Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Targeting the androgen receptor in estrogen receptor-driven breast cancer (#110)

Theresa E Hickey 1 , Luke A Selth 1 , Kee Ming Chia 2 , Heloisa Helena Milioli 2 , Daniel Roden 3 , Esmaeil Ebrahimie 1 , Suzan Stelloo 4 , Mun Hui 3 , Wilbert Zwart 4 , Carlo Palmieri 5 6 , Jessica Findlay-schultz 7 , Carol Sartorius 7 , Alex Swarbrick 3 , Elgene Lim 2 , Jason Carroll 8 , Wayne D Tilley 1
  1. Dame Roma Mitchell Cancer Research Laboratories, Dept. of Medicine, University of Adelaide, Adelaide, South Australia, Australia
  2. Connie Johnson Breast Cancer Research Group, Garvan Institute of Medical Research, Sydney, New South Wales , Australia
  3. Tumour Progression Group, Garvan Institute of Medical Research, Sydney, New South Wales , Australia
  4. Hormone Associated Cancer Group, Netherlands Cancer Institute, Amsterdam, Netherlands
  5. Institute of Translational Medicine, University of Liverpool, , Liverpool, UK
  6. Department of Medical Oncology, Clatterbridge Cancer Centre, NHS Foundation Trust, Wirral, UK
  7. Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora , CO, USA
  8. Nuclear Transcription Factor Laboratory, Cancer Research UK-Cambridge Institute, Cambridge, UK

The estrogen receptor alpha (ER) stimulates normal breast development but abnormal ER activity drives the majority of breast cancers. In contrast, the androgen receptor (AR) inhibits breast development and may restrain ER-mediated breast carcinogenesis. To investigate the genomic mechanisms involved, we interrogated ER activation alone or ER and AR activation in contemporary ex vivo and in vivo patient-derived models of normal and malignant breast tissue and breast cancer cell lines that endogenously express ER and AR. Estrogen treatment induced a proliferative transcriptome in patient-derived explants (PDEs) of normal and malignant breast tissues cultured ex vivo while co-treatment with androgen induced an anti-proliferative, anti-estrogenic transcriptome. The opposing effects of estrogen and androgen hormones on proliferative indices were also observed in ZR75-1 xenograft and patient-derived xenograft (PDX) models of ER-driven breast cancer. In these experiments, the action of natural androgen was mimicked by treatment with a clinically relevant selective AR modulator (SARM).  Importantly, androgen or SARM treatment also inhibited in vivo growth of cell line xenograft and ER-positive PDX models resistant to standard-of-care anti-estrogenic agents. ChIP-seq experiments revealed that activated AR reduced (4 hr in vitro; 5 days in vivo) estrogen-stimulated ER binding to chromatin, which curtailed ER-mediated transcription and resulted in long-term inhibition of tumour growth. Transcriptional profiling of androgen- or SARM-treated tumours revealed AR-associated gene signatures that were enriched in the least aggressive subtype of breast cancer (Luminal A) and were predictive of better disease outcomes. Altogether, our work suggests that AR-mediated genomic activity inhibits growth of normal breast tissues and can be induced to inhibit ER-driven malignant breast tissues, including those that are resistant to drugs currently used to treat this subtype of disease.  The data supports the use of AR stimulating SARMs as a therapeutic means of preventing or treating ER-driven breast cancer.