Ligand-activated AR promotes the survival of endocrine therapy-responsive ER+ breast cancer

Giredestrant, a next-generation oral selective ERalpha degrader (SERD), is a potent and full antagonist that recently demonstrated statistically significant and clinically meaningful improvement in progression free survival (PFS) in the phase III evERA Breast Cancer trial (NCT05306340). Given its potent ER antagonism, giredestrant is currently under evaluation in multiple clinical studies, including those involving premenopausal participants with an intact hypothalamus-pituitary-ovary (HPO) axis, both with and without gonadotropin-releasing hormone (GnRH) agonists. To anticipate potential mechanisms of tumor cell survival and resistance, we sought to investigate the biology of giredestrant response in tumor-bearing mice with an intact HPO axis, using the intraductal xenograft model- a physiologically relevant system for ER+ breast cancer that supports tumor growth without exogenous estrogen. We established and characterized multiple ER+ breast cancer cell lines and patient-derived intraductal xenografts with distinct growth and metastatic profiles. Giredestrant treatment significantly suppressed tumor proliferation and reduced invasive and metastatic burden. Transcriptomic and chromatin profiling of giredestrant-treated tumors revealed a marked decrease in gene sets and chromatin sites associated with ER signaling and proliferation, as anticipated. Unexpectedly, giredestrant treatment also consistently led to the activation of androgen receptor (AR) signaling, which was accompanied by increased AR motif accessibility and chromatin occupancy. We find that systemic ER inhibition engages the HPO axis, resulting in increased ovarian production of testosterone, and thus driving ligand-dependent AR activation in tumor cells. Dual inhibition of ER and AR demonstrated enhanced anti-proliferative effects compared to ER antagonism alone. Transcriptomic data suggest that this is mediated by the suppression of proliferation-associated programs, potentially through PI3K/mTOR pathway inhibition. By leveraging the novel mouse intraductal model, we identified dual ER and AR blockade, as well as ER-PI3K/mTOR pathway co-targeting, as promising therapeutic strategies to improve outcomes for premenopausal women with ER+ breast cancer, particularly those not receiving GnRH agonists.