title: Progesterone receptor A stability is mediated by glycogen synthase kinase-3β in the Brca1-deficient mammary gland.
abstract: Germ line mutations of the BRCA1 gene increase the risk of breast and ovarian cancer, but the basis of this tissue-specific tumor predisposition is not fully understood. Previously, we reported that the progesterone receptors are stabilized in Brca1-deficient mammary epithelial cells, and treating with anti-progesterone delays mammary tumorigenesis in Brca1/p53 conditional knock-out mice, suggesting that the progesterone has a critical role in breast carcinogenesis. To further explore how the stability of progesterone receptor is modulated, here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. Expression of PR-A(S390A) mutant in the human breast epithelial cells, MCF-10A, results in enhanced proliferation and formation of aberrant acini structure in the three-dimensional culture. Consistently, reduction of phosphorylation of serine 390 of PR-A and GSK-3β activity is observed in the Brca1-deficient mammary gland. Taken together, these results provide important aspects of tissue specificity of BRCA1-mediated suppression of breast carcinogenesis.
authors.affiliation: From the Department of Biological Chemistry, University of California Irvine, Irvine, California 92697.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Capital Medical University, Beijing 100069, China, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: the Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: From the Department of Biological Chemistry, University of California Irvine, Irvine, California 92697.
authors.forename: Sou-Ying
authors.initials: SY
authors.lastname: Lee
authors.affiliation: From the Department of Biological Chemistry, University of California Irvine, Irvine, California 92697.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: From the Department of Biological Chemistry, University of California Irvine, Irvine, California 92697,. Electronic address: elee@uci.edu.
authors.forename: Eva Y-H P
authors.initials: EYP
authors.lastname: Lee
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010766:Phosphorylation / Q000502:physiology; D055550:Protein Stability; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: BRCA1; Bard1; Breast Cancer; GSK-3; Mammary Gland; PR-A; Phosphorylation; Protein Degradation; Ubiquitination