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1.  Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype 
BMC Cancer  2013;13:403.
Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC.
Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs.
IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis.
FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA in the tumorigenesis of triple negative, basal-like FMAs. The strong similarities in clinical behavior, morphology and IHC phenotype suggest that triple negative, basal-like FMAs may be a suitable spontaneous animal model for studying novel therapeutic approaches against human basal-like TNBC.
PMCID: PMC3849986  PMID: 24004841
Basal phenotype; BRCA; Feline; Mammary adenocarcinoma; Triple negative
2.  The Management of Early Stage and Metastatic Triple Negative Breast Cancer: A Review 
Triple negative breast cancer (TNBC) defined as lacking expression of the estrogen receptor, progesterone receptor and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. It is increasingly clear that TNBC is heterogeneous and that there are several biologically distinct subtypes within TNBC, in particular the basal-like subtype but also the claudin-low, among others. While the incidence of BRCA mutations across all subsets of breast cancer is quite low (~5%), BRCA mutations are more common among those with TNBC (~20%) and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early stage TNBC and non-TNBC. There is a trend, however, to treat TNBC at a lower stage with chemotherapy as this is the only way to systemically reduce recurrence risk. In the metastatic setting, while cytotoxic chemotherapy is the mainstay of treatment for advanced TNBC, there are many promising targeted therapies in development in both the preclinical and early phase clinical trial settings. While the treatment of TNBC remains a challenge, coordinated efforts between clinician/scientist partnerships providing a comprehensive understanding of TNBC genomic, proteomic and other biologic processes may result in individualized therapy for TNBC faster than other subtypes -- driven by both the heterogeneity we know exists within this clinical entity and the intense need for improved treatment.
PMCID: PMC3737488  PMID: 23915742
breast cancer; triple negative; chemotherapy; targeted agents; radiation; BRCA mutation
3.  A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease 
BMC Cancer  2012;12:120.
Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems.
To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis.
We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A).
Taken together, we have developed a TNBC-TICs model system based on the 4T1 cells which is a very useful metastasis model with the advantage of being able to be transplanted into immune competent recipients. Our data demonstrates that the TNBC-TICs model system could be a useful tool for studies on the pathogenesis and therapeutic treatment for TNBC.
PMCID: PMC3340297  PMID: 22452810
Triple-negative breast cancer; Mouse and human HspB1; Hsp25; Hsp27; Hsp72/HspA1A; Heat shock; Cancer stem cells; Tumor-initiating cells
4.  Triple negative breast cancer: unmet medical needs 
Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor–2 (HER2) overexpression. It shows substantial overlap with basal-type and BRCA1-related breast cancers, both of which also have aggressive clinical courses. However, this overlap is not complete, and the expression of ER, PR, and HER2 has been noted in basal-like tumors. TNBC also includes the normal-like subtype, and not all patients with TNBC harbor BRCA1 mutations. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic chemotherapy. Overall survival, whether in early-stage or advanced disease, is poor compared with that in patients who have other phenotypes. A number of targeted approaches to TNBC are undergoing clinical evaluation, including the use of agents with poly(ADP-ribose) polymerase inhibitory properties such as iniparib (the United States Adopted Name for the investigational agent BSI-201), olaparib (AZD2281), and veliparib (ABT-888), antiangiogenic agents such as bevacizumab and sunitinib, and epidermal growth factor receptor blockers such as cetuximab and erlotinib. Encouraging results with some of these agents have been reported, thereby offering the promise for improved outcomes in patients with TNBC. The clinical characteristics of TNBC and clinical experience to date with novel targeted agents under development for this aggressive phenotype is reviewed.
PMCID: PMC3244802  PMID: 21161370
Breast cancer; triple negative; phenotype; basal-like; BRCA1; targeted therapy
5.  Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas 
BMC Cancer  2011;11:262.
Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC.
We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1).
Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022).
Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC.
