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1.  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.
doi:10.1007/s10549-010-1293-1
PMCID: PMC3244802  PMID: 21161370
Breast cancer; triple negative; phenotype; basal-like; BRCA1; targeted therapy
2.  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.
doi:10.1155/2012/829315
PMCID: PMC3262603  PMID: 22295252
3.  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.
doi:10.5306/wjco.v5.i2.125
PMCID: PMC4014784  PMID: 24829859
Breast cancer; Triple negative; Basal like; BRCA1; Poly (ADP-ribose) polymerase 1; Targeted therapy; Chemotherapy
4.  A clinically relevant gene signature in triple negative and basal-like breast cancer 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/bcr3035
PMCID: PMC3262210  PMID: 21978456
5.  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.
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
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.
doi:10.1186/1471-2407-12-120
PMCID: PMC3340297  PMID: 22452810
Triple-negative breast cancer; Mouse and human HspB1; Hsp25; Hsp27; Hsp72/HspA1A; Heat shock; Cancer stem cells; Tumor-initiating cells
6.  The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer 
Pharmaceutics  2013;5(2):10.3390/pharmaceutics5020353.
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.
doi:10.3390/pharmaceutics5020353
PMCID: PMC3826456  PMID: 24244833
nanoparticle; lipoprotein; triple negative breast cancer; targeted therapy
7.  The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer 
Pharmaceutics  2013;5(2):353-370.
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.
doi:10.3390/pharmaceutics5020353
PMCID: PMC3826456  PMID: 24244833
nanoparticle; lipoprotein; triple negative breast cancer; targeted therapy
8.  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.
doi:10.1371/journal.pone.0081126
PMCID: PMC3880256  PMID: 24404125
9.  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.
doi:10.1371/journal.pone.0078641
PMCID: PMC3827056  PMID: 24265703
10.  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.
doi:10.1016/j.bbcan.2009.06.003
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
11.  Meta-analysis of the global gene expression profile of triple-negative breast cancer identifies genes for the prognostication and treatment of aggressive breast cancer 
Oncogenesis  2014;3(4):e100-.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking expression of estrogen and progesterone receptors (ER/PR) and HER2, thus limiting therapy options. We hypothesized that meta-analysis of TNBC gene expression profiles would illuminate mechanisms underlying the aggressive nature of this disease and identify therapeutic targets. Meta-analysis in the Oncomine database identified 206 genes that were recurrently deregulated in TNBC compared with non-TNBC and in tumors that metastasized or led to death within 5 years. This ‘aggressiveness gene list' was enriched for two core functions/metagenes: chromosomal instability (CIN) and ER signaling metagenes. We calculated an ‘aggressiveness score' as the ratio of the CIN metagene to the ER metagene, which identified aggressive tumors in breast cancer data sets regardless of subtype or other clinico-pathological indicators. A score calculated from six genes from the CIN metagene and two genes from the ER metagene recapitulated the aggressiveness score. By multivariate survival analysis, we show that our aggressiveness scores (from 206 genes or the 8 representative genes) outperformed several published prognostic signatures. Small interfering RNA screen revealed that the CIN metagene holds therapeutic targets against TNBC. Particularly, the inhibition of TTK significantly reduced the survival of TNBC cells and synergized with docetaxel in vitro. Importantly, mitosis-independent expression of TTK protein was associated with aggressive subgroups, poor survival and further stratified outcome within grade 3, lymph node-positive, HER2-positive and TNBC patients. In conclusion, we identified the core components of CIN and ER metagenes that identify aggressive breast tumors and have therapeutic potential in TNBC and aggressive breast tumors. Prognostication from these metagenes at the mRNA level was limited to ER-positive tumors. However, we provide evidence that mitosis-independent expression of TTK protein was prognostic in TNBC and other aggressive breast cancer subgroups, suggesting that protection of CIN/aneuploidy drives aggressiveness and treatment resistance.
