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Breast cancer identity is determined by glucocorticoid receptor activity status

ABSTRACT: Glucocorticoid receptor (GR) is a ligand-inducible transcription factor with an intricate role in cancer biology. Using an in silico designed GR activity signature we show that GR is a tumor suppressor across diverse primary cancers. In breast cancer, GR activity status determines luminal identity, and importantly, relates to patients’ outcomes. We illustrate that GR suppresses tumor growth, mediated through its engagement with the estrogen receptor-α (ER). This steroid hormone receptor cross-talk leads to redistribution of ERα on chromatin, ultimately leading to expression of ZBTB16 gene. We define ZBTB16 as a transcriptional repressor and a tumor suppressor in ER-positive breast cancer. Importantly, highly aggressive ER-positive breast cancer cells displaying absence of GR activity can be eradicated if GR-induced gene repression is mimicked by inhibitors of the epigenetic pathway. In line with this, epigenetic regulators are highly expressed upon GR activity loss, leading to vulnerability of aggressive breast cancer cells to clinically available epigenetic inhibitors. Our findings indicate that GR functions as a tumor suppressor by repositioning ER to specific sites on chromatin, modulating targetable pathways, which has important implications for patients’ prognosis and therapeutic interventions.

INSTRUMENT(S): Orbitrap Fusion, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast

DISEASE(S): Breast Cancer

SUBMITTER: Liesbeth Hoekman

LAB HEAD: Maarten Altelaar

PROVIDER: PXD039209 | Pride | 2023-10-02

REPOSITORIES: Pride

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			Action	DRS
	20210626_Fusion_Project_501_Zwart_Stefan_RIME_wz_951.raw	Raw
	20210626_Fusion_Project_501_Zwart_Stefan_RIME_wz_952.raw	Raw
	20210626_Fusion_Project_501_Zwart_Stefan_RIME_wz_953.raw	Raw
	20210626_Fusion_Project_501_Zwart_Stefan_RIME_wz_954.raw	Raw
	20210626_Fusion_Project_501_Zwart_Stefan_RIME_wz_955.raw	Raw

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Project description:Estrogen receptor (ER) positive breast cancers exist in a complex environment of steroid hormones and their cognate receptors. Receptors for estrogens, progestogens (PR), androgens (AR), glucocorticoids (GR) and mineralocorticoids (MR) are variably expressed in these hormone- sensitive breast cancers. Clinical translation of crosstalk among these receptors has been limited by an incomplete understanding of ER reprogramming by PR, GR, AR and MR (NR3C receptors). This study reports that each of the NR3C receptors reprograms ER chromatin binding to sites enriched for NR3C binding motifs and that hormonal co-treatment increases the likelihood of ER binding to estrogen response elements. A major overlap is observed among ER conserved sites, but not among ER sites that are lost or gained due to reprogramming by each of the NR3C receptors. This stability of ER genomic binding is reflected in the resulting transcriptomes, as there is significant overlap among genes whose expression is unaltered in response to joint hormonal interventions but not among genes whose expression is enhanced or opposed by an individual NR3C receptor. The addition of NR3C ligands can enhance or oppose estrogen-mediated induction and repression of gene transcription, resulting in net agonism or antagonism of ER-mediated actions at gene loci and of cellular pathways of interest. In addition to differential modulation of chromatin binding, differences in cofactor associations for ER, PR and GR likely contribute to the divergent functions of these receptors in breast cancer. Among the NR3C receptors, MR activation differentially reprograms ER chromatin binding and, in contrast to ligands for PR, GR or AR, the MR ligand aldosterone does not inhibit estrogen-induced cell proliferation or potentiate the anti-proliferative effect of tamoxifen in ER+ MCF7 cells. PR, GR, AR and MR may be functionally relevant in ER+ breast cancer because higher expression of these NR3C receptors; or genes whose estrogen-regulated expression is altered by each of these receptors is significantly associated with better overall and relapse-free survival. In summary, this study highlights the diverse yet overlapping activities of NR3C receptors in reprogramming ER signaling.

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Breast cancer identity is determined by glucocorticoid receptor activity status

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