were premenopausal (56.8%). Another 39 patients came from the TP group with a median age of 46 years, and 22 out of these 39 patients were premenopausal (56.4%). All of the 37 patients in EC-T group completed the planned treatment whereas 2 patients of the 39 cases in TP group did not because of bone marrow suppression. During the treatments, 9 patients had dose adjustment in each group. Adverse events of grade 1/2 were common. Specific incidence of adverse events with grade 3/4 in each group was as follows: alopecia, 29.7% vs. 10.3% (P = 0.033), vomiting 21.6% vs. 7.7% (P = 0.085), leukopenia 54.1% vs.25.6% (P = 0.011) and neutropenia 51.4% vs. 35.9% (P = 0.174). Other grade 3/4 toxicities were rare. All the adverse

  17. Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome

    Czech Academy of Sciences Publication Activity Database

    Švec, Jiří; Schwarzová, L.; Janošíková, B.; Štekrová, J.; Mandys, V.; Kment, M.; Vodička, Pavel

    2014-01-01

    Roč. 7, č. 8 (2014), s. 5196-5202 ISSN 1936-2625 Grant - others:GA MŠk(CZ) Prvouk-P27/LF1/1; Univerzita Karlova(CZ) CZ.2.16/3.1.00/24024 Institutional support: RVO:68378041 Keywords : germline mutation * gastric cancer * MLH1 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.891, year: 2014

  18. Evaluation of Survival Rate and Pattern of Risk Factors and Recurrence Rate in Patients with Triple-Negative Breast Cancer with other Subtypes

    Directory of Open Access Journals (Sweden)

    Seyed Mohammad Reza Mortazavizadeh

    2017-10-01

    Full Text Available Introduction: Breast cancer nowadays is one the major health issue especially in industrial population. Despite excessive researches in this regard, there is still no detailed and relevant information on the association between the risk factors of this cancer and its many outcomes. Due to increasing rate of breast cancer in Iran, including Yazd city, the present study was designed to evaluate the relationship between survival and recurrence rate with pattern of risk factors in breast cancer patients. Methods: This analytical study was conducted retrospectively on 333 patients with breast cancer during 8 years (2005-2013. Total survival and recurrence rates recorded in month for all samples, and then were analyzed and compared other obtained data. Chi-square and log rank were selected tests for analyzing and Kaplan-Meier was applicable curve for survival analyzing. Results: The mean age of subjects was 57.02 ± 12.32 years. The mean total survival rate was 93.15 ± 1.25 months (97.9%. The mean total recurrence rate was 84.59 ± 1.91 months (89.8%. The subgroups of breast cancer had no significant relationship with risk factors (P>0.05 though BMI and recurrence rate had significant relationship (P=0.045. Other risk factors had no significant relationship with total survival and recurrence rates. The mean duration of OCP (oral contraceptive pill consumption was significantly more in the patients with ER-PR-Her2+ subgroup than other groups (P=0.03.   Conclusion: According the findings, BMI lower than 25 is strong prognostic factor for recurrence rate in patients with triple-negative breast cancer. Because of high survival rate of patients with breast cancer during eight years, it is recommended to study on high survival period with larger sample sizes for accessing reliable evidence.

  19. Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers.

    Science.gov (United States)

    Bhaskari, J; Premalata, C S; Shilpa, V; Rahul, B; Pallavi, V R; Ramesh, G; Krishnamoorthy, Lakshmi

    2016-01-01

    In this study, we have analyzed six genetic polymorphisms of the VEGF-A gene and correlated the genetic data with plasma and tissue expression of VEGF-A in epithelial ovarian carcinomas. A total of 130 cases including 95 malignant carcinomas, 17 low malignant potential and 18 benign tumours were studied. rs699947, rs833061, rs1570360, rs2010963, rs1413711 and rs3025039 were studied by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma levels of VEGF-A were estimated by enzyme-linked immunosorbent assay (ELISA) and tissue expression of VEGF-A by immunohistochemistry (IHC). Four polymorphisms of the above excluding rs699947 and rs3025039 showed significant association with malignancy, and we observed the presence of positive correlation between haplotype CCGGCC and increased expression of VEGF-A in both plasma and tissues which also correlated with poor prognosis and recurrence suggesting a probable increase in resistance to treatment in such carriers. Highly upregulated tissue expression of VEGF-A was seen in all epithelial ovarian carcinomas with intensity of expression increasing from benign to malignant cases. ELISA data from our study showed an increase in circulating levels of VEGF-A in malignancies. VEGF-A plasma levels can be employed as a biomarker for high-grade malignancy in epithelial ovarian cancers alongside tissue expression and CA-125 levels. This study is unique due to the fact that a simultaneous analysis of plasma and tissue expression has been demonstrated and is a first such study in epithelial ovarian cancers and representing the Indian population (South-east Asian) synchronized with genetic polymorphism data as well.

  20. Cancers du sein bilat?raux synchrones et grossesse a l'institut Joliot Curie de Dakar (S?n?gal)

    OpenAIRE

    Zongo, Nayi; Sawadogo, Yobi Alexis; Some, Some Ollo Roland; Bagre, Sidpawalmd? Carine; Ka, Sidy; Diouf, Doudou; Dieng, Mamadou Moustapha; Gaye, Papa Macoumba; Dem, Ahmadou

    2016-01-01

    D?crire notre strat?gie diagnostique et th?rapeutique dans les cancers du sein bilat?raux synchrones pendant la grossesse. L??ge gestationnel au moment du diagnostic du cancer ?tait respectivement de 7; 21 et 25 semaines. Il s'agissait de stade IV et IIIA respectivement dans deux et un cas. Elles ont toutes b?n?fici? d'une chimioth?rapie dans deux cas pendant la grossesse (6TEC et 3AC) et dans un cas apr?s l'accouchement. Une mastectomie bilat?rale a ?t? r?alis?e dans un cas. Une patiente est...

  1. 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.

  2. Recurrent triple-negative breast cancer (TNBC tissues contain a higher amount of phosphatidylcholine (32:1 than non-recurrent TNBC tissues.

    Directory of Open Access Journals (Sweden)

    Yuko Hosokawa

    Full Text Available Triple-negative breast cancer (TNBC is one of the breast cancer subtype that displays a high risk of early recurrence and short overall survival. Improvement of the prognosis of patients with TNBC requires identifying a predictive factor of recurrence, which would make it possible to provide beneficial personalized treatment. However, no clinically reliable predictive factor is currently known. In this study, we investigated the predictive factor of recurrence in TNBC using matrix-assisted laser desorption/ionization-imaging mass spectrometry for lipid profiling of breast cancer specimens obtained from three and six patients with recurrent and non-recurrent TNBC, respectively. The signal for phosphatidylcholine (PC (32:1 at m/z 732.5 was significantly higher in the recurrence group compared to the non-recurrence group (P = 0.024. PC (32:1 was more abundant in the cancer epithelial area than it was in the surrounding stroma, suggesting that abnormal lipid metabolism was associated with malignant transformation. Our results indicate PC (32:1 as a candidate predictive factor of TNBC recurrence. A future prospective study investigating whether personalized therapy based on PC (32:1 intensity improves the prognosis of patients with TNBC is recommended.

  3. Combination Treatment of Polo-Like Kinase 1 and Tankyrase-1 Inhibitors Enhances Anticancer Effect in Triple-negative Breast Cancer Cells.

    Science.gov (United States)

    Ha, Geun-Hyoung; Kim, Dong-Young; Breuer, Eun-Kyoung; Kim, Chung Kwon

    2018-03-01

    Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of β-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  4. Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models.

    Science.gov (United States)

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2017-03-01

    We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Cisplatin With or Without Veliparib in Treating Patients With Recurrent or Metastatic Triple-Negative and/or BRCA Mutation-Associated Breast Cancer With or Without Brain Metastases

    Science.gov (United States)

    2018-03-12

    Breast Carcinoma Metastatic in the Brain; Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma

  6. Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer.

    Science.gov (United States)

    Sirkisoon, Sherona R; Carpenter, Richard L; Rimkus, Tadas; Anderson, Ashley; Harrison, Alexandria; Lange, Allison M; Jin, Guangxu; Watabe, Kounosuke; Lo, Hui-Wen

    2018-02-16

    Signal transducer and activator of transcription 3 (STAT3), glioma oncogene homolog 1 (GLI1), and truncated GLI1 (tGLI1) are oncogenic transcription factors playing important roles in breast cancer. tGLI1 is a gain-of-function GLI1 isoform. Whether STAT3 physically and/or functionally interacts with GLI1/tGLI1 has not been explored. To address this knowledge gap, we analyzed 47 node-positive breast cancer specimens using immunohistochemical staining and found that phosphorylated-STAT3 (Y705), GLI1, and tGLI1 are co-overexpressed in the majority of triple-negative breast carcinomas (64%) and HER2-enriched (68%) breast carcinomas, and in lymph node metastases (65%). Using gene set enrichment analysis, we analyzed 710 breast tumors and found that STAT3 activation and GLI1/tGLI1 activation signatures are co-enriched in triple-negative subtypes of breast cancers and HER2-enriched subtypes of breast cancers, but not in luminal subtypes of breast cancers. Patients with high levels of STAT3 and GLI1/tGLI1 co-activation in their breast tumors had worse metastasis-free survival compared to those with low levels. Since these proteins co-overexpress in breast tumors, we examined whether they form complexes and observed that STAT3 interacted with both GLI1 and tGLI1. We further found that the STAT3-GLI1 and STAT3-tGLI1 complexes bind to both consensus GLI1-binding and STAT3-binding sites using chromatin immunoprecipitation (ChIP) assay, and that the co-overexpression markedly activated a promoter controlled by GLI1-binding sites. To identify genes that can be directly co-activated by STAT3 and GLI1/tGLI1, we analyzed three ChIP-seq datasets and identified 34 potential target genes. Following validations using reverse transcription polymerase chain reaction and survival analysis, we identified three genes as novel transcriptional targets of STAT3 and GLI1/tGLI1, R-Ras2, Cep70, and UPF3A. Finally, we observed that co-overexpression of STAT3 with GLI1/tGLI1 promoted the ability of

  7. A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

    Directory of Open Access Journals (Sweden)

    Siraj M. Ali

    2016-02-01

    Full Text Available After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC. We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%. A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

  8. 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)

    Kaur, Punit; Nagaraja, Ganachari M; Zheng, Hongying; Gizachew, Dawit; Galukande, Moses; Krishnan, Sunil; Asea, Alexzander

    2012-01-01

    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 + /CD44 high /ALDH1 + cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24 + /CD44 high /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

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

    Directory of Open Access Journals (Sweden)

    Kau Punit

    2012-03-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions

  10. Breast-conserving therapy (BCT) in stage I-II synchronous bilateral breast cancer (SBBC)

    International Nuclear Information System (INIS)

    Gollamudi, Smitha V.; Gelman, Rebecca S.; Peiro, Gloria; Schneider, Lindsey; Connolly, James L.; Schnitt, Stuart; Silver, Barbara; Harris, Jay R.