doi:10.1038/oncsis.2014.14
PMCID: PMC4007196  PMID: 24752235
Triple-negative breast cancer; aggressive breast cancer; therapeutic targets; kinetochore attachment; chromosome segregation; chromosomal instability
12.  Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects 
Triple-negative breast cancer (TNBC), as defined by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression, is a challenging disease with the poorest prognosis of all breast cancer subtypes. Importantly, there are currently no known molecular targets for this subgroup of patients. Recent advances in genomics and gene expression profiling have shed new light on the molecule heterogeneity of TNBC. We present an overview of the scientific evidence suggesting that clinical outcome in TNBC is affected by tumor-infiltrating immune cells. We also describe tumor-associated antigens recently identified in TNBC. Finally, we review the current literature on promising immunotherapies for TNBC, including tumor vaccine approaches, immune-checkpoint inhibitors, antagonists of immunosuppressive molecules and adoptive cell therapies. It is our contention that selected patients with TNBC with lymphocytic tumor infiltrates at diagnosis may benefit from immune-based therapies and that these immunotherapies will be most beneficial in combination with cytotoxic drugs that potentiate adaptive anti-tumor immunity.
doi:10.1177/1758834012475152
PMCID: PMC3630481  PMID: 23634195
basal like; breast cancer; immunotherapy; T cell
13.  Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype 
BMC Cancer  2013;13:403.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2407-13-403
PMCID: PMC3849986  PMID: 24004841
Basal phenotype; BRCA; Feline; Mammary adenocarcinoma; Triple negative
14.  Characteristics of triple-negative breast cancer 
Background
Triple-negative breast cancers (TNBC) neither express hormone receptors, nor overexpress HER2. They are associated with poor prognosis, as defined by low five-year survival and high recurrence rates after adjuvant therapy. Overall, TNBC share striking similarities with basal-like breast cancers (BBC), so a number of studies considered them being the same. The purpose of this review is to summarise the latest findings on TNBC concerning its relation and delineation to BBC, discuss the developmental pathways involved and address clinical implications for this complex type of breast cancer.
Methods
The recent literature from PubMed and Medline databases was reviewed.
Results
Not all TNBC are of the intrinsic BBC subtype (nonbasal (NB)-TNBC), nor are all BBC triple-negative (non-triple-negative (NTN)-BBC). There is increasing evidence that a triple-negative, basal-like breast cancer (TNBBC) subtype develops mainly through a BRCA1-related pathway. Somatic mutations that contribute to NTN-BBC and NB-TNBC development are possibly not related to this pathway, but may occur randomly due to increased genomic instability in these tumours. Several therapeutic options exist for TNBBC, which exhibited promising results in recent clinical trials. Cytotoxic therapies, e.g. combined treatment with anthracyclines or taxanes, achieved good tumour regression rates in the neo-adjuvant setting, but also showed considerable recurrence during the first 5 years after therapy. Targeted therapy options involve PARP1 and EGFR inhibition, although both approaches still need further investigation.
Conclusions
TNBC and BBC are not the same disease entity. The TNBBC subtype shows the largest homogeneity in terms of tumour development, prognosis and clinical intervention options.
doi:10.1007/s00432-010-0957-x
PMCID: PMC3018596  PMID: 21069385
Triple-negative breast cancer (TNBC); Basal-like breast cancer (BBC); BRCA1; Adjuvant treatment; Patient outcome
15.  Identification of New Candidate Therapeutic Target Genes in Triple-Negative Breast Cancer 
Genes & Cancer  2012;3(1):63-70.
Triple-negative breast cancer (TNBC) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and ERBB2 protein expression. It is characterized by its aggressive behavior and by the lack of targeted therapies. To identify new therapeutic targets in TNBC, we used real-time quantitative RT-PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer. Six of the 26 genes tested (VEGFA, SRC, PARP1, PTK2, RAF1, and FGFR3) were significantly upregulated in 13% to 46% of the TNBCs. None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes. No association was observed between overexpression of these 6 genes (except for FGFR3) and PIK3CA mutation status. These results confirm the interest of targeting VEGFA and PARP1 in ongoing clinical trials in TNBC patients and also identify new target genes (SRC, PTK2, RAF1, and FGFR3). Clinical trials could be initiated easily with existing drugs. Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response.
