title: Reductive 17beta-hydroxysteroid dehydrogenases which synthesize estradiol and inactivate dihydrotestosterone constitute major and concerted players in ER+ breast cancer cells.
abstract: The reductive 17β-hydroxysteroid dehydrogenases which catalyze the last step in estrogen activation for estrogen dependent breast cancer cells were studied. Their biological function and the effects of their knockdown for cancer cell proliferation were demonstrated. The multidisciplinary study involves enzyme catalysis, sex-hormone and cell cycle regulation, as well as cell proliferation in breast cancer cells. Reductive 17β-HSD1, -7 and -12 were studied in the main breast cancer epithelial cells MCF-7 and T47D. Modification of estradiol and 5α-dihydrotestosterone concentrations was monitored by ELISA assay while corresponding cell viability measured by MTT assay. Cell cycle was determined by flow cytometry. Dual activity of estradiol activation and 5α-dihydrotestosterone reduction by 17β-HSD1 and -7 was critical for breast cancer cell (T47D and MCF-7) viability. Cell viability was decreased by 35.8% ± 1.6% in T47D cells after simultaneously knocking down 17β-HSD1 and -7. MCF-7 cell viability was decreased by 29.3% ± 4.2% using a combination of siRNAs and inhibitors. By knocking down 17β-HSD7, we have provided the first demonstration of the significant role of this enzyme in the stimulation of breast cancer cell viability as a result of its high activity on androgen reduction with positive feedback on estradiol production. A further decrease in cell viability was not observed with additional knockdown of 17β-HSD12 after 17β-HSD1 and 7. Breast cancer cell cycle progression was impeded to enter the S phase from G0-G1 after knocking down 17β-HSD1 and -7. In summary, this is the first demonstration that the dual activity in estrone activation and 5α-dihydrotestosterone reduction are the functional basis of reductive 17β-HSDs in breast cancer cells. 17β-HSD1 and -7 are principal reductive 17β-HSDs and major players in the viability of estrogen-dependent breast cancer cells. Combined targeting of these enzymes may be potential for molecular therapy of such cancer.
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, CHU de Quebec-Research Center (CHUL) and Laval University, Québec City, Québec G1V4G2, Canada; Key Laboratory for Space Bioscience and Biotechnology, Faculty of Life Sciences, Northwestern Polytechnic University, Xi'an, Shaanxi, China.
authors.forename: Chen-Yan
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Shanghai Engineer and technology Research Center of Reproductive Health Drug and Devices, Shanghai, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Shanghai Engineer and technology Research Center of Reproductive Health Drug and Devices, Shanghai, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, CHU de Quebec-Research Center (CHUL) and Laval University, Québec City, Québec G1V4G2, Canada; Shanghai Engineer and technology Research Center of Reproductive Health Drug and Devices, Shanghai, China. Electronic address: 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; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D013196:Dihydrotestosterone / Q000378:metabolism*; D004958:Estradiol / Q000096:biosynthesis*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D013196:Dihydrotestosterone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human
keywords: Androgen reduction; Breast cancer; Cell viability; Estrogen activation; Reductive 17β-HSDs