    1995-01-01

    PURPOSE: To determine whether patients with early-stage SBBC can be safely and effectively treated with bilateral BCT. MATERIALS and METHODS: We retrospectively reviewed records of 26 patients with clinical Stage I-II SBBC treated between 1968-1989 with bilateral BCT. SBBC was defined as tumors diagnosed no more than one month apart, with both sides demonstrating invasive cancer. Maximum (max) clinical stage was based on the more advanced breast tumor. Median age at diagnosis was 56 years (range, 32-85 years); menopausal status was 6 pre-, 16 post-, 3 peri-, and 1 unknown at diagnosis. Median follow-up for surviving pts is 95 months (range, 68-157). Outcome was compared to 1325 pts with unilateral Stage I or II breast cancer, within the same age range, treated during the same time period. There were no significant differences in median age, median total dose, tumor size, estrogen receptor (ER) status, pathologic nodal status, and use of systemic therapy between the study population and the comparison group. Local recurrence (LR) was evaluated as true recurrence (TR, i.e., in the original tumor bed), marginal miss (MM, at the edge of the boost field), or elsewhere (E). Median total dose to the primary was 6100 cGy (range, 5000-7000). Pathology was available for review in 19 cases. Cytology (nuclear and cytoplasmic features) was similar in (7(19)) evaluable cases, and architecture (growth pattern, ie, papillary, solid) was similar in (5(19)) cases. The presence of either cytologic or architectural similarity was noted in(9(19)) cases. 7 of 19 pts who had axillary lymph node evaluation on at least one side had pathological confirmation of lymph node metastasis. Stage was the same in both breasts in 13 cases (10 Stage I, 3 Stage II); ER status data was complete in 11 pts, and the same in both primaries in 9 cases. Cosmetic results and complications after BCT were scored. Statistical significance was evaluated by use of the Fisher exact test. RESULTS: The 5-yr actuarial

  11. A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index.

    Directory of Open Access Journals (Sweden)

    Liang Huang

    Full Text Available OBJECTIVE: The aim of this study was to evaluate clinicopathologic factors that could possibly affect the outcome of patients with triple negative breast cancer and subsequently build a prognostic model to predict patients' outcome. METHODS: We retrospectively analyzed clinicopathologic characteristics and outcome of 504 patients diagnosed with triple-negative invasive ductal breast cancer. 185 patients enrolled between 2000 and 2002 were designated to the training set. The variables that had statistically significant correlation with prognosis were combined to build a model. The prognostic value of the model was further validated in the separate validation set containing 319 patients enrolled between 2003 and 2006. RESULTS: The median follow-up duration was 66 months. 174 patients experienced recurrence, and 111 patients died. Positivity for ≥4 lymph nodes, Cathepsin-D positivity, and Ki-67 index ≥20% were independent factors for DFS, while the lymph nodes status and Ki-67 index were the prognostic factors for OS. The prognostic model was established based on the sum of all three factors, where positivity for ≥4 lymph nodes, Cathepsin-D and Ki-67 index ≥20% would individually contribute 1 point to the risk score. The patients in the validation set were assigned to a low-risk group (0 and 1 point and a high-risk group (2 and 3 points. The external validation analysis also demonstrated that our prognostic model provided the independent high predictive accuracy of recurrence. CONCLUSION: This model has a considerable clinical value in predicting recurrence, and will help clinicians to design an appropriate level of adjuvant treatment and schedule adequate appointments of surveillance visits.

  12. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Martey O

    2017-10-01

    Full Text Available Orleans Martey,1 Mhairi Nimick,1 Sebastien Taurin,1 Vignesh Sundararajan,1 Khaled Greish,2 Rhonda J Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene-1-methylpiperidine-4-one (RL71, that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles. Keywords: curcumin derivatives, nanomedicine, EGFR, biodistribution

  13. c-Met and ERβ expression differences in basal-like and non-basal-like triple-negative breast cancer.

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    Ren, Xinyu; Yuan, Li; Shen, Songjie; Wu, Hanwen; Lu, Junliang; Liang, Zhiyong

    2016-08-01

    Basal-like breast cancer (BLBC) and triple-negative breast cancer (TNBC) are two entities of breast cancer that share similar poor prognosis. Even though both cancers have overlaps, there are still some differences between those two types. It has been reported that the c-Met high expression was associated with poor prognosis not only in breast cancer but also in many other cancers. The role of ERβ in pathogenesis and treatment of breast cancer has remained controversial. In this study, we firstly distinguished basal-like from nonbasal-like cancer patients in TNBC patients using CK5/6 and EGFR as markers and next determined the relationship of basal-like breast cancer with c-Met or ERβ expression levels and prognosis in TNBC patients. One hundred twenty-seven patients who had been diagnosed with TNBC were enrolled. The clinical and pathological characteristics of the patients were recorded. The expression of EGFR, CK5/6, ERβ, and c-Met were evaluated with immunohistochemical methods using paraffin blocks. The median age of patients was 50.7 years. CK5/6 immunopositivity was 31.5 % (40/127), and EGFR was 40.2 % (51/127). Of the TNBC cases, 55.1 % (71/127) were positive for either CK5/6 or EGFR and were thus classified as basal-like breast cancer. C-Met (P nodes and tumor size (>5 cm), which were both important prognostic predictors, were significantly associated with recurrence and mortality. BLBC typically demonstrates a unique profile. CK5/6 and EGFR expression combination indicates a higher basal-like phenotype possibility. The expression of c-Met and ERβ were significantly related to the basal-like phenotype. The classical markers, lymph node metastasis, and tumor size were found to have important prognostic value. However, high c-Met expression and basal-like phenotypes did not show a direct correlation with poor prognosis.

  14. A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib.

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    Ebelt, Nancy D; Kaoud, Tamer S; Edupuganti, Ramakrishna; Van Ravenstein, Sabrina; Dalby, Kevin N; Van Den Berg, Carla L

    2017-12-01

    Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients. Herein, we report that treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these compounds as single agents have little effect. The combination significantly increases survival of mice bearing xenografts of MDA-MB-231 human TNBC cells. Our studies demonstrate that lapatinib treatment increases c-Jun and JNK phosphorylation indicating a mechanism of resistance. Combined, these compounds significantly reduce transcriptional activity of Nuclear Factor kappa B, Activating Protein 1, and Nuclear factor erythroid 2-Related Factor 2. As master regulators of antioxidant response, their decreased activity induces a 10-fold increase in reactive oxygen species that is cytotoxic, and is rescued by addition of exogenous antioxidants. Over expression of p65 or Nrf2 also significantly rescues viability during JNK-IN-8 and lapatinib treatment. Further studies combining JNK-IN-8 and lapatinib may reveal a benefit for patients with TNBC, fulfilling a critical medical need.

  15. Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

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    Kyung-Min Yang

    2017-12-01

    Full Text Available Summary: Triple-negative breast cancer (TNBC is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2, which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer. : The mechanisms controlling the pro- and anti-oncogenic roles of cathepsin B are unclear. Yang et al. find that BAG2 is a regulator of the dual functions of its client protein, CTSB, facilitating the progression of TNBC. Keywords: BAG2, cathepsin B, TNBC, tumorigenesis, metastasis, breast cancer, TGN38

  16. Development of a novel near-infrared fluorescent theranostic combretastain A-4 analogue, YK-5-252, to target triple negative breast cancer.

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    Kong, Yali; Smith, Jacqueline; Li, Kongwen; Cui, Jake; Han, John; Hou, Shujie; Brown, Milton L

    2017-04-01

    The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models

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    Stelitano, Debora; Leticia, Yamila Peche; Dalla, Emiliano; Monte, Martin; Piazza, Silvano; Schneider, Claudio

    2017-01-01

    GTSE1 over-expression has been reported as a potential marker for metastasis in various types of malignancies, including breast cancer. Despite this, the transcriptional regulation of this protein and the causes of its misregulation in tumors remain largely unknown. The aims of this work were to elucidate how GTSE1 is regulated at the transcriptional level and to clarify the mechanism underlying GTSE1-dependent cell functions in triple-negative breast cancer (TNBC). Here, we identified GTSE1 as a novel target gene of the TEAD4 transcription factor, highlighting a role for the YAP and TAZ coactivators in the transcriptional regulation of GTSE1. Moreover, we found that TEAD4 controls the formation of cell protrusions required for cell migration through GTSE1, unveiling a relevant effector role for this protein in the TEAD-dependent cellular functions and confirming TEAD4 role in promoting invasion and metastasis in breast cancer. Finally, we highlighted a role for the pRb-E2F1 pathway in the control of GTSE1 transcription and observed that treatment with drugs targeting the pRb-E2F1 or YAP/TAZ-TEAD pathways dramatically downregulated the expression levels of GTSE1 and of other genes involved in the formation of metastasis, suggesting their potential use in the treatment of TNBC. PMID:28978043

  18. Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes.