PMCID: PMC3141776  PMID: 21693047
6.  Histological Analysis of γδ T Lymphocytes Infiltrating Human Triple-Negative Breast Carcinomas 
Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic, and prognostic factors. Triple-negative breast carcinomas (TNBCs) lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs) with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs) are somewhat less frequent. Infiltrating T-cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of γδ T-cells within CD3+ tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs, and 12 MBCs, using immunohistochemistry for the quantity and patterns of γδ T-cell infiltrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of γδ T-cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating γδ T-cells were higher in MBCs than in IDCs. γδ T-cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most γδ T-cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient’s prognosis in MBCs is better than that in IDCs. Further studies to characterize these γδ T-cells at the molecular and functional level are in progress.
PMCID: PMC4261817  PMID: 25540645
γδ T-cells; breast cancer; triple-negative breast cancer; histology; paraffin material
7.  Platinum-based chemotherapy in triple-negative breast cancer: A meta-analysis 
Oncology Letters  2012;5(3):983-991.
Triple-negative breast cancer (TNBC) tumors do not express estrogen, progesterone or HER2/neu-receptors. There are no specific treatment guidelines for TNBC patients, however, it has been postulated that their phenotypic and molecular similarity to BRCA1-associated cancers would confer sensitivity to certain cytotoxic agents, including platinum. The aim of this meta-analysis was to evaluate the clinical outcome of breast cancer patients treated with platinum-based chemotherapy who had TNBC compared with those with non-TNBC. Electronic (MEDLINE, EMBASE and Cochrane Library databases) and manual searches were conducted throughout December 2011 to identify trials evaluating the use of platinum-based chemotherapy for patients with breast cancer. The methodological quality was assessed in accordance with the QUOROM statement. Seven studies met the eligibility criteria, with a total of 717 patients. Of these patients, 225 were TNBC patients (31%), 492 were non-TNBC patients (69%), 275 received platinum-based neo-adjuvant chemotherapy and 442 had advanced/metastatic breast cancers. The results showed that during neo-adjuvant chemotherapy, the clinical complete response (cCR) rate and the pathological complete response (pCR) rates were significantly higher for the TNBC group compared with the non-TNBC group (OR, 2.68; 95% CI, 1.69–6.57; P=0.03 and OR, 2.89; 95% CI, 1.28, 6.53; P= 0.01, respectively). However, in advanced/metastatic breast cancers, the cCR, partial response (PR) and the disease control rates for the TNBC group were not significantly different compared with the non-TNBC group. The 6-month progression-free survival (PFS) rate for the TNBC group was higher than that of the non-TNBC group in all patients (OR, 1.81; 95% CI, 1.11–2.96; P= 0.02). However, the 1- and 2-year PFS rates were not significantly different (OR, 1.42; 95% CI, 0.69–2.92; P=0.35 and OR, 1.11; 95% CI, 0.35–3.52; P= 0.85, respectively). Furthermore, the PFS rates were not significantly different between the groups in patients with advanced/metastatic breast cancer. In conclusion, platinum-based chemotherapy in the breast cancer patients with TNBC showed an improved short-term efficacy compared with the non-TNBC group during neo-adjuvant chemotherapy, but has not yet been demonstrated to have an improved effect in advanced breast cancer.
PMCID: PMC3576281  PMID: 23426861
meta-analysis; triple-negative breast cancer; platinum
8.  ERα-Negative and Triple Negative Breast Cancer: Molecular Features and Potential Therapeutic Approaches 
Biochimica et biophysica acta  2009;1796(2):162-175.
Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ – mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC.
