title: Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment.
abstract: Recent evidence indicates that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that breast carcinoma and tumorigenic breast cell lines have higher 5alpha-reductase and lower 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO activities and mRNA expression levels than normal tissue and non-tumorigenic cell lines. The 5alpha-reduced progesterone metabolites such as 5alpha-dihydroprogesterone (5alphaP) promote both mitogenic and metastatic activity in breast cell lines in culture, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaHP) have the opposite (anti-cancer-like) effects. The 5alpha-reductase inhibitor dutasteride has been shown to inhibit 5alpha-reduction of testosterone to 5alpha-dihydrotestosterone in prostate tissue, resulting in decreased prostate volume. The aim of this study was to determine if dutasteride is an effective inhibitor of progesterone 5alpha-reduction in human breast cell lines and if such inhibition reduces mammary cell proliferation and detachment. The effect of dutasteride on progesterone metabolizing enzyme activities and mRNA expression were examined in tumorigenic MCF-7 and non-tumorigenic MCF-10A human breast cell lines. Dutasteride (10(-6)M) inhibited progesterone conversion to 5alpha-pregnanes by >95% and increased 4-pregnene production. The results indicated that effects of dutasteride on the progesterone metabolizing enzymes are due to direct inhibition of 5alpha-reductase activity and to altered levels of expression of 5alpha-reductase and HSO mRNAs. Treatment of cells with progesterone without medium change for 72 h resulted in significant conversion to 5alpha-pregnanes and increases in cell proliferation and detachment. The increases in proliferation and detachment were blocked by dutasteride and were reinstated by concomitant treatment with 5alphaP, providing proof-of-principle that the effects were due not to progesterone but to the 5alpha-reduced metabolites. This study provides the first evidence that dutasteride is a potent progesterone 5alpha-reductase inhibitor and that such inhibition may be beneficial in breast cancer.
authors.affiliation: Department of Biology, Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, London, Ont., N6A 5B7 Canada. jwiebe@uwo.ca
authors.forename: J P
authors.initials: JP
authors.lastname: Wiebe
authors.forename: L
authors.initials: L
authors.lastname: Souter
authors.forename: G
authors.initials: G
authors.lastname: Zhang
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids / Q000378:metabolism*; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D015394:Molecular Structure; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011278:Pregnanes / Q000737:chemistry / Q000378:metabolism; D011283:Pregnenes / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004791:Enzyme Inhibitors; D011278:Pregnanes; D011283:Pregnenes; D012333:RNA, Messenger; D011374:Progesterone; D010088:Oxidoreductases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000068538:Dutasteride