Merel Roest1, Yanis Zekri1, Sebastian Gregoricchio1, Stefan Prekovic2, Wilbert Zwart1
1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2 Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands
Glucocorticoid receptor (GR) functions as a tumor suppressor in hormone receptor–positive breast cancer, which makes it a potential therapeutic target. Although the effects of acute GR activation have been extensively studied, the long-term consequences of sustained GR signaling remain poorly understood. This knowledge gap is clinically significant, as most breast tumors are exposed to long term GR activity. Besides, given GR’s pleiotropic roles across tissues, clarifying the pathways through which it exerts tumor-suppressive effects in breast cancer may enable selective targeting of downstream effectors while avoiding the systemic side effects of broad GR activation.
To elucidate the temporal and epigenetic dynamics of GR signaling, we treated MCF7 cells with dexamethasone for 6 hours, 48 hours, or 7 days, with untreated cells as a control. We profiled genome-wide H3K27ac, a histone mark associated with active enhancers and promoters, using ChIP-seq. This analysis revealed five distinct temporal patterns of GR-mediated epigenetic change, capturing regulatory sites showing early or late activation or repression. Linking these dynamic regions to nearby genes uncovered pathways selectively engaged at each timepoint. Complementary RNA-seq across the same time course enabled us to connect H3K27ac changes to transcriptional outcomes. In addition, integrative analysis with published ChIP-seq datasets from 158 chromatin-associated proteins identified unique transcriptional complex compositions associated with each temporal cluster.
Together, this dataset provides a detailed temporal and epigenetic map of GR signaling in breast cancer, revealing new insights into a clinically relevant but incompletely understood tumor-suppressive pathway, working towards selective targeting of GR-driven mechanisms.