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Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

ABSTRACT: Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but resistance to hormonal treatment is common. The pan-hormonal action of steroid hormonal receptors including Estrogen Receptor alpha (ERα), Androgen Receptor (AR), Progesterone Receptor (PR) and Glucocorticoid Receptor (GR) in this understudied tumor type remains wholly unexamined. This pioneering study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to patient outcome. Using chromatin immunoprecipitation coupled with massively-parallel sequencing (ChIP-seq), we characterized human MBCs for epigenetic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR and GR, along with pioneer factor FOXA1 and enhancer-enriched histone mark H3K4me1. These data were integrated with transcriptomics analyses to reveal gender-selective and genomic location-specific hormone receptor action, that are associated with survival in MBC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104399 | GEO | 2018/02/02

REPOSITORIES: GEO

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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.

Project description:Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets. Comparison of reference samples against treatment

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Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

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