title: Research resource: enhanced genome-wide occupancy of estrogen receptor α by the cochaperone p23 in breast cancer cells.
abstract: p23 is a chaperone with multiple heat shock protein 90 dependent and independent cellular functions, including stabilizing unliganded steroid receptors and modulating receptor-DNA dynamics. p23 protein is also up-regulated in several cancers, notably breast cancer. We previously demonstrated that higher expression of p23 in the estrogen-dependent breast cancer line MCF-7 (MCF-7+p23) selectively increased estrogen receptor (ER) target gene transcription and ER recruitment to regulatory elements, promoted cell invasion, and predicted a poor prognosis in breast cancer patients. To probe the impact of p23 on ER binding throughout the human genome, we compared ER occupancy in MCF-7+p23 cells relative to MCF-7-control cells by using chromatin immunoprecipitation followed by ultrahigh-throughput DNA sequencing in the absence and presence of 17β-estradiol (E2) treatment. We found that increased expression of p23 resulted in a 230% increase in the number of E2-induced ER-binding sites throughout the genome compared with control cells and also increased ER binding under basal conditions. Motif analysis indicated that ER binds to a similar DNA sequence regardless of p23 status. We also observed that ER tends to bind closer to genes that were induced, rather than repressed by either E2 treatment or p23 overexpression. Interestingly, we also found that the increased invasion of MCF-7+p23 cells was not only p23 dependent but also ER dependent. Thus, a small increase in the expression of p23 amplifies ER-binding genome wide and, in combination with ER, elicits an invasive phenotype. This makes p23 an attractive target for combating tumor cell metastasis in breast cancer patients.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Simpson
authors.forename: Jason
authors.initials: J
authors.lastname: Gertz
authors.forename: Keren
authors.initials: K
authors.lastname: Imberg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018832:Molecular Chaperones; D010750:Phosphoproteins; D004958:Estradiol; D004247:DNA; C490849:PTGES3 protein, human; D000071876:Prostaglandin-E Synthases
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