    Science.gov (United States)

    Forero, Andres; Li, Yufeng; Chen, Dongquan; Grizzle, William E; Updike, Katherine L; Merz, Natalie D; Downs-Kelly, Erinn; Burwell, Todd C; Vaklavas, Christos; Buchsbaum, Donald J; Myers, Richard M; LoBuglio, Albert F; Varley, Katherine E

    2016-05-01

    Triple-negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately 40% of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis, we performed RNA-seq on 47 macrodissected tumors from newly diagnosed patients with TNBC (n = 47; 22 relapse, 25 no relapse; follow-up median, 8 years; range, 2-11 years). We discovered that expression of the MHC class II (MHC II) antigen presentation pathway in tumor tissue was the most significant pathway associated with progression-free survival (HR, 0.36; log-rank P = 0.0098). The association between MHC II pathway expression and good prognosis was confirmed in a public gene expression database of 199 TNBC cases (HR, 0.28; log-rank P = 4.5 × 10(-8)). Further analysis of immunohistochemistry, laser-capture microdissected tumors, and TNBC cell lines demonstrated that tumor cells, in addition to immune cells, aberrantly express the MHC II pathway. MHC II pathway expression was also associated with B-cell and T-cell infiltration in the tumor. Together, these data support the model that aberrant expression of the MHC II pathway in TNBC tumor cells may trigger an antitumor immune response that reduces the rate of relapse and enhances progression-free survival. Cancer Immunol Res; 4(5); 390-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  19. Silencing β3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple-Negative Breast Cancer.

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    Parvani, Jenny G; Gujrati, Maneesh D; Mack, Margaret A; Schiemann, William P; Lu, Zheng-Rong

    2015-06-01

    Metastatic breast cancer is the second leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Because previous studies coupled β3 integrin (ITGB3) to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/siβ3). Treatment of TNBC cells with ECO/siβ3 was sufficient to effectively silence β3 integrin expression, attenuate TGFβ-mediated EMT and invasion, restore TGFβ-mediated cytostasis, and inhibit three-dimensional organoid growth. Modification of ECO/siβ3 nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/siβ3 nanoparticles in vivo alleviated primary tumor burden and, more importantly, significantly inhibited metastasis. In the span of 16 weeks of the experiments and observations, including primary tumor resection at week 9 and release from the treatment for 4 weeks, the mice bearing orthotopic, TGFβ-prestimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/siβ3 nanoparticles were free of metastases and relapse, in comparison with untreated mice. Collectively, these results highlight ECO/siβ3 nanoparticles as a promising therapeutic regimen to combat TNBC. ©2015 American Association for Cancer Research.

  20. Reactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.

    Science.gov (United States)

    Stark, Karri; Burger, Angelika; Wu, Jianmei; Shelton, Phillip; Polin, Lisa; Li, Jing

    2013-01-01

    Aminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. In vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou-Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERα was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. Luminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERα expression and restored AhR-mediated transcriptional induction of CYP1A1. The response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERα expression and restoring the responsiveness of AhR to AF.

  1. Clinicopathological, therapeutic and prognostic features of the triple-negative tumors in moroccan breast cancer patients (experience of Hassan II university hospital in Fez

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    Akasbi Yousra

    2011-11-01

    Full Text Available Abstract Introduction Triple-negative breast cancer (TNBC is defined as a group of breast carcinomas that are negative for expression of hormone receptors (ER, PR and Her2, we can distinguish between two groups: basal-like (ER-, PR-, Her2-, cytokeratin (CK 5/6+ and/or Her1+ and unclassified subtype (ER-, PR-, Her2-, Her1- and CK5/6-. The aim of this study is to determine the clinicopathological, histological, therapeutic and prognostic features associated with this type of breast cancer. Methods This is a retrospective study of 366 female breast cancer patients, diagnosed between January 2007 and June 2010 at the Department of Pathology. Epidemiological, clinical, histological, therapeutic and evolutive data were analyzed. OS and DFS rates were estimated by Kaplan-Meier analysis and a log-rank test to estimate outcome. Results A total of 64 women were identified as having TNBC (17.5% of all female breast cancer patients, 12.6% were basal-like, 4.9% were unclassified subtype, with a median age of 45 years. The median histological tumor diameter was 4.3 cm. TNBC were most often associated with a high grade, 49.2% grade III (53% for unclassified subtype, 47.6% for basal-like. Vascular invasion was found in 26.6% of cases (22% for unclassified subtype and 28.3% for basal-like. For the lymph node involvement: 51% had positive lymph nodes, and 22.4% had distant metastases. Neoadjuvant chemotherapy was administered to 18% patients with 26% of complete pathologic response; therefore adjuvant chemotherapy was given to 82%. 98% received anthracycline based regimen and only 30% received taxanes. The Kaplan-Meier curves based showed the lowest survival probability at 3-years (49% of OS, and 39% of DFS. Conclusion TNBC is associated with young age, high grade tumors, advanced stage at diagnosis, difference chemo response compared to other subtypes, and shortest survival. Critical to optimal future management is accurate identification of truly triple

  2. The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer.

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    Iram Fatima

    Full Text Available Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC are highly metastatic and are devoid of estrogen receptor (ER, progesterone receptor (PR and human epidermal growth factor receptor 2 (HER2 amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA, derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50 responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone

  3. Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

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

    2014-01-01

    Abstract Introduction The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75–95% of estrogen receptor (ER)-positive and 40–70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to ...

  4. The prognostic value of the neoadjuvant response index in triple-negative breast cancer: validation and comparison with pathological complete response as outcome measure.

    Science.gov (United States)

    Jebbink, M; van Werkhoven, E; Mandjes, I A M; Wesseling, J; Lips, E H; Vrancken Peeters, M-J T D F; Loo, C E; Sonke, G S; Linn, S C; Falo Zamora, C; Rodenhuis, S

    2015-08-01

    The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (>0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.

  5. Effect of metformin on estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells.

    Science.gov (United States)

    Amaral, Inês; Silva, Cláudia; Correia-Branco, Ana; Martel, Fátima

    2018-03-15

    This work aimed to investigate the effect of metformin on cellular glucose uptake and metabolism by breast cancer cells, as a mechanism contributing to its anticancer properties. Estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines were used as in vitro models of breast cancer. Short-term (26 min) exposure of MCF-7 and MDA-MB-231 cells to metformin inhibited uptake of 3 H-deoxy-D-glucose ( 3 H-DG). In contrast, long-term (24 h) exposure to metformin (5 μM-1 mM) concentration-dependently increased 3 H-DG uptake in both cell lines. This effect was associated with an increase in lactate production but was not associated with changes in GLUT1 mRNA expression. Long-term exposure of MCF-7 and MDA-MB-231 cells to metformin (5 μM-1 mM) concentration-dependently reduced cell viability and culture mass and slightly increased cell proliferation rates. Combination of metformin (1 mM) with the facilitative glucose transporter (GLUT) inhibitor kaempferol (30 μM) did not change the effect of metformin on culture growth. In conclusion, short-term exposure to metformin reduces cellular glucose uptake, probably by direct inhibition of GLUT1. However, after long-term exposure to metformin, cellular uptake of glucose is significantly increased, not associated to changes in GLUT1 transcription rates. We suggest that, in the long-term, metformin induces a compensatory increase in glucose uptake in response to cellular energy depletion resulting from its inhibitory effect on mitochondrial oxidative phosphorylation machinery. Metformin-induced dependence of breast cancer cells on glycolytic pathway, associated with an anticarcinogenic effect of the drug, provides a biochemical basis for the design of new therapeutic strategies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. MicroRNA-145 functions as a tumor suppressor by targeting matrix metalloproteinase 11 and Rab GTPase family 27a in triple-negative breast cancer.

    Science.gov (United States)

    Tang, L; Wei, D; Yan, F

    2016-08-01

    Although increasing evidence has documented that microRNA-145 (miR-145) acts as a tumor suppressor in breast cancer, its exact role in triple-negative breast cancer (TNBC) remains poorly defined. In this study, the expression of miR-145 in human TNBC cells and samples from 30 patients was analyzed by stem-loop real-time PCR. We found that miR-145 was significantly downregulated in TNBC tissues and cells. Upregulating miR-145 in HCC1937 cells dramatically suppressed cell proliferation and induced G1-phase arrest, whereas MDA-MB-231 cells did not show growth inhibition. MiR-145 exhibited an inhibitory role in cell invasion through the post-transcriptional regulation of the novel targets MMP11 and Rab27a in TNBC cells. Additionally, miR-145 silencing could be reversed by 5-aza-2'-deoxycytidine (DAC). These results demonstrated that miR-145 has an inhibitory role in TNBC malignancy by targeting MMP11 and Rab27a, which might be potential therapeutic and diagnostic targets for TNBC.

  7. Toxicity evaluation of magnetic hyperthermia induced by remote actuation of magnetic nanoparticles in 3D micrometastasic tumor tissue analogs for triple negative breast cancer.

    Science.gov (United States)

    Stocke, Nathanael A; Sethi, Pallavi; Jyoti, Amar; Chan, Ryan; Arnold, Susanne M; Hilt, J Zach; Upreti, Meenakshi

    2017-03-01

    Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles or magnetic nanocomposites (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/mL) caused significant increase in cellular death/damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. 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. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

  9. AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.

    Science.gov (United States)

    Qiao, Yichun; Shiue, Chiou-Nan; Zhu, Jian; Zhuang, Ting; Jonsson, Philip; Wright, Anthony P H; Zhao, Chunyan; Dahlman-Wright, Karin

    2015-04-10

    The molecular determinants of malignant cell behaviour in triple-negative breast cancer (TNBC) are poorly understood. Recent studies have shown that regulators of epithelial-mesenchymal transition (EMT) are potential therapeutic targets for TNBC. In this study, we demonstrate that the inflammatory cytokine TNFα induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1. We further investigated in detail AP-1 regulation of ZEB2 expression. We show that two ZEB2 transcripts derived from distinct promoters are both expressed in breast cancer cell lines and breast tumor samples. Using the chromosome conformation capture assay, we demonstrate that AP-1, when activated by TNFα, binds to a site in promoter 1b of the ZEB2 gene where it regulates the expression of both promoter 1b and 1a, the latter via mediating long range chromatin interactions. Overall, this work provides a plausible mechanism for inflammation-induced metastatic potential in TNBC, involving a novel regulatory mechanism governing ZEB2 isoform expression.

  10. Elucidation of Altered Pathways in Tumor-Initiating Cells of Triple-Negative Breast Cancer: A Useful Cell Model System for Drug Screening.

