Abstract B051: The identification of the Thromboxane A2 receptor as an oncogenic driver in triple-negative breast cancer
Authors: Orr K S. , Buckley N E. , Quinn J E. , James C R. , Blainey J. , Mullan. P. B. 
Published: May 2015

Purpose of Study: To identify and characterise genes involved in driving the oncogenesis of Triple Negative Breast Cancer (TNBC), and assess the possibility of use as potential therapeutic targets.

Triple Negative Breast Cancer (TNBC) is defined by the lack of the Estrogen Receptor α (ERα), Progesterone Receptor (PR) and low expression of the HER2 receptor and represents the breast cancer subtype with the poorest clinical outcomes. The majority of TNBCs are also basal-like breast cancers (BLBCs) which express basal cytokeratins found in the normal basal epithelia of the breast. BRCA1 mutant breast cancers closely resemble the TNBC/BLBC subtypes and BRCA1 expression is downregulated in up to 30% of sporadic invasive BLBCs. Whilst luminal or HER2-positive breast cancers can be targeted by endocrine and Herceptin therapies, respectively, TNBCs have no specific therapy designed against them as they lack targetable receptors. Our aim is to identify genes involved in TNBC pathogenesis which could represent novel therapeutic targets.

We have performed microarray profiling of 16 triple negative breast tumors (8 good and 8 poor response tumors, following treatment with 5-fluorouracil, epirubicin and cyclophosphamide). Elevated levels of the thromboxane A2 receptor gene (TBXA2R) were observed in TNBCs, and siRNA knockdown of TBXA2R consistently showed dramatic growth inhibition in BLBC cell lines but not in ‘normal’ HME-1 basal cells indicating specificity for BLBC. TBXA2R is a G-protein coupled receptor with a well-established role in platelet activation and haemostasis but also regulates diverse cellular processes such as angiogenesis, cell survival and cytoskeletal arrangement. TBXA2R mRNA was higher in both Basal A and B cell lines than other subtypes and basal cell lines were sensitive to knockdowns suggesting that TBXA2R may represent a novel driver of TNBC proliferation. TBXA2R mRNA is upregulated following BRCA1 siRNA in MCF10-A and MCF7 cells and TBXA2R promoter activity is enhanced by knockdown of BRCA1 in T47D cells. We have mapped the minimal BRCA1-responsive region on the proximal TBXA2R promoter and have identified cMyc to be involved in TBXA2R repression. We are currently investigating pathways downstream of TBXA2R to determine the mechanism by which it enhances cell proliferation in TNBC and have shown that TBXA2R may also contribute to migration and invasion of TNBC via signalling through the Rho pathway. We are also currently determining the feasibility of using TBXA2R antagonists or inhibitors of the Rho-associated kinases in the treatment of TNBC.

Conclusions: Our current understanding of the mechanisms underlying the pathogenesis of TNBC is lacking. Here we report a novel gene required for proliferation and migration of poor outcome TNBCs which could provide us with the opportunity to improve current therapy or develop novel, more effective treatments.

Citation Format: K S. Orr, N E. Buckley, J E. Quinn, C R. James, J. Blainey, P. B. Mullan. The identification of the Thromboxane A2 receptor as an oncogenic driver in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B051.