PMCID: PMC2937358  PMID: 19527773
Breast cancer; CXC chemokine; CXCL8; ERα; ERβ; estrogen carcinogenesis; GRCP-30/EGFR; mircoRNAs; therapeutic approaches for TN-breast cancer; triple negative breast cancer
9.  Systemic treatment strategies for triple-negative breast cancer 
Triple-negative breast cancer (TNBC) is defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2 (EGFR2). Most TNBC has a basal-like molecular phenotype by gene expression profiling and shares clinical and pathological features with hereditary BRCA1 related breast cancers. This review evaluates the activity of available chemotherapy and targeted agents in TNBC. A systematic review of PubMed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with chemotherapy and targeted agents. Our review identified TNBC studies of chemotherapy and targeted agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth and survival pathways. TNBC is sensitive to taxanes and anthracyclins. Platinum agents are effective in TNBC patients with BRCA1 mutation, either alone or in combination with poly adenosine diphosphate polymerase 1 inhibitors. Combinations of ixabepilone and capecitabine have added to progression-free survival (PFS) without survival benefit in metastatic TNBC. Antiangiogenic agents, tyrosine kinase inhibitors and EGFR inhibitors in combination with chemotherapy produced only modest gains in PFS and had little impact on survival. TNBC subgroups respond differentially to specific targeted agents. In future, the treatment needs to be tailored for a specific patient, depending on the molecular characteristics of their malignancy. TNBC being a chemosensitive entity, combination with targeted agents have not produced substantial improvements in outcomes. Appropriate patient selection with rationale combinations of targeted agents is needed for success.
PMCID: PMC4014784  PMID: 24829859
Breast cancer; Triple negative; Basal like; BRCA1; Poly (ADP-ribose) polymerase 1; Targeted therapy; Chemotherapy
10.  PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis 
Cell Death and Differentiation  2014;21(9):1469-1481.
Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.
PMCID: PMC4131178  PMID: 24786829
11.  BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers 
Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences.
We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model.
We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients.
In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.
PMCID: PMC4322455  PMID: 25583261
12.  A clinically relevant gene signature in triple negative and basal-like breast cancer 
Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.
We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.
Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.
We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.
PMCID: PMC3262210  PMID: 21978456
13.  Characteristics of Triple-Negative Breast Cancer in Patients With a BRCA1 Mutation: Results From a Population-Based Study of Young Women 
Journal of Clinical Oncology  2011;29(33):4373-4380.
Triple-negative breast cancers (TNBCs) are tumors with low or no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. These tumors have a poor prognosis, remain a clinical challenge, and are more common among women with BRCA1 mutations. We tested whether there are distinguishing features of TNBC after BRCA1 mutation status has been taken into account.
Patients and Methods
We sequenced BRCA1 and BRCA2 genes in a population-based sample of 1,469 patients with incident breast cancer age 20 to 49 years from Los Angeles County (California). Information on tumor receptor status was available for 1,167 women. Clinical, pathologic, and hormone-related lifestyle characteristics were compared across patient subgroups defined by BRCA1 mutation status and triple-negative receptor status.
Forty-eight percent of BRCA1 mutation carriers had TNBC compared with only 12% of noncarriers. Within BRCA1 mutation carriers, as well as within noncarriers, triple-negative receptor status was associated with younger age at diagnosis and higher tumor grade. Among women without a BRCA1 mutation, we observed that women with TNBC had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age at menarche and other reproductive factors were not associated with triple-negative status regardless of BRCA1 mutation status. Within BRCA1 mutation carriers, Ashkenazi Jewish women were about five times more likely to have TNBC than non–Ashkenazi Jewish women.
Our results suggest that among BRCA1 mutation carriers, as among noncarriers, there are unique characteristics associated with the triple-negative subtype. The findings in Ashkenazi Jewish BRCA1 mutation carriers should be confirmed.
PMCID: PMC3221522  PMID: 22010008
14.  Nottingham Prognostic Index in Triple-Negative Breast Cancer: a reliable prognostic tool? 
BMC Cancer  2011;11:299.
A breast cancer prognostic tool should ideally be applicable to all types of invasive breast lesions. A number of studies have shown histopathological grade to be an independent prognostic factor in breast cancer, adding prognostic power to nodal stage and tumour size. The Nottingham Prognostic Index has been shown to accurately predict patient outcome in stratified groups with a follow-up period of 15 years after primary diagnosis of breast cancer. Clinically, breast tumours that lack the expression of Oestrogen Receptor, Progesterone Receptor and Human Epidermal growth factor Receptor 2 (HER2) are identified as presenting a "triple-negative" phenotype or as triple-negative breast cancers. These poor outcome tumours represent an easily recognisable prognostic group of breast cancer with aggressive behaviour that currently lack the benefit of available systemic therapy. There are conflicting results on the prevalence of lymph node metastasis at the time of diagnosis in triple-negative breast cancer patients but it is currently accepted that triple-negative breast cancer does not metastasize to axillary nodes and bones as frequently as the non-triple-negative carcinomas, favouring instead, a preferentially haematogenous spread. Hypothetically, this particular tumour dissemination pattern would impair the reliability of using Nottingham Prognostic Index as a tool for triple-negative breast cancer prognostication.
