Abstract P3-04-18: The impact of circulating androgens on the androgen receptor in aromatase inhibitor resistant breast cancer

Aromatase Inhibitor (AI) therapy is the gold standard first line therapy for post-menopausal breast cancer. Following AI treatment the conversion of circulating androgens into estrone can be diminished by >99%, completely altering the tumour steroid microenvironment. Estrogens have been extensively studied in terms of the role of sex steroids as causative agents of breast cancer but interestingly, a case–control study nested within the European Prospective Investigation into Cancer and Nutrition reported that elevated levels of both serum androgens and estrogens are associated with increased breast cancer risk (E2 RR: 2.28 and androstenedione RR: 1.94). Also clinical studies have reported increases in the serum levels of androstenedione (4AD) in patients that recur on AI therapy. In order to begin to address the role of circulating androgens and the androgen receptor (AR) in AI resistant breast cancer, RNA sequencing was performed on AI resistant (MCF7-aro-LetR) cells cultured with 4AD in the presence of letrozole. Gene expression analysis was performed using the cBioPortal software found that PI3K signalling pathways were upregulated in response to 4AD treatment as well as the upregulation of pathways involved in exocytosis and hormone secretion. We found elevated levels of PI3K and AR in endocrine resistant breast cancer compared to sensitive cell lines and that our AI resistant LetR cells showed significant reduction in cell growth in response to the combined pan class PI3K inhibitor BEZ235 and anti-AR treatment. Clinically, we evaluated the potential role of PI3K signalling in AI resistance a breast cancer patient TMA (n=488) was stained immunohistochemically for phospho-AKT and AR. The protective effect conferred by high AR expression in the total patient population (p=0.02) and tamoxifen treated population (p=0.05) was lost in the AI treated population (p=0.49). For p-AKT staining, patients that were positive for p-AKT significantly associate with the more aggressive luminal B classification yet exhibit an inverse association with luminal A subtype. Kaplan Meier analysis revealed that AR is associated with a more favourable outcome in p-AKT negative patients but that this is lost in the context of elevated p-AKT. Furthermore, interrogation of the breast invasive carcinoma TCGA dataset (n=963) revealed that patients with upregulated AR mRNA and wildtype PI3K exhibited more invasive disease compared with those harbouring a PI3K mutation (p=0.02) (n=56). Further investigations into the AR interacting partners will help elucidate potential mechanisms of action and the role of androgens and AR in facilitating breast cancer tumourigenesis. Citation Format: Creevey L, Ali A, Bleach R, Hill ADK, Young L, McIlroy M. The impact of circulating androgens on the androgen receptor in aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-18.