|Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer.|
|PMID: 20036328 Owner: NLM Status: MEDLINE|
|Aldo-keto reductase (AKR) 1C3 (type 5 17beta-hydroxysteroid dehydrogenase and prostaglandin F synthase), may stimulate proliferation via steroid hormone and prostaglandin (PG) metabolism in the breast. Purified recombinant AKR1C3 reduces PGD(2) to 9alpha,11beta-PGF(2), Delta(4)-androstenedione to testosterone, progesterone to 20alpha-hydroxyprogesterone, and to a lesser extent, estrone to 17beta-estradiol. We established MCF-7 cells that stably express AKR1C3 (MCF-7-AKR1C3 cells) to model its over-expression in breast cancer. AKR1C3 expression increased steroid conversion by MCF-7 cells, leading to a pro-estrogenic state. Unexpectedly, estrone was reduced fastest by MCF-7-AKR1C3 cells when compared to other substrates at 0.1muM. MCF-7-AKR1C3 cells proliferated three times faster than parental cells in response to estrone and 17beta-estradiol. AKR1C3 therefore represents a potential target for attenuating estrogen receptor alpha induced proliferation. MCF-7-AKR1C3 cells also reduced PGD(2), limiting its dehydration to form PGJ(2) products. The AKR1C3 product was confirmed as 9alpha,11beta-PGF(2) and quantified with a stereospecific stable isotope dilution liquid chromatography-mass spectrometry method. This method will allow the examination of the role of AKR1C3 in endogenous prostaglandin formation in response to inflammatory stimuli. Expression of AKR1C3 reduced the anti-proliferative effects of PGD(2) on MCF-7 cells, suggesting that AKR1C3 limits peroxisome proliferator activated receptor gamma (PPARgamma) signaling by reducing formation of 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)).|
|Michael C Byrns; Ling Duan; Seon Hwa Lee; Ian A Blair; Trevor M Penning|
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|Type: Journal Article Date: 2009-12-28|
|Title: The Journal of steroid biochemistry and molecular biology Volume: 118 ISSN: 1879-1220 ISO Abbreviation: J. Steroid Biochem. Mol. Biol. Publication Date: 2010 Feb|
|Created Date: 2010-02-03 Completed Date: 2010-03-11 Revised Date: 2013-05-29|
Medline Journal Info:
|Nlm Unique ID: 9015483 Medline TA: J Steroid Biochem Mol Biol Country: England|
|Languages: eng Pagination: 177-87 Citation Subset: IM|
|Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, United States.|
|APA/MLA Format Download EndNote Download BibTex|
3-Hydroxysteroid Dehydrogenases / genetics, metabolism*
5-alpha-Dihydroprogesterone / metabolism
Androstenedione / metabolism
Androsterone / metabolism
Breast Neoplasms / enzymology, genetics, metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Dihydrotestosterone / metabolism
Dinoprost / metabolism, pharmacology
Estradiol / metabolism, pharmacology
Estrone / metabolism, pharmacology
Etiocholanolone / analogs & derivatives, metabolism
Gene Expression Regulation, Neoplastic*
Gonadal Steroid Hormones / metabolism*, pharmacology
Hydroxyprostaglandin Dehydrogenases / genetics, metabolism*
Ketosteroids / metabolism
Progesterone / analogs & derivatives, metabolism
Prostaglandin D2 / analogs & derivatives, metabolism, pharmacology
Prostaglandins / metabolism*, pharmacology
Recombinant Proteins / genetics, metabolism
Testosterone / metabolism
|P30 ES013508-04/ES/NIEHS NIH HHS; R01 CA090744-08/CA/NCI NIH HHS; R01 CA090744-10/CA/NCI NIH HHS|
|0/15-deoxyprostaglandin J2; 0/Gonadal Steroid Hormones; 0/Ketosteroids; 0/Prostaglandins; 0/Recombinant Proteins; 145-14-2/20-alpha-Dihydroprogesterone; 41598-07-6/Prostaglandin D2; 50-28-2/Estradiol; 521-18-6/Dihydrotestosterone; 53-16-7/Estrone; 53-41-8/Androsterone; 53-42-9/Etiocholanolone; 551-11-1/Dinoprost; 566-65-4/5-alpha-Dihydroprogesterone; 57-83-0/Progesterone; 58-22-0/Testosterone; 5982-99-0/androstane-3,17-dione; 63-05-8/Androstenedione; EC 1.1.-/3-Hydroxysteroid Dehydrogenases; EC 1.1.1.-/AKR1C3 protein, human; EC 1.1.1.-/Hydroxyprostaglandin Dehydrogenases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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