doi:10.1177/1947601912449832
PMCID: PMC3415670  PMID: 22893791
breast cancer; triple negative; therapeutic target
16.  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.
doi:10.3892/ol.2012.1093
PMCID: PMC3576281  PMID: 23426861
meta-analysis; triple-negative breast cancer; platinum
17.  Epidemiological and clinical profile of triple negative breast cancer at a cancer hospital in North India 
Background:
Triple negative breast cancer (TNBC) is a recent concept and the burning topic of research today. Various studies have been reported in western literature on TNBCs or the similar group of basal like cancers, all highlighting the poor prognostic features of this molecular subtype in comparison to the other types of breast cancers. However extensive data from India is lacking. The aim of this study was to analyze the epidemiological and clinical profile of TNBcs at our institute.
Materials and Methods:
Data on 171 patients of TNBCs registered at this hospital between 2005 and 2008 and followed up until December 2010 was collected and reviewed for epidemiological and clinical features.
Results:
The median age at presentation was 49 years (22-75 years). Sixty eight patients (40%) had lump in the breast of less than 1 month duration. Fourteen (8%) were nulliparous and 10 (7%) patients had crossed the age of 30 years at first full-term pregnancy, 89 (52%) were pre or peri-menopausal at presentation. Only 8 (5%) patients had a family history of breast or ovarian cancer. One hundred and six (62%) patients were stage II, 26 (15%) stage III, 21 (12%) stage I and 18 (10%) stage IV at presentation. One hundred and twenty eight patients (75%) had early breast cancer eligible for surgery at presentation, 25 (15%) were locally advanced and received neoadjuvant chemotherapy (NACT) and 18 (10%) were found to be metastatic. Modified radical mastectomy was the preferred surgical option by most patients (76%) who underwent upfront surgery in our study. The pathological overall response rates (complete and partial response) after NACT was 75% with complete response rate of 25% and there were no relapses in the complete responders. The median follow-up was 30 months (9-70 months). One hundred and twenty two patients (71%) were alive at last follow-up, 34 (22%) had relapsed, 18 (11%) had died due to progressive disease. Thirty one patients (18%) were lost to follow-up. Most of the relapses were systemic and rarely preceded by local relapses.
Conclusions:
TNBCs are aggressive cancers with high rates of systemic relapses within the first 3 years of presentation. Longer follow-up of these patients is required for more mature data on these cancers.
doi:10.4103/0971-5851.116185
PMCID: PMC3764751  PMID: 24049294
Clinical profile; epidemiology; India; outcomes; triple negative breast cancer
18.  High expression of thymidine phosphorylase in basal-like breast cancers: Stromal expression in EGFR- and/or CK5/6-positive breast cancers 
Oncology Letters  2010;1(2):261-266.
Expression of the estrogen receptor (ER), the progesterone receptor (PgR) or the human epidermal growth factor receptor-2 (HER2) in tumors is a good prognostic marker for breast cancer patients. However, approximately 15–20% of breast cancer patients have triple-negative breast cancer (TNBC; negative for ER, PgR and HER2), and efficient therapeutic modalities for these patients are under investigation. We focused on thymidine phosphorylase (TP), an enzyme metabolizing 5′-DFUR, an intermediate of capecitabine, to 5-fluorouracil in order to investigate the application of well-known therapeutics for TNBC. Results of a gene expression analysis showed that TP expression in TNBC and basal-like breast cancer (BLBC) was higher than that of other subtypes. Immunohistochemically, the high expression of TP in TNBC and BLBC reflected expression in stromal but not tumor cells. Notably, a high TP expression was observed in the stromal cells of EGFR- and/or CK5/6-positive breast tumors. Our present results showing a high expression of TP in BLBC indicate that capecitabine-based chemotherapy would be of benefit for patients with TNBC.
doi:10.3892/ol_00000046
PMCID: PMC3436479  PMID: 22966291
thymidine phosphorylase; estrogen receptor; human epidermal growth factor receptor-2; basal-like breast tumor
19.  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.
doi:10.1158/0008-5472.CAN-12-1699
PMCID: PMC3654815  PMID: 23536562
20.  Prognostic role of BRCA1 mutation in patients with triple-negative breast cancer 
Oncology Letters  2013;7(1):278-284.