The present study tested the effectiveness of the Nottingham Prognostic Index in stratifying breast cancer patients of different subtypes with special emphasis in a triple-negative breast cancer patient subset versus non- triple-negative breast cancer.
We demonstrated that besides the fact that TNBC disseminate to axillary lymph nodes as frequently as luminal or HER2 tumours, we also showed that TNBC are larger in size compared with other subtypes and almost all grade 3. Additionally, survival curves demonstrated that these prognostic factors are equally important to stratify different survival outcomes in non-TNBC as in TNBC. We also showed that the NPI retains the ability to stratify and predict survival of TNBC patients.
The importance of this study relies on the need of prognostication improvements on TNBC, showing, at a clinical standpoint, that Nottingham Prognostic Index is as a truthful prognostic tool in TNBC.
PMCID: PMC3151231  PMID: 21762477
15.  A Study of Triple Negative Breast Cancer at a Tertiary Cancer Care Center in Southern India 
Triple negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER-2 gene. The majority of the tumors classified as TNBCs are highly malignant, patients are usually young and only a subgroup of patients responds to conventional chemotherapy with a favorable prognosis. Various studies have been reported in western literature on TNBCs, all highlighting the poor prognosis of this subtype. However, extensive data from India is lacking.
The aim of this study was to analyze the epidemiological and clinical profile of TNBCs at our institute.
Materials and Methods:
This was the retrospective study carried out in Tertiary Cancer Care Center in South India. 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.
A total of 322 patients were registered during the period of 1 year and 26% (84/322) of total patients were TNBC. Median age of presentation was 44.5 years. About 94% (79/84) of patients had first full-term delivery before the age of 30 years. The most common presenting symptom was left sided breast lump. Locally advanced and early breast cancer (EBC) was 51% (43/84) and 42% (36/84), respectively. Metastatic breast cancer was seen in five patients. The highest numbers of patients were node negative disease (36.9%) [31/84], followed by N1 30.95% (26/84). Most of the patients had high-grade tumor. 94% (34/36) of cases of EBC had undergone upfront modified radical mastectomy. Invasive ductal carcinoma was the predominant histology except one who had medullary carcinoma. Twenty-four patients received neoadjuvant chemotherapy (NACT). There was no pathological complete remission, but all patients responded to NACT. Metastatic disease was seen in five patients. All patients had bone metastasis.
TNBCs are highly aggressive subtype, with high grade with limited treatment options and very poor prognosis. Incidence is more in our country than the western literature. Even in our country also the incidence is varies in different region. TNBCs are significantly associated with young aged patients. There was a lack of association between tumor size and lymph node positivity.
PMCID: PMC4250994  PMID: 25506489
Breast cancer; Triple negative; Invasive ductal carcinoma
16.  Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer 
Journal of Clinical Oncology  2010;28(7):1145-1153.
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 (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m2 every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers.
Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03).
Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
PMCID: PMC2834466  PMID: 20100965
17.  Current Status of Poly(ADP-ribose) Polymerase Inhibitors as Novel Therapeutic Agents for Triple-Negative Breast Cancer 
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.
PMCID: PMC3262603  PMID: 22295252
18.  Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells 
Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%–20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC.
Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell proliferation and apoptosis were tested in vitro. The inhibitory effects of iCRT-3 on canonical Wnt signaling in TNBC was evaluated by quantitative real-time RT-PCR analysis of Axin2 and dual-luciferase reporter assays. The effects of shRNA knockdown of SOX4 in combination with iCRT-3 and/or genistein treatments on cell proliferation, migration and invasion on BT-549 cells were also evaluated.
