title: Nucleophosmin/B23 is a negative regulator of estrogen receptor α expression via AP2γ in endometrial cancer cells.
abstract: Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/B23) suppression can restore the expression of estrogen receptor α (ESR1/ERα) in endometrial cancer cells. Mechanistically, B23 and activator protein-2γ (TFAP2C/AP2γ) form a complex that acts as a transcriptional repressor of ERα. Our results indicate that B23 or AP2γ knockdown can restore ERα levels and activate ERα-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2γ knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. An increased immunohistochemical expression of AP2γ is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2γ may act in combination to suppress ERα expression in endometrial cancer cells. The inhibition of B23 or AP2γ can restore ERα expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.|Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.|Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taiwan.
authors.forename: Angel
authors.initials: A
authors.lastname: Chao
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.|Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Statistics, Clinical Trial Center, Chang Gung Memorial Hospital, Taipei City, Taiwan.
authors.forename: Lan-Yan
authors.initials: LY
authors.lastname: Yang
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taiwan.
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Tsai
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Shih
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.|Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chyong-Huey
authors.initials: CH
authors.lastname: Lai
mesh_terms: D000818:Animals; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D000090243:Nucleophosmin
keywords: activator protein-2γ; endometrial cancer; estrogen receptor α; hormonal therapy; nucleophosmin