Split Decisions in Hormone Signaling: Distinct Roles for Progesterone Receptor Isoforms in Breast Cancer Biology

The progesterone receptor (PR) is a critical regulator of hormone signaling in breast tissue, with its 2 primary isoforms, PR-A and PR-B, exhibiting distinct and sometimes opposing functions. These isoforms arise from alternative promoter usage within the PGR gene, resulting in structural differences that influence their transcriptional activity, regulatory interactions, and post-translational modifications. This review explores the historical discovery of PR isoforms, their structural and functional differences, and the molecular mechanisms governing their transcriptional regulation. We also discuss their physiological roles in normal mammary gland development and how their dysregulation contributes to breast cancer progression, endocrine resistance, and cancer stem cell expansion. Understanding the distinct roles of PR isoforms in breast cancer biology holds significant implications for developing targeted therapeutic strategies aimed at modulating isoform-specific PR activity in hormone-driven cancers.