Triple-negative breast cancer (TNBC) is proposed to be an immunohistochemical surrogate of the basal-like breast cancer subtype. In spite of the relative chemosensitivity of this cancer subtype, it is characterized by aggressive clinical behavior; therefore, a further subclassification of TNBC is required to develop new targeted treatment. In previous studies, a strong correlation between BRCA1 mutation-associated tumors and TNBC has been identified. The aim of the present study was to investigate the prognostic significance of carrying two germline BRCA1 founder mutations (4153delA and 5382insC) in patients with TNBC in the Latvian population. A total of 78 consecutive BRCA1 mutation-negative and 38 BRCA1 mutation-positive invasive TNBC patients in stage I–IV with no history of ovarian or other primary advanced cancers, who had undergone definitive surgery and genetic testing between 2005 and 2011, were deemed eligible for study. Relapse rates and breast cancer-specific survival (BCS) outcomes were compared between mutation carriers and non-carriers. Univariate and multivariate analyses Cox proportional-hazards models were used to compute independent predictors of survival outcomes. No statistically significant differences were identified in relation to tumor size, T stage, stage, Ki-67 status and tumor differentiation grade between the two groups. The median follow-up period was 36 months for mutation carriers and 41 months for non-carriers. A higher proportion of BRCA1 mutation non-carriers experienced distant recurrence compared with that of mutation carriers (P<0.03). BRCA1 mutation carriers had a significantly higher BCS than non-carriers (94.9 vs. 76.9%; P<0.02). In the univariate analyses, BRCA1-positive status was associated with decreased risk of distant recurrence (HR, 0.228; 95% Cl, 0.052–0.997; P<0.049) and breast cancer-specific mortality (HR, 0.209; 95% Cl, 0.048–0.902; P<0.036). In the multivariate analysis Cox proportional-hazards model, BRCA1-positive status was an independent favorable prognostic factor for distant recurrence-free survival (HR, 3.301; 95% Cl, 1.102–9.893; P<0.033). In conclusion, results of the present study demonstrate that positive BRCA1 founder mutation status in TNBC, with no evidence of ovarian or other cancer type in advanced stage, significantly improves prognosis.
doi:10.3892/ol.2013.1684
PMCID: PMC3861604  PMID: 24348864
triple-negative breast cancer; breast cancer; BRCA1 mutation
21.  Triple-Negative Breast Cancer: Adjuvant Therapeutic Options 
Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.
doi:10.1155/2011/696208
PMCID: PMC3265248  PMID: 22312556
22.  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 
BMC Cancer  2014;14:73.
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 ubiquitin ligase activity.
Conclusions
This study has revealed the ability of ruthenium complexes to inhibit cell proliferation, induce cell cycle progression and apoptosis. Ruthenium treatment upregulated the marker genes involved in apoptosis and cell cycle progression while it downregulated BRCA1 mRNA and replication of HCC1937 cells. Our results could provide an alternative approach to finding effective therapeutic ruthenium-based agents with promising anticancer activity, and demonstrated that the BRCA1 RING domain protein was a promising therapeutic target for breast cancers.
