title: Synergistic control of sex hormones by 17β-HSD type 7: a novel target for estrogen-dependent breast cancer.
abstract: 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer. Recent confirmation of the role of dyhydroxytestosterone (DHT) in counteracting estrogen-induced cell growth prompted us to study the reductive 17β-HSD type 7 (17β-HSD7), which activates estrone while markedly inactivating DHT. The role of DHT in breast cancer cell proliferation is demonstrated by its independent suppression of cell growth in the presence of a physiological concentration of estradiol (E2). Moreover, an integral analysis of a large number of clinical samples in Oncomine datasets demonstrated the overexpression of 17β-HSD7 in breast carcinoma. Inhibition of 17β-HSD7 in breast cancer cells resulted in a lower level of E2 and a higher level of DHT, successively induced regulation of cyclinD1, p21, Bcl-2, and Bik, consequently arrested cell cycle in the G(0)/G(1) phase, and triggered apoptosis and auto-downregulation feedback of the enzyme. Such inhibition led to significant shrinkage of xenograft tumors with decreased cancer cell density and reduced 17β-HSD7 expression. Decreased plasma E2 and elevated plasma DHT levels were also found. Thus, the dual functional 17β-HSD7 is proposed as a novel target for estrogen-dependent breast cancer by regulating the balance of E2 and DHT. This demonstrates a conceptual advance on the general belief that the major role of this enzyme is in cholesterol metabolism.
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gérard
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Thériault
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Doillon
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada sxlin@crchul.ulaval.ca.
authors.forename: Sheng-Xiang
authors.initials: SX
authors.lastname: Lin
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D013196:Dihydrotestosterone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D004960:Estradiol Dehydrogenases / Q000737:chemistry; D004967:Estrogens / Q000097:blood / Q000378:metabolism*; D004970:Estrone / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D064251:Multifunctional Enzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016192:Resting Phase, Cell Cycle
chemical_list: D000728:Androgens; D051017:Apoptosis Regulatory Proteins; C000595707:BCL2 protein, human; C096820:BIK protein, human; C530104:CCND1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004967:Estrogens; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D064251:Multifunctional Enzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D013196:Dihydrotestosterone; D019938:Cyclin D1; D004970:Estrone; D004958:Estradiol; D002784:Cholesterol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human
keywords: 17β-hydroxysteroid dehydrogenase type 7; breast cancer; steroid enzyme inhibition; xenograft tumor