Abstract PD1-09: Constitutively active estrogen receptor mutants enhance breast cancer pathogenesis by co-opting progesterone receptor activity, which can be countered by Giredestrant
Authors: Liang Jackson , Metcalfe Ciara 
Published: March 2022

ESR1 mutations contribute significantly to resistance against standard-of-care endocrine therapies and are associated with poor outcomes for estrogen receptor-positive (ER+) breast cancer patients. Structural, biochemical and cellular data all support a model in which such mutations trigger estrogen-independent ER activity, consistent with their emergence in patients who have been treated with Aromatase Inhibitors. Engineered cell line models have further suggested that the ESR1 mutations display gain-of-function effects that extend beyond constitutive canonical ER activity by influencing, for example, epithelial to mesenchymal transition and metastatic potential. However, concerns over potential engineering artifacts and limitations of in vitro conditions have challenged interpretation. Importantly, the mechanisms by which ER mutants might broadly impact cell behavior and whether the latest candidate ER therapeutics will inhibit the full spectrum of ESR1 mutant phenotypes are currently unknown. To address these questions, we generated conditional knock-in Esr1-mutant mice, allowing us to study the fundamental properties of the mutations under physiological conditions (equivalent to those experienced by wildtype ESR1) in the mammary gland, as a hormone-sensitive tissue and the origin of breast tumors. We find that ER mutations profoundly re-wire the transcriptional and cellular response of the mammary gland to hormones, including over the normal estrus cycle. In particular, mutant ER cells display hyper-sensitivity to progesterone, which triggers a proliferative program reminiscent of pregnancy (in nulliparous/virgin mice)- a phenotype that is entirely distinct from ESR1 wildtype mammary glands, both under physiological conditions and when stimulated with high levels of exogenous hormones. The ESR1 mutant-specific PR-mediated proliferative program does not reflect elevated Pgr expression but rather correlates with an altered PR cistrome and transcriptome. We found that this PR program also appears important for human tumor biology because progesterone stimulates the growth of ESR1-mutant patient-derived xenograft tumors (PDXs), in contrast to previous work showing progesterone to be generally tumor-suppressive in ESR1 wildtype tumor models. Importantly, Giredestrant (GDC-9545), a latest-generation orally bioavailable ER antagonist and degrader (SERD), counters the PR-mediated proliferative program, both in the mouse mammary model and in human PDXs. Taken together, these data suggest that in addition to promoting estrogen-independence, mutant ER collaborates with PR to drive a pro-tumorigenic proliferative program, perhaps co-opting a relationship between the hormone receptors established to be key for mammary gland development.

Citation Format: Jackson Liang, Ciara Metcalfe. Constitutively active estrogen receptor mutants enhance breast cancer pathogenesis by co-opting progesterone receptor activity, which can be countered by Giredestrant [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-09.