    Science.gov (United States)

    Christensen, Anne G; Ehmsen, Sidse; Terp, Mikkel G; Batra, Richa; Alcaraz, Nicolas; Baumbach, Jan; Noer, Julie B; Moreira, José; Leth-Larsen, Rikke; Larsen, Martin R; Ditzel, Henrik J

    2017-08-01

    A limited number of cancer cells within a tumor are thought to have self-renewing and tumor-initiating capabilities that produce the remaining cancer cells in a heterogeneous tumor mass. Elucidation of central pathways preferentially used by tumor-initiating cells/cancer stem cells (CSCs) may allow their exploitation as potential cancer therapy targets. We used single cell cloning to isolate and characterize four isogenic cell clones from a triple-negative breast cancer cell line; two exhibited mesenchymal-like and two epithelial-like characteristics. Within these pairs, one, but not the other, resulted in tumors in immunodeficient NOD/Shi-scid/IL-2 Rγ null mice and efficiently formed mammospheres. Quantitative proteomics and phosphoproteomics were used to map signaling pathways associated with the tumor-initiating ability. Signaling associated with apoptosis was suppressed in tumor-initiating versus nontumorigenic counterparts with pro-apoptotic proteins, such as Bcl2-associated agonist of cell death (BAD), FAS-associated death domain protein (FADD), and myeloid differentiation primary response protein (MYD88), downregulated in tumor-initiating epithelial-like cells. Functional studies confirmed significantly lower apoptosis in tumor-initiating versus nontumorigenic cells. Moreover, central pathways, including β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signaling, exhibited increased activation in the tumor-initiating cells. To evaluate the CSC model as a tool for drug screening, we assessed the effect of separately blocking NF-κB and Wnt/β-catenin signaling and found markedly reduced mammosphere formation, particularly for tumor-initiating cells. Similar reduction was also observed using patient-derived primary cancer cells. Furthermore, blocking NF-κB signaling in mice transplanted with tumor-initiating cells significantly reduced tumor outgrowth. Our study demonstrates that suppressed apoptosis, activation

  11. 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.

  12. Proteomic Profiling of β-hCG-Induced Spheres in BRCA1 Defective Triple Negative Breast Cancer Cells.

    Science.gov (United States)

    Sengodan, Satheesh Kumar; Rajan, Arathi; Hemalatha, Sreelatha Krishnakumar; Nadhan, Revathy; Jaleel, Abdul; Srinivas, Priya

    2018-01-05

    Previously, we identified that β-hCG is expressed by BRCA1 mutated but not wild type breast cancers in vitro/in vivo and exhibited a novel event in β-hCG overexpressing BRCA1 mutated HCC1937 cells where the cells were able to form spheres (HCC1937 β spheres) in adherent cell culture plates even in the absence of any growth factors. These spheres express stem cell and EMT markers. In the present study, we carried out the total proteomic profiling of these HCC1937 β spheres obtained from BRCA1 defective β-hCG expressing stable breast cancer cells to analyze the cell signaling pathways that are active in these cells. Functional annotation revealed proteins (164 cellular and 97 secretory) predominantly involved in oxygen binding, nucleosome assembly, cytoskeleton organization, protein folding, etc. Many of the proteins identified from HCC1937 β spheres in this study are also up regulated in breast cancers, which are directly linked with poor prognosis in human cancer samples as analyzed using TCGA data set. Survival analysis shows that β-hCG expressing cancer patients are linked with poor survival rate. Interestingly, hemoglobins were identified at both cellular and secretory level in HCC1937 β spheres and experiments after treating with ROS inducers revealed that β-hCG induces hemoglobin and protects the cancer cells during oxidative stress. Our proteomic data strongly propose β-hCG as an oncogenic molecule associated with BRCA1 mutation, and hence, targeting β-hCG could be a strategy to treat BRCA1 defective breast cancers.

  13. Programmed Death Ligand 1 (PD-L1 Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Gerardo Botti

    2017-02-01

    Full Text Available Triple Negative Breast Cancers (TNBC subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1 is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs, to define its real prognostic value, optimizing immunohistochemistry method with an “approved for diagnostic assay” antibody. PD-L1 expression directly correlated with proliferation index (Ki-67, glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan–Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS but not correlated with overall survival (OS. Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC.

  14. Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial.

    Science.gov (United States)

    González-Rivera, Milagros; Lobo, Miriam; López-Tarruella, Sara; Jerez, Yolanda; Del Monte-Millán, María; Massarrah, Tatiana; Ramos-Medina, Rocío; Ocaña, Inmaculada; Picornell, Antoni; Santillán Garzón, Sonia; Pérez-Carbornero, Lucía; García-Saenz, José A; Gómez, Henry; Moreno, Fernando; Márquez-Rodas, Iván; Fuentes, Hugo; Martin, Miguel

    2016-04-01

    We describe the status and frequency of germline DNA genetic findings in an unselected prospective cohort of triple negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. Study population includes 124 consecutive patients with stage II-III TNBC from a trial exploring the antitumor activity of neoadjuvant carboplatin/docetaxel chemotherapy enrolled between 2012 and March 2015, to determine the frequency of germline DNA genetic mutations. 17.1 % of the patients with germline DNA tested had deleterious mutations in any of the analyzed genes (12.38 % in BRCA1, 1.9 % in BRCA2 and BARD1 and 0.95 % in RAD51D). Attending the intrinsic subtype, all the BRCA1/2 carriers tested had basal-like subtype. Among wild-type (WT) patients, 70.11 % had basal subtype, 16.09 % HER2 enriched, 1.15 % Luminal B, and 4.60 % Normal-like. Mean age at diagnosis was significantly lower in mutation-carriers compared with no carriers (43.72 vs 53.10, p = 0.004). 3 BRCA1/2 carriers were detected between 51 and 60 years, and only one deleterious mutation (BARD1) over 60 years. A positive familiar history of breast and ovarian cancer was more frequent in patients with deleterious mutations (39.39 vs 17.94 %, p = 0.043). Our study confirms the prevalence of BRCA1/2 mutations in TNBC patients. TNBC should therefore be considered by itself as a criterion for BRCA1/2 genetic testing. Determination of other breast cancer predisposition genes implicated in homologous recombination should also be discussed in this population. However, no definitive conclusions can be reached due to the low prevalence and the uncertain clinical impact of most of the genes included.

  15. Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67

    Science.gov (United States)

    2011-01-01

    Introduction Triple-negative breast cancer (TNBC), which is characterized by negativity for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), is a high risk breast cancer that lacks specific targets for treatment selection. Chemotherapy is, therefore, the primary systemic modality used in the treatment of this disease, but reliable parameters to predict the chemosensitivity of TNBC have not been clinically available. Methods A total of 190 TNBC patients who had undergone a curative resection of a primary breast cancer were enrolled. The adjuvant chemotherapy was performed for 138 (73%) of 190 TNBC cases; 60 cases had an anthracyclin-based regimen and 78 a 5-fluorouracil-based regimen. The prognostic value of E-cadherin, Ki67 and p53 expression in the outcome of TNBC patients with adjuvant chemotherapy was evaluated by immunohistochemistry. Results The adjuvant therapy group, especially those with Stage II TNBC, had a more favorable prognosis than the surgery only group (P = 0.0043), while there was no significant difference in prognosis between the anthracyclin-based regimen and 5-fluorouracil-based regimen. Patients with E-cadherin-negative and Ki67-positive expression showed significantly worse overall survival time than those with either E-cadherin-positive or Ki67-negative expression (P Ki67-positive expression was strongly predictive of poor overall survival (P = 0.004) in TNBC patients receiving adjuvant chemotherapy. In contrast, p53 status was not a specific prognostic factor. Conclusions Adjuvant therapy is beneficial for Stage II TNBC patients. The combination of E-cadherin and Ki67 status might be a useful prognostic marker indicating the need for adjuvant chemotherapy in Stage II TNBC patients. PMID:22126395

  16. lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

    Science.gov (United States)

    Eades, Gabriel; Wolfson, Benjamin; Zhang, Yongshu; Li, Qinglin; Yao, Yuan; Zhou, Qun

    2015-02-01

    Triple-negative (ER(-), HER2(-), PR(-)) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth-suppressive activity in some breast cancers; however, these data in TNBC indicate that miR-145 does not affect proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145-regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and affects cell-cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs. The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival. ©2014 American Association for Cancer Research.

  17. Effects of cIAP-1, cIAP-2 and XIAP triple knockdown on prostate cancer cell susceptibility to apoptosis, cell survival and proliferation.

    LENUS (Irish Health Repository)

    Gill, Catherine

    2009-01-01

    BACKGROUND: Manipulating apoptotic resistance represents an important strategy for the treatment of hormone refractory prostate cancer. We hypothesised that the Inhibitor of Apoptosis (IAP) Proteins may be mediating this resistance and knockdown of cIAP-1, cIAP-2 and XIAP would increase sensitivity to apoptosis. METHODS: cIAP-1, cIAP-2 and XIAP where knocked down either individually or in combination using siRNA in androgen independent prostate cancer PC-3 cells as confirmed by real-time PCR and western blotting. Cells were then treated with TRAIL, Etoposide, or Tunicamycin, and apoptosis assessed by PI DNA staining. Apoptosis was confirmed with Annexin V labelling and measurement of PARP cleavage, and was inhibited using the pan-caspase inhibitor, zVAD.fmk. Clonogenic assays and assessment of ID-1 expression by western blotting were used to measure recovery and proliferation. RESULTS: PC-3 are resistant to TRAIL induced apoptosis and have elevated expression of cIAP-1, cIAP-2 and XIAP. Combined knockdown sensitised PC-3 to TRAIL induced apoptosis, but not to Etoposide or Tunicmycin, with corresponding increases in caspase activity and PARP cleavage which was inhibited by ZVAD.fmk. Triple knock down decreased proliferation which was confirmed by decreased ID-1 expression. CONCLUSION: Simultaneous knock down of the IAPs not only sensitised the PC-3 to TRAIL but also inhibited their proliferation rates and clonogenic survival. The inability to alter sensitivity to other triggers of apoptosis suggests that this effect is specific for death receptor pathways and knock down might facilitate immune-surveillance mechanisms to counter cancer progression and, in combination with therapeutic approaches using TRAIL, could represent an important treatment strategy.

