Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico-designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER-positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer-driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER-positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER-positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment. imageActivity of the Glucocorticoid Receptor across various cancer types is inversely related to proliferative signatures. In breast cancer, heightened Glucocorticoid Receptor (GR) activity correlates with improved patient outcomes and is linked to the regulation of the tumor suppressor ZBTB16.GR activity correlates negatively with proliferative capacity across various cancer types.In breast cancer, a distinct link is observed between GR activity status and luminal subtype identity, influencing patient outcomes.Hormone-regulated gene ZBTB16, is pivotal in controlling the growth of ER-positive breast cancer.Significant epigenetic changes accompanied GR activation, including diminished histone acetylation near cancer-driving genes.The insights gained suggest potential novel therapeutic candidates and advanced patient prognostication methods in breast cancer treatment. Activity of the glucocorticoid receptor across various cancer types is inversely related to proliferative signatures. In breast cancer, heightened glucocorticoid receptor (GR) activity correlates with improved patient outcomes and is linked to the regulation of the tumor suppressor ZBTB16.image