Abstract IA20: Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome

Abstract

Abstract Estrogen receptor (ER) occupies many thousands of regions throughout the human genome. Interestingly, the functional implications of most of these chromatin-bound sites remain completely elusive. In two interconnected stories, I will highlight distinct genomic features that differentiate ER genomic action between patient subgroups, but also between individual patients. Between patients subgroups, we identify clearlty distinct profiles of ER action, dictated by Glucocorticoid Receptor (GR) activity. We show that the activity status of GR determines luminal subtype identity and is associated with patient outcome. GR suppresses tumor growth by engaging with ER, leading to redistribution of ER on the chromatin and upregulation of the tumor suppressor gene ZBTB16. We importantly demonstrate that clinically available epigenetic inhibitors, which mimic GR-induced gene repression, can effectively suppress the growth of highly aggressive ER-positive breast cancer cells displaying absence of GR activity. In a second study, I will elaborate on the massive inter-patient heterogeneity of ER chromatin interactions, with direct biological and clinical implications. While the vast majorty of ER/DNA binding events are poorly conserved between patients, common ER sites are most-transcriptionally active and enriched for breast cancer risk SNPs. With that, we present a natural hierarchy of ER genomic action, identifying those regiosn with the most-direct impact on breast cancer development and progresion. Citation Format: Wilbert Zwart. Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA20.