  18. Effects of cIAP-1, cIAP-2 and XIAP triple knockdown on prostate cancer cell susceptibility to apoptosis, cell survival and proliferation

    Directory of Open Access Journals (Sweden)

    Dowling Catherine

    2009-06-01

    Full Text Available Abstract Background Manipulating apoptotic resistance represents an important strategy for the treatment of hormone refractory prostate cancer. We hypothesised that the Inhibitor of Apoptosis (IAP Proteins may be mediating this resistance and knockdown of cIAP-1, cIAP-2 and XIAP would increase sensitivity to apoptosis. Methods cIAP-1, cIAP-2 and XIAP where knocked down either individually or in combination using siRNA in androgen independent prostate cancer PC-3 cells as confirmed by real-time PCR and western blotting. Cells were then treated with TRAIL, Etoposide, or Tunicamycin, and apoptosis assessed by PI DNA staining. Apoptosis was confirmed with Annexin V labelling and measurement of PARP cleavage, and was inhibited using the pan-caspase inhibitor, zVAD.fmk. Clonogenic assays and assessment of ID-1 expression by western blotting were used to measure recovery and proliferation. Results PC-3 are resistant to TRAIL induced apoptosis and have elevated expression of cIAP-1, cIAP-2 and XIAP. Combined knockdown sensitised PC-3 to TRAIL induced apoptosis, but not to Etoposide or Tunicmycin, with corresponding increases in caspase activity and PARP cleavage which was inhibited by ZVAD.fmk. Triple knock down decreased proliferation which was confirmed by decreased ID-1 expression. Conclusion Simultaneous knock down of the IAPs not only sensitised the PC-3 to TRAIL but also inhibited their proliferation rates and clonogenic survival. The inability to alter sensitivity to other triggers of apoptosis suggests that this effect is specific for death receptor pathways and knock down might facilitate immune-surveillance mechanisms to counter cancer progression and, in combination with therapeutic approaches using TRAIL, could represent an important treatment strategy.

  19. Characterization of inorganic phosphate transport in the triple-negative breast cancer cell line, MDA-MB-231.

    Science.gov (United States)

    Russo-Abrahão, Thais; Lacerda-Abreu, Marco Antônio; Gomes, Tainá; Cosentino-Gomes, Daniela; Carvalho-de-Araújo, Ayra Diandra; Rodrigues, Mariana Figueiredo; Oliveira, Ana Carolina Leal de; Rumjanek, Franklin David; Monteiro, Robson de Queiroz; Meyer-Fernandes, José Roberto

    2018-01-01

    Recent studies demonstrate that interstitial inorganic phosphate is significantly elevated in the breast cancer microenvironment as compared to normal tissue. In addition it has been shown that breast cancer cells express high levels of the NaPi-IIb carrier (SLC34A2), suggesting that this carrier may play a role in breast cancer progression. However, the biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive. In this work, we characterize the kinetic parameters of Pi transport in the aggressive human breast cancer cell line, MDA-MB-231, and correlated Pi transport with cell migration and adhesion. We determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport. We observed that the inorganic phosphate is dependent on sodium transport (K0,5 value = 21.98 mM for NaCl). Furthermore, the transport is modulated by different pH values and increasing concentrations of Pi, following the Michaelis-Menten kinetics (K0,5 = 0.08 mM Pi). PFA, monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion. Taken together, these results showed that the uptake of Pi in MDA-MB-231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient. General Significance: Pi transport might be regarded as a potential target for therapy against tumor progression.

  20. The role of primary tumor resection in colorectal cancer patients with asymptomatic, synchronous unresectable metastasis: Study protocol for a randomized controlled trial.

    Science.gov (United States)

    Kim, Chang Woo; Baek, Jeong-Heum; Choi, Gyu-Seog; Yu, Chang Sik; Kang, Sung Bum; Park, Won Cheol; Lee, Bong Hwa; Kim, Hyeong Rok; Oh, Jae Hwan; Kim, Jae-Hwang; Jeong, Seung-Yong; Ahn, Jung Bae; Baik, Seung Hyuk

    2016-01-19

    Approximately 20 % of all patients with colorectal cancer are diagnosed as having Stage IV cancer; 80 % of these present with unresectable metastatic lesions. It is controversial whether chemotherapy with or without primary tumor resection (PTR) is effective for the treatment of patients with colorectal cancer with unresectable metastasis. Primary tumor resection could prevent tumor-related complications such as intestinal obstruction, perforation, bleeding, or fistula. Moreover, it may be associated with an increase in overall survival. However, surgery delays the use of systemic chemotherapy and affects the systemic spread of malignancy. Patients with colon and upper rectal cancer patients with asymptomatic, synchronous, unresectable metastasis will be included after screening. They will be randomized and assigned to receive chemotherapy with or without PTR. The primary endpoint measure is 2-year overall survival rate and the secondary endpoint measures are primary tumor-related complications, quality of life, surgery-related morbidity and mortality, interventions with curative intent, chemotherapy-related toxicity, and total cost until death or study closing day. The authors hypothesize that the group receiving PTR following chemotherapy would show a 10 % improvement in 2-year overall survival, compared with the group receiving chemotherapy alone. The accrual period is 3 years and the follow-up period is 2 years. Based on the inequality design, a two-sided log-rank test with α-error of 0.05 and a power of 80 % was conducted. Allowing for a drop-out rate of 10 %, 480 patients (240 per group) will need to be recruited. Patients will be followed up at every 3 months for 3 years and then every 6 months for 2 years after the last patient has been randomized. This randomized controlled trial aims to investigate whether PTR with chemotherapy shows better overall survival than chemotherapy alone for patients with asymptomatic, synchronous unresectable

  1. Synchronous development of breast cancer and chest wall fibrosarcoma after previous mantle radiation for Hodgkin's disease

    Energy Technology Data Exchange (ETDEWEB)

    Patlas, Michael [Hamilton General Hospital, Department of Radiology, Hamilton, ON (Canada); McCready, David [University Health Network and Mount Sinai Hospital, Department of Surgery, Toronto, ON (Canada); Kulkarni, Supriya; Dill-Macky, Marcus J. [University Health Network and Mount Sinai Hospital, Department of Medical Imaging, Toronto, ON (Canada)

    2005-09-01

    Survivors of Hodgkin's disease are at increased risk of developing a second malignant neoplasm, including breast carcinoma and sarcoma. We report the first case of synchronous development of chest wall fibrosarcoma and breast carcinoma after mantle radiotherapy for Hodgkin's disease. Mammographic, sonographic and MR features are demonstrated. (orig.)

  2. Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states.

    Science.gov (United States)

    Sulaiman, Andrew; McGarry, Sarah; Li, Li; Jia, Deyong; Ooi, Sarah; Addison, Christina; Dimitroulakos, Jim; Arnaout, Angel; Nessim, Carolyn; Yao, Zemin; Ji, Guang; Song, Haiyan; Gadde, Suresh; Li, Xuguang; Wang, Lisheng

    2018-04-01

    Triple-negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer-related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal-like and epithelial-like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β-catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β-catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44 high /CD24 -/low CSCs were upregulated while Wnt/β-catenin signaling and ALDH+ CSCs were downregulated in mesenchymal-like TNBC cells, and vice versa in their epithelial-like counterparts. Dual knockdown of YAP and Wnt/β-catenin, but neither alone, was required for effective suppression of both CD44 high /CD24 -/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG-001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients' samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44 high /CD24 -/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG-001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new

  3. Targeting the S1P Axis and Development of a Novel Therapy for Obesity Related Triple Negative Breast Cancer

    Science.gov (United States)

    2017-09-01

    a Novel Therapy for Endocrine-Resistant Breast Cancer, Keystone Symposium on Lipidomics and Bioactive Lipids in Metabolism and Disease, Lake Tahoe...phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells. Am. J. Pathol. 169, 294–302 (2006). 15. Kang, B

  4. Metastatic carcinoma of the urinary bladder in a 67-year-old female with underlying triple primary cancers

    Directory of Open Access Journals (Sweden)

    Chia-Yen Hung

    2016-06-01

    A 67-year-old Taiwanese female presented to our institution in November 1997 with gastric signet ring cell carcinoma, pT2N0M0, status post subtotal gastrectomy. In February 2003 she was diagnosed with left breast invasive lobular carcinoma status post modified radical mastectomy, pT2N2M0. Further examination in January 2005 revealed proximal transverse colon cancer, Dukes' C2, with status post right hemicolectomy. She achieved disease-free status from all three malignancies after surgical resection and adjuvant chemotherapy for breast and colon cancers sequentially. In November 2011, she complained about sudden onset of gross hematuria for several days. Diagnostic cystoscopy showed a mass lesion over her urinary bladder. Cystoscope-assisted biopsy showed metastatic poorly differentiated adenocarcinoma with signet ring appearance. Herein we have discussed the pathologic role in the diagnosis of metastatic tumor involving a patient with multiple primary cancers. We also explored the epidemiologic risk and potential causal mechanism of patients with multiple primary cancers.

  5. Liquid Chromatography - Triple Quadrupole Mass Spectrometry : The gold standard for quantitative bioanalysis of anti-cancer agents

    NARCIS (Netherlands)

    Vainchtein, L.D.

    2008-01-01

    To understand the pharmacologic mechanisms of action, efficacy and toxicity of any anti-cancer drug it is important to know how the compound is transformed in the body: either into active metabolites or inactive and toxic (degradation) products. This information may lead to the success or failure of

  6. A Novel Differentiation Therapy Approach to Reduce the Metastatic Potential of Basal, Highly Metastatic, Triple-Negative Breast Cancers

    Science.gov (United States)

    2012-05-01

    Acknowledgements We thank Drs Lalage Wakefield and Li Yang for helpful scientific discussions. We also thank Lara El-Touny, Dalit Barkan, Zi-Yao Liu... Gonzalez -Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS et al. (2009). Characterization of a naturally occurring breast cancer

  7. Development of biodegradable PLGA nanoparticles surface engineered with hyaluronic acid for targeted delivery of paclitaxel to triple negative breast cancer cells.