doi:10.1186/1471-2407-14-73
PMCID: PMC3933379  PMID: 24507701
Ruthenium; BRCA1; Triple-negative; Cell cycle; Apoptosis; BRCA1; Ubiquitination
23.  Exploring Molecular Pathways of Triple-Negative Breast Cancer 
Genes & Cancer  2011;2(9):870-879.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a high rate of proliferation and metastasis, as well as poor prognosis for advanced-stage disease. Although TNBC was previously classified together with basal-like and BRCA1/2-related breast cancers, genomic profiling now shows that there is incomplete overlap, with important distinctions associated with each subtype. The biology of TNBC is still poorly understood; therefore, to define the relative contributions of major cellular pathways in TNBC, we have studied its molecular signature based on analysis of gene expression. Comparisons were then made with normal breast tissue. Our results suggest the existence of molecular networks in TNBC, characterized by explicit alterations in the cell cycle, DNA repair, nucleotide synthesis, metabolic pathways, NF-κB signaling, inflammatory response, and angiogenesis. Moreover, we also characterized TNBC as a cancer of mixed phenotypes, suggesting that TNBC extends beyond the basal-like molecular signature and may constitute an independent subtype of breast cancer. The data provide a new insight into the biology of TNBC.
doi:10.1177/1947601911432496
PMCID: PMC3352156  PMID: 22593799
triple-negative breast cancer (TNBC); molecular pathways; DNA repair; cell cycle; NF-κB; tumor metabolism
24.  TMPRSS4 as a Poor Prognostic Factor for Triple-Negative Breast Cancer 
Triple-negative breast cancer (TNBC) is characterized by the lack of immunohistochemical staining for estrogen receptors (ER), progesterone receptors (PR), and lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). Our aim was to investigate the expression of transmembrane protease, serine 4 (TMPRSS4) in TNBC patients and its possible relationship to the outcome of the disease. A total of 72 TNBC patients and 109 non-TNBC patients who were diagnosed between 2003 and 2008 were enrolled in this study. Immunohistochemistry was used to compare the expression pattern of TMPRSS4 in TNBC and non-TNBC groups, and the prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression in TNBC patients. The rate of high expression of TMPRSS4 was significantly higher in TNBC group than that in non-TNBC group. High expression of TMPRSS4 was significantly correlated with lymph node metastasis, histological grade, and tumor size. TNBC patients with high TMPRSS4 expression showed the poorer overall survival (OS) and disease-free survival (DFS) than those patients with low TMPRSS4 expression. In multivariate analysis, only lymph node metastasis and TMPRSS4 expression were the independent prognostic factors for OS and DFS in TNBC. Our study provides evidence that TMPRSS4 expression is associated with lymph node metastasis, tumor size, and histological grade in TNBC patients, and also is an independent prognostic factor for TNBC.
doi:10.3390/ijms140714659
PMCID: PMC3742265  PMID: 23857060
transmembrane protease; triple-negative breast cancer; prognosis; immunohistochemistry
25.  Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival 
BMC Cancer  2010;10:507.
Background
Triple-negative breast cancers (TNBCs) and basal-like breast cancers (BLBCs) are known as poor outcome subtypes with a lack of targeted therapy. Previous studies have shown conflicting results regarding the difference of prognostic significance between TNBCs and BLBCs. In this study, we aimed to characterize the prognostic features of TNBCs, in view of BLBCs and quintuple-negative breast cancers (QNBC/5NPs).
Methods
Using tissue microarray-based immunohistochemical analysis, we categorized 951 primary breast cancers into four or five subtypes according to the expression of ER, PR, HER2, and basal markers (CK5/6, EGFR).
Results
The results of this study showed that both TNBCs and BLBCs were associated with high histological and/or nuclear grades. When the TNBCs are divided into two subtypes by the presence of basal markers, the clinicopathologic characteristics of TNBCs were mainly maintained in the BLBCs. The 5-subgrouping was the better prediction model for both disease free and overall survival in breast cancers than the 4-subgrouping. After multivariate analysis of TNBCs, the BLBCs did not have a worse prognosis than the QNBC/5NPs. Interestingly, the patients with BLBCs showed significant adjuvant chemotherapy benefit. In addition, QNBC/5NPs comprised about 6~8% of breast cancers in publicly available breast cancer datasets
Conclusion
The QNBC/5NP subtype is a worse prognostic subgroup of TNBCs, especially in higher stage and this result may be related to adjuvant chemotherapy benefit of BLBCs, calling for caution in the identification of subgroups of patients for therapeutic classification.
doi:10.1186/1471-2407-10-507
PMCID: PMC2957395  PMID: 20860845

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