Abstract
Triple Negative Breast Cancer (TNBC) is defined by the lack of ERα, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets.We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5-Fluorouracil/Epirubicin/Cyclophosphamide -‘good’ outcome no relapse > 3 years; ‘poor’ outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in ‘good’ outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up-regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression.We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments.
Highlights
Breast cancer research has been revolutionised over the past decade by the advent of gene expression profiling, which at the molecular level, has subdivided breast cancers into five ‘intrinsic subtypes’ (Luminal A and Luminal B, basal-like, HER2 -enriched and a normal breast-like group) [1, 2]
We have shown for the first time that thromboxane A2 receptor (TBXA2R) is transcriptionally repressed by BRCA1, providing a potential mechanism by which TBXA2R is up-regulated in Triple Negative Breast Cancer (TNBC)/Basal-Like Breast Cancers (BLBCs)
TBXA2R mRNA expression was measured in a panel of breast cell lines by quantitative real time PCR, showing that TBXA2R expression is elevated in TNBC cell lines relative to nontumorigenic breast, HER2-overexpressing or luminal breast cancer lines (Figure 1E)
Summary
Breast cancer research has been revolutionised over the past decade by the advent of gene expression profiling, which at the molecular level, has subdivided breast cancers into five ‘intrinsic subtypes’ (Luminal A and Luminal B, basal-like, HER2 -enriched and a normal breast-like group) [1, 2]. Triple negative breast cancers (TNBCs), which account for approximately 15% of all breast cancers, are characterised by a lack of ERα, PR expression and HER2 overexpression, and the majority of TNBCs share similar gene expression profiles with Basal-Like Breast Cancers (BLBCs), there is not complete overlap between the two groups [3]. Lacking ERα expression and HER2 receptor amplification/ overexpression, TNBC patients do not benefit from either hormonal or HER2-targeting therapies, and as a result, the risk of relapse is 30–40%, compared to less than 25% in ERα positive patients treated with endocrine therapies [4]. Since there are no targeted treatments available for TNBC, these patients are entirely reliant on chemotherapy and the current standard of care is to treat with a combination of DNA damaging agents, most notably the FEC regimen [5]
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