    Science.gov (United States)

    Cerqueira, Brenda Brenner S; Lasham, Annette; Shelling, Andrew N; Al-Kassas, Raida

    2017-07-01

    This study aimed at development of poly (lactic-co-glycolic acid) (PLGA) nanoparticles embedded with paclitaxel and coated with hyaluronic acid (HA-PTX-PLGA) to actively target the drug to a triple negative breast cancer cells. Nanoparticles were successfully fabricated using a modified oil-in-water emulsion method. The effect of various formulations parameters on the physicochemical properties of the nanoparticles was investigated. SEM imaging confirmed the spherical shape and nano-scale size of the nanoparticles. A sustained drug release profile was obtained and enhanced PTX cytotoxicity was observed when MDA-MB-231 cells were incubated with the HA-PTX-PLGA formulation compared to cells incubated with the non-HA coated nanoparticles. Moreover, HA-PLGA nanoparticles exhibited improved cellular uptake, based on a possible receptor mediated endocytosis due to interaction of HA with CD44 receptors when compared to non-coated PLGA nanoparticles. The non-haemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Expression of Intratumoral IGF-II Is Regulated by the Gene Imprinting Status in Triple Negative Breast Cancer from Vietnamese Patients

    Directory of Open Access Journals (Sweden)

    Vinodh Kumar Radhakrishnan

    2015-01-01

    Full Text Available African American women suffer higher incidence and mortality of triple negative breast cancer (TNBC than Caucasian women. TNBC is very aggressive, causing the worst clinical outcome. We previously demonstrated that tumors from these patients express high IGF-II and exhibit high activation of the IGF signaling pathways. IGF-II gene expression is imprinted (monoallelic, promotes tumor progression, and metastasis and regulates Survivin, a TNBC prognostic marker. Since BC mortality has increased among young Vietnamese women, we analyzed 48 (paired TNBC samples from Vietnamese patients to assess IGF-II expression. We analyzed all samples by qrtPCR for identification of IGF-II heterozygosity and to determine allelic expression of the IGF-II gene. We also analyzed the tissues for proIGF-II and Survivin by RT-PCR and Western blotting. A total of 28 samples displayed IGF-II heterozygosity of which 78% were biallelic. Tumors with biallelic IGF-II gene expression exhibited the highest levels of proIGF-II and Survivin. Although 100% of these tissues corresponding normal samples were biallelic, they expressed significantly lower levels of or no proIGF-II and Survivin. Thus, IGF-II biallelic gene expression is differentially regulated in normal versus tumor tissues. We propose that intratumoral proIGF-II is dependent on the IGF-II gene imprinting status and it will promote a more aggressive TNBC.

  9. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Science.gov (United States)

    Park, In Ah; Hwang, Seong-Hye; Song, In Hye; Heo, Sun-Hee; Kim, Young-Ae; Bang, Won Seon; Park, Hye Seon; Lee, Miseon; Gong, Gyungyub; Lee, Hee Jin

    2017-01-01

    Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  10. 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)

    Heravi, Mitra; Kumala, Slawomir; Rachid, Zakaria; Jean-Claude, Bertrand J.; Radzioch, Danuta; Muanza, Thierry M.

    2015-01-01

    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

  11. Low dose of kaempferol suppresses the migration and invasion of triple-negative breast cancer cells by downregulating the activities of RhoA and Rac1.

    Science.gov (United States)

    Li, Shoushan; Yan, Ting; Deng, Rong; Jiang, Xuesong; Xiong, Huaping; Wang, Yuan; Yu, Qiao; Wang, Xiaohua; Chen, Cheng; Zhu, Yichao

    2017-01-01

    Triple-negative breast cancer (TNBC) is an especially aggressive and hard-to-treat disease. Although the anticancer role of kaempferol has been reported in breast cancer, the effect of kaempferol on TNBC remains unclear. This experiment investigated the migration-suppressive role of a low dose of kaempferol in TNBC cells. Wound-healing assays and cell invasion assays were used to confirm the migration and invasion of cells treated with kaempferol or transfected indicated constructs. We evaluated the activations of RhoA, Rac1 and Cdc42 in TNBC cells with a Rho activation assay. A panel of inhibitors of estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) treated non-TNBC (SK-BR-3 and MCF-7) cells and blocked the ER/PR/HER2 activity. Wound-healing assays and Rho activation assays were employed to measure the effect of kaempferol and ER/PR/HER2 inhibitors on Rho activation and cell migration rates. A low dose of kaempferol (20 μmol/L) had a potent inhibitory effect on the migration and invasion of TNBC cells, but not on the migration of non-TNBC (SK-BR-3 and MCF-7) cells. The low dose of kaempferol downregulated the activations of RhoA and Rac1 in TNBC cells. Moreover, the low dose of kaempferol also inhibited the migration and RhoA activations of HER2-silence SK-BR-3 and ER/PR-silence MCF-7 cells. Overexpressed HER2 rescued the cell migration and RhoA and Rac1 activations of kaempferol-treated MDA-MB-231 cells. The low dose of kaempferol inhibits the migration and invasion of TNBC cells via blocking RhoA and Rac1 signaling pathway.

  12. Ultrasensitive electrochemical immunosensor for PSA biomarker detection in prostate cancer cells using gold nanoparticles/PAMAM dendrimer loaded with enzyme linked aptamer as integrated triple signal amplification strategy.

    Science.gov (United States)

    Kavosi, Begard; Salimi, Abdollah; Hallaj, Rahman; Moradi, Fathollah

    2015-12-15

    In the present study, a triple signal amplification strategy was developed for ultrasensitive immunosensing of prostate-specific antigen (PSA) tumor marker. The proposed system was achieved by modification of glassy carbon electrode with graphene oxide/chitosan film and covalently attached of monoclonal PSA antibody and thionine as redox probe onto the modified electrode surface. Then, immunosensing was completed using sandwich-type immunoreaction of the PSA-antigen between anti-PSA immobilized on the graphene/chitosan interface and PSA-aptamer. For improve the sensitivity, polyamidoamine dendrimer-encapsulated gold nanoparticles (AuNPs-PAMAM) was used for covalent attachment of PSA-aptamer and HRP linked aptamer (Au-PAMA/aptamer-HRP) as electrochemical label in the sandwich format and electrocatalytic reduction of H2O2 in the presence of enzymatically oxidized thionine was measured. Under optimized condition, the obtained detection limit and linear concentration range were 10 fg ml(-1)(S/N=3) and 0.1 pg ml(-1) to 90 ngml(-1) respectively, using differential pulse voltammetry as measuring technique. In addition, electrochemical impedance spectroscopy (EIS) was used as simple, rapid, low cost label free analytical technique for PSA measurement with detection limit of 5 pg ml(-1) at concentration range up to 35 ng ml(-1). Finally, the immunosensor is used to PSA detection in human serum and prostate tissue samples and the obtained result is well agreed with the values obtained by the standard ELISA method. The obtained results indicate the proposed immunosensor can be used for monitor the differences in PSA concentration in cancer tissue samples which holds great promise in clinical screening of cancer biomarkers. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Estrogen receptor-α promoter methylation is a biomarker for outcome prediction of cisplatin resistance in triple-negative breast cancer.

    Science.gov (United States)

    Xu, Junnan; Sun, Tao; Guo, Xiangyu; Wang, Yan; Jing, Mingxi

    2018-03-01

    A number of previous studies have indicated the presence of a link between estrogen receptor-α (ERα) methylation and triple-negative breast cancer (TNBC). However, the association between ERα methylation and drug resistance during the treatment of TNBC remains unclear. Methylation-specific polymerase chain reaction was used to investigate the methylation of ERα in the genomic DNA of 35 patients with TNBC who were defined as cisplatin-based chemotherapy-resistant using chemosensitivity testing. Survival probabilities by covariates were assessed using Kaplan-Meier estimator survival analysis and Cox's proportional hazards models, adjusting for age, menopausal status, tumor size, lymph node metastasis and ERα promoter DNA methylation. Of the 35 patients with TNBC analyzed, 8 exhibited ERα promoter DNA methylation. Cisplatin resistance was confirmed to be overwhelmingly associated with ERα methylation by univariate and multivariate analysis. Even in a limited analysis in patients with ERα methylation, the results generated from methylated tumor tissue and unmethylated tumor tissue revealed that expression of breast cancer type 1/2 susceptibility proteins was increased in ERα-methylated breast tumor tissue compared with in unmethylated tissue. The ERα methylation group tended to have significantly shorter progression-free (P=0.010) and overall (P=0.023) survival times compared with those in the unmethylated group. Similarly, shorter progression-free (P=0.024) and overall (P=0.018) survival times were observed in the cisplatin-resistant group compared with the cisplatin-non-resistant group. ERα methylation predicts a poor clinical outcome for patients with TNBC. The results of the present study indicated that ERα methylation may be a candidate surrogate biomarker for outcome prediction and cisplatin resistance in TNBC. Further investigation is required to identify potential biomarkers in a larger cohort in a prospective study.

  14. The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer.

    Science.gov (United States)

    Wang, Kai; Shen, Tiansheng; Siegal, Gene P; Wei, Shi

    2017-11-01

    Compelling evidence has demonstrated the prognostic value of tumor-infiltrating lymphocytes (TILs), especially in triple-negative breast cancer (TNBC). However, only a limited number of studies to investigate the importance of the subsets of T cells in TILs have been carried out, less so the significance of the location of these TILs. In this study, we explored in a cohort of 42 consecutive TNBC cases the prognostic significance of TIL subsets at the tumor-host interface (within 1 high-power field [0.5 mm] of the invasive front) and compared them with TILs within the intratumoral stroma. Given the reported importance of TILs in HER2-overexpressing breast cancer, a subset of such tumors was also included for comparison. The range was wide in both locations; nevertheless, the mean CD4 + and CD8 + T cell count was significantly higher at the tumor-host interface than that found within the intratumoral stroma (both P<.0001). The number of CD4 + or CD8 + T cells at either location was not significantly associated with distant relapse-free or overall survival. However, the CD4/CD8 ratio at the tumor-host interface was significantly associated with both relapse-free survival (hazard ratio 0.2, P=.002) and overall survival (hazard ratio 0.13, P=.002), whereas this association was not seen for the CD4/CD8 ratio within the intratumoral stroma. As expected, both tumor size and nodal status were significantly associated with survival outcomes. The findings further support the contention that TILs, as markers of regional immune escape, are of prognostic importance in TNBC progression and that the CD4/CD8 ratio of TILs at the tumor-host interface plays a distinctive role, thus appearing to be of clinical relevance. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

    Science.gov (United States)

    Wu, Ying-Min; Chen, Zhuo-Jia; Jiang, Guan-Min; Zhang, Kun-Shui; Liu, Qiao; Liang, Shu-Wei; Zhou, Yan; Huang, Hong-Bin; Du, Jun; Wang, Hong-Sheng

    2016-03-15

    There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and IκBα, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-κB attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-κB/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERRα-based therapies for TNBC patients.