Immunofluorescence staining of β-catenin in TNBC cell lines showed both nuclear and cytoplasmic localization, indicating activation of Wnt pathway in TNBC cells. iCRT-3 was the most effective compound for inhibiting proliferation and antagonizing Wnt signaling in TNBC cells. In addition, treatment with iCRT-3 resulted in increased apoptosis in vitro. Knockdown of the Wnt pathway transcription factor, SOX4 in triple negative BT-549 cells resulted in decreased cell proliferation and migration, and combination treatment of iCRT-3 with SOX4 knockdown had a synergistic effect on inhibition of cell proliferation and induction of apoptosis.
These data suggest that targeting SOX4 and/or the Wnt pathway could have therapeutic benefit for TNBC patients.
PMCID: PMC4228255  PMID: 24188694
Triple-negative breast cancer; Wnt signaling pathway; iCRT-3; SOX4
19.  Triple-negative vimentin-positive heterogeneous feline mammary carcinomas as a potential comparative model for breast cancer 
BMC Veterinary Research  2014;10:185.
Human breast cancer is a heterogeneous disease classified by molecular subtyping into luminal A, luminal B, HER2-overexpressing, basal-like, claudin-low and normal-breast like. The routinely applied and standardized immunohistochemical-based surrogates of this classification group together the last three entities as triple-negative breast cancer (TNBCs) that show the most diverse and complex heterogeneity and represent a therapeutic challenge.
In the present work 156 feline mammary lesions consisting of feline mammary carcinomas (FMCs), benign neoplasms, and hyperplastic/dysplastic tissues were evaluated histologically and by immunohistochemistry for expression of basal and luminal cytokeratins (CK), vimentin, alpha-smooth muscle actin, calponin, estrogen receptor (ER) alpha (a), and progesterone receptor (PR). Thirty-seven FMCs with 27 matched non-neoplastic controls were also investigated for gene expression of ERa, ER beta, PR, and HER2.
A large group of hormone receptors (HRs)-negative aggressive carcinomas - that did not overexpress HER2 - could be distinguished from the less aggressive (10.8%) and benign (8%) HRs + tumors, that showed bilineage (luminal and myoepithelial) differentiation. Immunohistochemical evaluations of cytoplasmic filaments indicated that HRs- FMCs are vimentin+, CK14+, and CK5_6+ carcinomas that may resemble the TNBCs (basal like/claudin low) described in women. The identification of luminal and myoepithelial progenitors within the mammary ductal system suggested potential cells/sites of origin of these tumors. A diffuse and never previously described CKs/vimentin luminal cell co-expression was detected in the non-neoplastic ducts, indicating a potential bilineage progenitor.
These results indicate and potentially explain the high incidence of triple-negative, vimentin + aggressive tumors in cats that may used to elucidate some of the challenging features of TNBCs in women.
PMCID: PMC4180584  PMID: 25249140
Mammary tumor; Feline; Human breast cancer; Vimentin; Markers; Triple-negative
20.  RB1 Status in Triple Negative Breast Cancer Cells Dictates Response to Radiation Treatment and Selective Therapeutic Drugs 
PLoS ONE  2013;8(11):e78641.
Triple negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1) tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1met, fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ∼3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA+/CD24−/low/CD44+ cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.
PMCID: PMC3827056  PMID: 24265703
21.  Genetic Susceptibility to Triple Negative Breast Cancer 
Cancer research  2013;73(7):2025-2030.
Triple negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression, account for 12-24% 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 16-23% 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 epidemiological 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 development of risk prediction models.
PMCID: PMC3654815  PMID: 23536562
22.  Metabotropic Glutamate Receptor-1 Contributes to Progression in Triple Negative Breast Cancer 
PLoS ONE  2014;9(1):e81126.
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.
PMCID: PMC3880256  PMID: 24404125
23.  Frequently increased epidermal growth factor receptor (EGFR) copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers 
BMC Cancer  2008;8:309.
Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative) (TNBC) is a high risk breast cancer that lacks specific therapy targeting these proteins.
We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR) gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years.
A total of 110 (11.3%) patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers.
TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.
