Endocrine Abstracts

Estrogen receptor alpha (ER) and progesterone receptor (PR) are widely used predictive and prognostic biomarkers in breast cancer. ER is also a well-established therapeutic target. A major unresolved clinical issue is the development of therapy resistance, especially to ER-targeted therapies. We, and others, have observed somatic ESR1 mutations in up to 40% of metastatic tumors obtained from women who have acquired resistance to endocrine therapies. The two most common mutations are Y537S and D538G, both of which stabilize and/or facilitate the formation of an active AF-2 conformation in the ER LBD. A combination of structural, biophysical, cell and animal studies have helped define the underlying molecular mechanisms that account for AI/SERM/SERD resistance related to ESR1 mutations, which has contributed to the development of novel SERMs and/or SERDs with potential improved clinical utility.

The clinical value of PR remains controversial and the role of PR is poorly understood. We have recently observed that PR reprograms and modulates estrogen signaling. Importantly, PR functions as a genomic ER agonist, while acting as a phenotypic antagonist in ER+/PR+ breast cancer models. Animal studies of ER+/PR+T47D human breast tumor xenografts demonstrate that combined treatment with tamoxifen (tam) and certain selective PR modulators (SPRMs) promote tumor regression compared to either treatment alone or to tam plus a progestin. Our results indicate that PR is an essential modulator of ER action and that appropriate co-targeting of ER and PR should be evaluated clinically. It is likely that other steroid receptors (AR, GR, MR) will also become viable co-targets in breast cancers that express these proteins.

DOI: 10.1530/endoabs.54.PL1