  16. mTOR inhibitors suppress homologous recombination repair and synergize with PARP inhibitors via regulating SUV39H1 in BRCA-proficient triple-negative breast cancer

    Science.gov (United States)

    Mo, Wei; Liu, Qingxin; Lin, Curtis Chun-Jen; Dai, Hui; Peng, Yang; Liang, Yulong; Peng, Guang; Meric-Bernstam, Funda; Mills, Gordon B.; Li, Kaiyi; Lin, Shiaw-Yih

    2016-01-01

    Purpose Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the utility of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2. Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC. Experimental Design We have studies the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSBs). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were employed to investigate the molecular mechanisms of action. Results We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs. Conclusions Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients. PMID:26546619

  17. Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy.

    Science.gov (United States)

    Miyashita, Minoru; Sasano, Hironobu; Tamaki, Kentaro; Chan, Monica; Hirakawa, Hisashi; Suzuki, Akihiko; Tada, Hiroshi; Watanabe, Go; Nemoto, Noriko; Nakagawa, Saki; Ishida, Takanori; Ohuchi, Noriaki

    2014-12-01

    The anti-tumor immune response was recently reported to play a critical role in the chemotherapeutic sensitivity of breast cancer. Therefore, we investigated the correlation between CD8+ and FOXP3+ tumor-infiltrating lymphocytes and the pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), in conjunction with neoangiogenesis, basal and proliferation markers. CD8+ and FOXP3+ lymphocytes were assessed in biopsy specimens by double-staining immunohistochemistry, in combination with immunostaining of vasohibin-1, CD31, EGFR, CK5/6, and Ki-67. Earlier age, pre-menopausal status, smaller tumor size, and high Ki-67 were significantly associated with pCR, as in high CD8+, high CD8+/FOXP3+ ratio, and low vasohibin-1 positive ratio. Multivariate analysis did reveal that a high CD8+/FOXP3+ ratio was a strong predictor of pCR with an odds ratio of 5.32 (P = 0.005). High Ki-67 was also significantly associated with pCR (P = 0.002). TNBCs with a high CD8+/FOXP3+ ratio and high Ki-67 had the highest pCR rate (70%) following NAC. However, the pCR rate of the patients with low CD8+/FOXP3+ ratio and low Ki-67 was only 5%. The pCR rates of a high CD8+/FOXP3+ ratio and low Ki-67 patients and those with a low CD8+/FOXP3+ ratio and high Ki-67 were 24 and 21%, respectively. TNBCs with a high CD8+/FOXP3+ ratio were more sensitive to anthracycline and taxane-based chemotherapeutic regimens, and the CD8+/FOXP3+ ratio in conjunction with Ki-67 could predict pCR following NAC in TNBC. This predictor may represent a new surrogate for testing the efficacy of investigational agents in the neoadjuvant setting.

  18. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Directory of Open Access Journals (Sweden)

    In Ah Park

    Full Text Available Tumor-infiltrating lymphocytes (TILs have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC. Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042; larger amounts of TILs (p < 0.001; frequent formations of tertiary lymphoid structures (p < 0.001; higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001; and higher expression of double-stranded RNA-activated protein kinase, which can be induced by interferons (p = 0.008. Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001. Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009. In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  19. 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.

  20. Novel Functions of EZH2 in Triple Negative Breast Cancer: Translation in to New Biomarker and Treatment Strategies

    Science.gov (United States)

    2016-07-01

    fresh breast cancer tissues from 2 patients with TNBC, and a lymph node metastasis from patient 2. EZH2 is elevated in all samples. EZH2 is also...1168-74. 5. Pang, J., et al., Invasive breast carcinomas in Ghana: high frequency of high grade, basal -like histology and high EZH2 expression. Breast...Detected EZH2 in the cytoplasm of TNBC cell lines.  Isolated TNBC cells from fresh samples of human breast carcinomas, and from one lymph node

  1. Rhopalurus junceus scorpion venom induces apoptosis in the triple negative human breast cancer cell line MDA-MB-231

    OpenAIRE

    Díaz-García, Alexis; Ruiz-Fuentes, Jenny Laura; Rodríguez-Sánchez, Hermis; Fraga Castro, José A

    2017-01-01

    Rhopalurus junceus scorpion venom has demonstrated high cytotoxic activity in epithelial cancer cells. In the present study, the effect of scorpion venom on cell viability and apoptosis was evaluated in the MDA-MB-231 human breast carcinoma cell line. Cell viability was analyzed using MTT assay. The cell death event was examined trough end-point RT-PCR to identify the expression of apoptosis-related genes, fluorescent microscopy and mitochondrial membrane potential (ΔΨm) alteration. The resul...

  2. Dermatomyositis with anti-TIF-1γ antibodies as a presenting symptom of underlying triple-negative breast cancer: a case report.

    Science.gov (United States)

    Kubeček, Ondřej; Soukup, Tomáš; Paulík, Adam; Kopecký, Jindřich

    2016-08-25

    Dermatomyositis is an autoimmune myopathy characterized by proximal muscle weakness, muscle inflammation, and typical skin findings. It is a rare disease with an incidence of ~1/100 000. About 15-30 % of adult-onset cases are caused by underlying malignancy and dermatomyositis can be the first symptom of undiagnosed cancer, mainly in the case of anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies presence. TIF-1γ is a transcriptional cofactor which is implicated in TGFβ signaling pathway that controls cell proliferation, differentiation, apoptosis, and tumorigenesis. Its expression was shown to be associated with younger age, higher tumor grade, more estrogen receptor negativity, tumors larger than 2 cm, and tendency towards poor outcome in early breast cancer. No association between anti-TIF-1γ antibodies and prognosis has been proposed yet. We report a case of a 43-year-old premenopausal woman presenting with the symptoms of systemic rheumatic disease, the most prominent being a typical skin rash and muscle pain. After a series of investigations, the patient was diagnosed with anti-TIF-1γ positive dermatomyositis and concurrent triple-negative breast cancer (cT1c N3c M0) as an underlying cause. Immediate intravenous corticosteroid therapy relieved the symptoms and enabled anticancer therapy to be commenced. Considering the tumor stage, neoadjuvant therapy with 4 courses of AC (Doxorubicin/Cyclophosphamide) followed by 4 courses of Paclitaxel/Carboplatin was administered. However, no tumor regression was documented and radiotherapy was chosen as the definitive treatment. Early detection of anti-TIF-1γ autoantibodies can contribute to a rapid diagnosis of tumor-associated dermatomyositis and enable immediate anticancer treatment. We demonstrate the emerging role of anti-TIF-1γ antibodies in the diagnostics of tumor-associated dermatomyositis. Furthermore, we propose a potential role of anti-TIF-1γ antibodies as a prognostic marker in

  3. 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

    Science.gov (United States)

    2014-01-01

    Background 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. Methods 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. Results 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

  4. Cancers du sein bilatéraux synchrones et grossesse a l'institut Joliot Curie de Dakar (Sénégal)

    Science.gov (United States)

    Zongo, Nayi; Sawadogo, Yobi Alexis; Some, Some Ollo Roland; Bagre, Sidpawalmdé Carine; Ka, Sidy; Diouf, Doudou; Dieng, Mamadou Moustapha; Gaye, Papa Macoumba; Dem, Ahmadou

    2016-01-01

    Décrire notre stratégie diagnostique et thérapeutique dans les cancers du sein bilatéraux synchrones pendant la grossesse. L’âge gestationnel au moment du diagnostic du cancer était respectivement de 7; 21 et 25 semaines. Il s'agissait de stade IV et IIIA respectivement dans deux et un cas. Elles ont toutes bénéficié d'une chimiothérapie dans deux cas pendant la grossesse (6TEC et 3AC) et dans un cas après l'accouchement. Une mastectomie bilatérale a été réalisée dans un cas. Une patiente est décédée. Les autres étaient vivantes mais toutes métastatiques. Une hypotrophie fœtale a été notée dans un cas. Le diagnostic du cancer est tardif dans cette association. La chirurgie est faisable et le type de chirurgie serait seulement fonction du stade du cancer. La chimiothérapie est possible avec moins de complications fœtales aux deux derniers trimestres. PMID:27279967

  5. Is there an epigenetic component underlying the resistance of triple-negative breast cancers to parp inhibitors?

    Science.gov (United States)

    Lovato, Amanda; Panasci, Lawrence; Witcher, Michael

    2012-01-01

    Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.

  6. Is there an epigenetic component underlying the resistance of triple-negative breast cancers to PARP inhibitors?

    Directory of Open Access Journals (Sweden)

    Amanda eLovato

    2012-12-01

    Full Text Available Poly(ADP-ribosepolymerase (Parp is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose chains (known as PARylation. Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.

  7. The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion.

    Science.gov (United States)

    Bogan, Danielle; Meile, Lucio; El Bastawisy, Ahmed; Yousef, Hend F; Zekri, Abdel-Rahman N; Bahnassy, Abeer A; ElShamy, Wael M

    2017-05-12

    Breast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt. To reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients' tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes. 96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local

  8. Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.

    Science.gov (United States)

    Karginova, Olga; Siegel, Marni B; Van Swearingen, Amanda E D; Deal, Allison M; Adamo, Barbara; Sambade, Maria J; Bazyar, Soha; Nikolaishvili-Feinberg, Nana; Bash, Ryan; O'Neal, Sara; Sandison, Katie; Parker, Joel S; Santos, Charlene; Darr, David; Zamboni, William; Lee, Yueh Z; Miller, C Ryan; Anders, Carey K

    2015-04-01

    Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further

  9. Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

    Science.gov (United States)

    Henry, Kelly E; Dilling, Thomas R; Abdel-Atti, Dalya; Edwards, Kimberly J; Evans, Michael J; Lewis, Jason S

    2018-01-01

    The current standard for breast PET imaging is 18 F-FDG. The heterogeneity of 18 F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18 F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm 3 MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with 89 Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that 89 Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of 18 F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, 89 Zr-transferrin and 18 F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 μM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that 89 Zr-transferrin targets TNBC tumors significantly better ( P Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA ( P MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells ( P MYC via TfR-targeted PET imaging in TNBC. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  10. Triple-axis spectrometer

    International Nuclear Information System (INIS)

    Toeroek, Gy.