PMCID: PMC2612006  PMID: 18950515
24.  Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer 
The goal of this study was to investigate the expression of sarcosine metabolism-related proteins, namely glycine N-methyltransferase (GNMT), sarcosine dehydrogenase (SARDH), and l-pipecolic acid oxidase (PIPOX), in the different breast cancer subtypes and to assess the implications of differences in expression pattern according to subtype.
We analyzed the expression of GNMT, SARDH, and PIPOX in a tissue microarray of 721 breast cancer cases using immunohistochemistry (IHC). We classified breast cancer cases into subtype luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) according to the status for the estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67. Sarcosine metabolism phenotype was stratified according to IHC results for GNMT, SARDH, and PIPOX: GNMT(+), SARDH and PIPOX(-) was classified as high sarcosine type; GNMT(-), SARDH or PIPOX(-) as low sarcosine type; GNMT(+), SARDH or PIPOX(+) as intermediate sarcosine type, and GNMT(-), SARDH and PIPOX(-) as null type.
Expression of sarcosine metabolism-related proteins differed significantly according to breast cancer subtype (GNMT, p = 0.005; SARDH, p = 0.012; tumoral PIPOX, p = 0.008; stromal PIPOX, p < 0.001). These proteins were the most frequently expressed in HER-2 type tumors and the least in TNBC. Sarcosine metabolism phenotype also varied according to breast cancer subtype, with high sarcosine type the most common in HER-2, and null type the most common in TNBC (p = 0.003). Univariate analysis revealed that GNMT expression (p = 0.042), tumoral PIPOX negativity (p = 0.039), and high sarcosine type (p = 0.021) were associated with shorter disease-free survival (DFS). Multivariate analysis also revealed GNMT expression was an independent factor for shorter DFS (hazard ratio: 2.408, 95% CI: 1.154-5.024, p = 0.019).
Expressions of sarcosine metabolism-related proteins varied according to subtype of breast cancer, with HER-2 type tumors showing elevated expression of these proteins, and TNBC subtype showing decreased expression of these proteins. Expression of sarcosine metabolism-related proteins was also associated with breast cancer prognosis.
PMCID: PMC4045904  PMID: 24884785
Breast cancer; Metabolism; Molecular subtype; Sarcosine
25.  Enhancement of taxol, doxorubicin and zoledronate anti-proliferation action on triple-negative breast cancer cells by a PTHrP blocking monoclonal antibody 
Triple-negative breast cancers (TNBCs) are heterogeneous cancers that present tumors without the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Because of the absence of these receptors, there are currently no known specific molecular targets for treatment, and although TNBC tumors are chemosensitive, prognosis is poor because this type of cancer relapses more frequently and more aggressively than hormone receptor-positive cancers. The mechanisms by which TNBCs escape control by chemotherapy are not clear, and it is crucial to identify novel molecular drivers that can be targeted in order to develop more efficient therapeutic approaches. We recently highlighted a pleiotropic role for parathyroid hormone-related protein (PTHrP) in all stages of breast cancer, and used our neutralizing anti-PTHrP monoclonal antibody (mAb M158) to efficiently inhibit progression and metastasis of human breast cancer xenografts in athymic mice. In the present study, we present evidence for a strong in vitro anti-proliferative effect of our blocking anti-PTHrP mAb M158 as a single agent on TNBC lines of various subtypes that are known to express PTHrP (MDA-MB-231, BT-549, MDA-MB-435). The same mAb is inactive in a TNBC line without detectable PTHrP expression (MDA-MB-468). In in vitro combination studies, the mAb enhances the effect of the chemotherapeutic drugs taxol and doxorubicin in PTHrP-positive TNBC cells in an additive manner. When combined with the bisphosphonate zoledronate, M158 can act in additive or antagonistic fashion in vitro depending on the cell line. Our observations identify PTHrP as a novel target against TNBC cell proliferation, and suggest that combination therapies that include an anti-PTHrP approach might increase treatment efficacy in patients with PTHrP-positive TNBC.
PMCID: PMC3816969  PMID: 24224127
Breast cancer cell lines; PTHrP; TNBC; zoledronate; doxorubicin; paclitaxel; neutralizing antibody

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