Abstract 941: Targeting androgen receptor in estrogen receptor-negative breast cancer

Abstract

Abstract Estrogen receptor (ER)-negative breast cancers account for 25-30% of all breast cancer cases and generally have a poor prognosis and little benefit from current endocrine therapy. Androgen receptor (AR) is expressed in 60-70% of human breast tumors independent of the ER status. Interestingly, while androgens inhibit the growth of ER+/AR+ breast cancer cells, they stimulate the growth of those that are ER-/AR+. However, the mechanism by which androgens and AR function to regulate breast cancer growth remains largely unknown. Analysis of gene expression microarray datasets from human breast tumors reveals enriched expression of AR in the ER- breast tumors that over-express HER2. Genome-wide analysis of the AR binding sites and androgen-regulated gene expression profiles in ER-/HER2+ breast cancer cells identified that AR mediates activation of oncogenic Wnt and HER2 signaling pathways through direct transcriptional up-regulation of WNT7B and HER3 in an androgen-dependent manner. Importantly, we demonstrate that FOXA1 and beta-catenin act as AR coactivators in inducing HER3, leading to the enforced HER2/HER3 signaling. Pharmacological inhibition of AR, Wnt or HER2 pathways impairs HER3 activation and androgen-stimulated tumor cell growth. While HER3 is receiving increased attention as a therapeutic target in HER2+ breast cancer, our study suggests that AR regulation may be yet another way to target HER3 in ER-/HER2+ tumors. Collectively, these findings not only highlight a previously unappreciated role of AR in breast cancer, but also reveals the mechanistic basis for targeting AR as a novel therapeutic opportunity for patients with invasive ER-/HER2+ breast tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 941. doi:10.1158/1538-7445.AM2011-941