    2001-01-01

    A triple-axis spectrometer has been designed for structural and dynamical studies of condensed matter. Because of the limited number of other operational equipment the triple axis spectrometer was used in a multi purpose regime, e.g. high resolution diffractometry, strain analysis, reflectometry, quasielastic and inelastic scattering. A polarization setup was also tested on this spectrometer. (R.P.)

  11. A Randomized Phase I/II Trial to Compare Weekly Usage with Triple Weekly Usage of Paclitaxel in Concurrent Radiochemotherapy for Patients with Locally Advanced Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Anhui SHI

    2011-03-01

    Full Text Available Background and objective Although the guidelines of the National Comprehensive Cancer Network of USA recommend that the standard therapy for locally advanced non-small cell lung cancer (LANSCLC is concurrent chemoradiotherapy. There is ongoing controversy about the treatment regimen which combines chemotherapy concurrently with radiotherapy. The aim of this study is to compare weekly usage with triple weekly usage of paclitaxel in concurrent radiochemotherapy for patients with LANSCLC, and to obtain the best paclitaxel regimen in the concurrent radiochemotherapy. Methods From April 2006 to April 2009, some LANSCLC patients in multicenter were randomly divided into weekly usage (45 mg/m2, 1 times/week, a total of 270 mg/m2 in six weeks and triple weekly usage (15 mg/m2, 3 times/week, a total of 270 mg/m2 in six weeks group of paclitaxel by a random number table. All patients were treated with 3D radiotherapy, and 95% planning target volume (PTV received a prescription dose of (60-70 Gy/(30-35times/(6-7weeks, (1.8-2.0 Gy/fraction. Then the side effects, response and overall survival rate were compared between two groups of patients. Results Thirty-eight LANSCLC patients were enrolled. Weekly usage and triple weekly usage group were 20 and 18 patients, respectively. In the triple weekly usage group, the side effects were 12 patients had radiation esophagitis of I-II degree, 1 patient had radiation esophagitis of III degree, 2 patients had radiation pneumonitis of I degree, 1 patient had radiation pneumonitis of II degree, 1 patient had radiation pneumonitis of III degree and died of respiratory failure, 2 patients developed weight loss of I degree. In the weekly usage group, the side effects were 11 patients had radiation esophagitis of I-III degree, 6 patients had radiation pneumonitis of II-III degree, 2 patients developed weight loss of I degree, 6 patients developed leucopenia of III-IV degree. The response rate of two groups was 88.8% and 50

  12. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer.

    Science.gov (United States)

    O'Shaughnessy, Joyce; Schwartzberg, Lee; Danso, Michael A; Miller, Kathy D; Rugo, Hope S; Neubauer, Marcus; Robert, Nicholas; Hellerstedt, Beth; Saleh, Mansoor; Richards, Paul; Specht, Jennifer M; Yardley, Denise A; Carlson, Robert W; Finn, Richard S; Charpentier, Eric; Garcia-Ribas, Ignacio; Winer, Eric P

    2014-12-01

    There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation. © 2014 by American Society of Clinical Oncology.

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

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    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.)

  14. Low level laser therapy for concurrent chemoradiotherapy induced oral mucositis in head and neck cancer patients – A triple blinded randomized controlled trial

    International Nuclear Information System (INIS)

    Gautam, Ajay Prashad; Fernandes, Donald J.; Vidyasagar, Mamidipudi S.; Maiya, Arun G.; Vadhiraja, Bejadi M.

    2012-01-01

    Background and purpose: Oral mucositis (OM) is most cumbersome acute side effect of concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC). OM associated pain affects oral functions and nutrition of the patient that may result in discontinuity of treatment. Several modalities have been tried to prevent and treat OM, but none proved completely successful until date. We used prophylactic low level laser therapy (LLLT) for the prevention and treatment of CCRT induced OM. Materials and methods: In this triple blinded study, 221 HNC patients scheduled to undergo CCRT (Cisplatin (1, 22, 43 day) + RT = 66 Grays (2 Gy/fraction), 33 fractions, 5 fractions/week, for 45 days) were block randomized into laser (n = 111) and placebo (n = 110) group. Laser group received LLLT (HeNe, λ = 632.8 nm, power-density = 24 mW, dosage = 3.0 J/point, total dosage/session = 36–40 J, spot-size = 1 cm 2 , 5 sessions/week) while placebo received sham treatment daily prior to radiation. OM (RTOG/EORTC Scale), oral pain (VAS), dysphagia (FIS), weight loss and CCRT break were assessed. Data were analyzed using frequencies and percentage, generalized estimating equations (GEE) and odds ratio. Results: There was significant reduction in incidence of severe OM (F = 16.64, df = 8876, p < 0.0001) and its associated pain (F = 25.06, df = 8876, p < 0.0001), dysphagia (F = 20.17, df = 8876, p < 0.0001) and opioid analgesics use (p < 0.0001) in laser than placebo group patients. Conclusions: LLLT decreased the incidence of CCRT induced severe OM and its associated pain, dysphagia and opioid analgesics use.

  15. Pathological complete response after cisplatin neoadjuvant therapy is associated with the downregulation of DNA repair genes in BRCA1-associated triple-negative breast cancers.

    Science.gov (United States)

    Domagala, Pawel; Hybiak, Jolanta; Rys, Janusz; Byrski, Tomasz; Cybulski, Cezary; Lubinski, Jan

    2016-10-18

    Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin. Altogether, 25 genes were significantly differentially expressed between tumors exhibiting pCR and non-pCR, and these genes were downregulated in the pCR group compared to the non-pCR group. A difference in expression level greater than 1.5-fold was detected for nine genes: MGMT, ERCC4, FANCB, UBA1, XRCC5, XPA, XPC, PARP3, and RPA1. The non-homologous end joining and nucleotide excision repair pathways of DNA repair showed the most significant relevance. Expression profile of DNA repair genes associated with pCR was different in the node-positive (20 genes with fold change >1.5) and node-negative (only 3 genes) subgroups. Although BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy. The results suggest that patients with node-positive BRCA1-associated TNBCs that do not exhibit pCR after cisplatin neoadjuvant chemotherapy may be candidates for subsequent therapy with PARP inhibitors, whereas UBA1 may be a potential therapeutic target in node-negative subgroup.

  16. 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.

  17. BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Hitomi Mori

    Full Text Available Triple-negative breast cancer (TNBC is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases.The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA. The tumor subtypes were determined immunohistochemically using resected specimens.Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4% tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003. There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS compared with the non-BRCAness group (P = 0.04 and had a shorter overall survival (OS although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS. Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.

  18. Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Anastasia A. Ionkina

    2017-05-01

    Full Text Available PurposeTriple-negative breast cancer (TNBC is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076.Experimental designp53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance.ResultsSensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance.ConclusionENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored.

  19. [Efficacy and toxicity of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes].

    Science.gov (United States)

    Du, Feng; Yuan, Peng; Luo, Yang; Wang, Jiayu; Ma, Fei; Cai, Ruigang; Fan, Ying; Li, Qing; Zhang, Pin; Xu, Binghe

    2015-10-01

    To assess the efficacy of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes. Clinical data of 48 patients diagnosed and treated for mTNBC between 2004 and 2012 at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) were retrospectively analyzed. All patients were pretreated with anthracyclines and at least one taxane in neo-adjuvant, adjuvant or chemotherapy for mTNBC and patients should be having at least one measurable metastatic lesion. Totally, 48 patients were included in this study, of which 21 cases received first-line chemotherapy and 27 cases received second-line chemotherapy. Based on the regimen they received, 22 patients were treated with NVB plus platinum (NP), and 26 patients with NVB plus capecitabine (NX). After 70 months follow-up, in the total group of patients, the objective response rate was 20.8%, clinical benefit rate was 43.8%, median progression free survival (PFS) was 4.4 months and median overall survival (OS) was 15.5 months. In addition, the ORR was significantly better in the NP arm versus NX arm (33.8% vs.7.7%, P=0.029) as well as PFS was statistically improved in the NP arm than NX arm (5.3 m vs. 3.0 m, P=0.023). Similar trend was observed in the OS, although the difference was not statistically significant (27.7 m vs. 14.8 m, P=0.077). In all, the most frequently reported adverse events were G1/2 gastrointestinal toxicity (68.8%) and neutropenia (62.5%) . No significant difference was observed between the NP arm and NX arm (P>0.05). The percentage of patients who delayed chemotherapy administration in the NP arm and NX arm was 9.1% (n=2), and 3.8% (n=1), respectively. NVB-based combination chemotherapy demonstrates moderate efficacy in mTNBC patients pretreated with anthracyclines and one taxane with manageable toxicity. NP regimen shows potential superiority over NX regimen, and should be further verified in randomized phase III

  20. Efficacy of carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple negative breast cancer

    Science.gov (United States)

    Karginova, Olga; Siegel, Marni B.; Van Swearingen, Amanda E. D.; Deal, Allison M.; Adamo, Barbara; Sambade, Maria J.; Bazyar, Soha; Nikolaishvili-Feinberg, Nana; Bash, Ryan; O’Neal, Sara; Sandison, Katie; Parker, Joel S.; Santos, Charlene; Darr, David; Zamboni, William; Lee, Yueh Z.; Miller, C. Ryan; Anders, Carey K.

    2015-01-01

    Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through poly(ADP-ribose)polymerase (PARP) inhibition. We evaluated brain penetrance and efficacy of Carboplatin +/− the PARP inhibitor ABT888, and investigated gene expression changes in murine intracranial (IC) TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intra-cerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low), or BRCA-wild-type: MDA-MB-468 (basal), MDA-MB-231BR (claudin-low) TNBC cells and treated with PBS control (IP, weekly), Carboplatin (50mg/kg/week, IP), ABT888 (25mg/kg/day, OG), or their combination. DNA-damage (γ-H2AX), apoptosis (cleaved-Caspase-3(cC3)) and gene expression were measured in IC tumors. Carboplatin+/−ABT888 significantly improved survival in BRCA-mutant IC models compared to control, but did not improve survival in BRCA-wild-type IC models. Carboplatin+ABT888 revealed a modest survival advantage versus Carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared to Control, while BRCA-wild-type MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene expression changes in BRCA-mutant models. Carboplatin+/−ABT888 penetrates the brain and improves survival in BRCA-mutant IC TNBC models with corresponding DNA damage and gene expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. PMID