Abstract BS1-1: PR

Abstract

Abstract Much debate exists surrounding how progesterone receptor (PR) expression and activation by native progesterone affects hormone receptor (HR)-positive breast cancer cells. While its expression is conserved in the majority of HR+ breast cancers, studies have failed to identify a clear link between progesterone signaling and breast cancer proliferation, in contrast to what has been shown for ER signaling. Clinically, many studies have utilized PR expression as an indicator of ER signaling, with associations between PR expression demonstrating greater responsiveness to anti-estrogen therapies and outcomes. However, convincing clinical trial data have shown that women taking progestin (synthetic progesterone)-containing hormone replacement therapy (HRT) have a significantly increased risk of developing breast cancer. Likewise, other clinical studies have demonstrated that progestins contribute to the development of more invasive breast cancers and increase mortality. These clinical findings are supported by a variety of pre-clinical studies using animal models, which collectively suggest that PR signaling enhances the development of invasive breast cancer. Finally, our studies and those of others suggest that PR has a specific transcriptional impact that is distinct from ER signaling. Collectively, these studies have demonstrated a key role for PR in the progression and outcome of HR+ breast cancer, which is distinct from estrogen-mediated proliferation signaling. We believe the lack of clinically available PR-targeted therapies in breast cancer is due to a lack of knowledge about exactly how PR contributes to breast cancer progression, as studies have failed to define a conclusive role for PR signaling in tumor growth. However, our recent studies have unexpectedly revealed a significant immune modulatory role for PR. Specifically, our results have demonstrated a clear role for PR in suppressing local anti-tumor immunity, which may explain reduced T-cell infiltrates and responsiveness to immune checkpoint inhibition observed in HR+ breast cancer. This presentation will discuss the current controversial data regarding PR and progesterone in promoting breast cancer proliferation, as well as highlight new data suggesting that PR/progesterone promote immune shielding for developing breast cancers. Citation Format: C Hagan. PR [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 BS1-1.