Abstract GS2-03: The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer

Abstract

Abstract The Androgen receptor (AR) is expressed in up to 90% of primary ER-positive (ER+) breast cancer and high expression of AR is an independent prognostic factor associated with good outcome. Its role in the context of ER+ breast cancer is very controversial and has constrained clinical implementation of new drugs that influence AR activity for treatment of women with this disease, resulting in concurrent clinical trials of opposite AR agonist and antagonist strategies. Herein, using RNA-seq and Chip-seq approaches, we demonstrate that therapeutic activation of AR for treatment of breast cancer leverages a natural regulatory mechanism that inhibits estrogen-stimulated proliferation and induction of cell cycle genes in patient-derived explants (PDE) of primary ER+ breast cancers, and in contemporary in vivo patient-derived xenograft (PDX) and cell line xenograft models of ER+ breast cancer resistant to standard-of-care ER targeting agents, including those harbouring genomic aberrations of ESR1. AR-mediated growth inhibition mechanistically involved loss of ER or co-activator p300 recruitment to chromatin at key cell cycle genes, leading to transcriptional down-regulation. A signature of AR activity derived from the xenograft models positively predicted disease survival in multiple large clinical cohorts of ER+ breast cancer, outperforming other breast cancer-specific prognostic signatures. Finally, the combination strategy of a new class of non virilising Selective Androgen Receptor Modulator (SARM) in combination with CDK4/6 inhibitors demonstrated additive effects in our preclinical models. Collectively, these findings provide compelling evidence that AR has a tumour suppressor role in ER+ breast cancer and advocate an AR agonist strategy for treatment, even in the context of therapy-resistant, ESR1 mutant disease, and should dispel widespread confusion over the role of AR in ER-driven breast cancer, an issue that currently hinders progress in leveraging modern AR-targeted therapies, including available SARMs that lack the undesirable side-effects of androgens, for clinical benefit. Citation Format: Elgene Lim, Theresa A Hickey, Luke A Selth, Kee Ming Chia, Heloisa H Milioli, Daniel Roden, Geraldine Laven-Law, Shalini Jindal, Mun Hui, Esmaeil Ebrahimie, Stephen N Birrell, Suzan Stelloo, C. Elizabeth Caldon, Jessica Finlay-Schultz, Tarek M Abdel-Fatah, Ian O Ellis, Willbert Zwart, Carlo Palmieri, Carol A Sartorius, Alex Swarbrick, Jason S Carroll, Wayne D Tilley. The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-03.