Abstract Invasive lobular carcinoma (ILC) is the second most common subtype of estrogen receptor (ER)-positive breast cancer. ILC relies, in part, on ER signaling for cell proliferation and tumor growth. Our laboratory is interested in understanding ER transcriptional activity in the context of glucocorticoid receptor (GR), the body’s stress response hormone. Previously, it was shown that ligand-dependent GR occupancy suppresses ER binding at shared enhancer regions of infiltrating ductal carcinoma (IDC) chromatin, and that GR activation inhibited ER-mediated proliferation gene expression (Tonsing-Carter et al., 2019). Similar to IDC, our lab observed that GR-activation of ER+ ILC cells also had an anti-proliferative effect on ER-mediated gene expression (Porter et al., 2023). To elucidate how ER and GR interact on chromatin in ILC models, we performed genome wide chromatin immunoprecipitation followed by sequencing (ChIP-seq) in ER+ ILC cell lines treated with vehicle, estradiol (E2), dexamethasone (Dex), or the combination (E2+Dex). ChIP-seq revealed that GR-driven chromatin remodeling reduces ER mediated proliferation. To measure the effect of liganded GR occupancy at cell cycle gene enhancers, directed ChIP-qPCR was performed at the CCND1 locus, a known ER-regulated gene. We found that activated GR recruitment to the ER-bound CCND1 enhancer element, suppressed CCND1 gene expression, suggesting that GR may inhibit ER-mediated cell cycle progression through direct chromatin interaction. To further understand how GR occupancy on chromatin impacts global gene expression we performed RNA-sequencing in parallel. RNA-seq analysis showed significant down regulation of cell-cycle-related genes supporting a model where GR recruitment to ER-bound chromatin contributes to reduced tumor cell proliferation. Additional genes that encode proteins involved in oxidative phosphorylation, mitochondrial function, and epithelial cell organization were also prominently regulated by GR activation. We hypothesize that GR activation leads to chromatin remodeling resulting in upregulation of gene expression pathways such as oxidative phosphorylation, while downregulating ER-mediated cell cycle progression and proliferation. Several genes including MTCO1P11, ZNF652, MT-CYP, and ITGA10 were upregulated upon treatment with a combination of 10nM estradiol + 100nM Dex and were linked to GR/ER co-regulated regions, suggesting functional relevance. Ongoing studies integrating GR and ER chromatin binding with gene expression data will uncover the hormone-responsive (and potentially modulatable) chromatin landscape that contributes to functional crosstalk between GR and ER. Future in vivo and gene expression studies using highly selective GR modulation (SGRMs) with and without systemic ER antagonism will define the physiological relevance of GR/ER crosstalk in ILC and therapeutic potential of SGRMs. Citation Format: A. Briceno, B. Porter, L. Bennett, S. Conzen. Glucocorticoid receptor activation leads to remodeling of the chromatin landscape in infiltrating lobular carcinoma cells and changes in estrogen receptor-mediated gene expression abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-15.
Briceno et al. (Tue,) studied this question.