Document Detail


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.
MedLine Citation:
PMID:  20036328     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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)).
Authors:
Michael C Byrns; Ling Duan; Seon Hwa Lee; Ian A Blair; Trevor M Penning
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Publication Detail:
Type:  Journal Article     Date:  2009-12-28
Journal Detail:
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 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-03-11     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  9015483     Medline TA:  J Steroid Biochem Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  177-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
20-alpha-Dihydroprogesterone / metabolism
3-Hydroxysteroid Dehydrogenases / genetics,  metabolism*
5-alpha-Dihydroprogesterone / metabolism
Androstenedione / metabolism
Androsterone / metabolism
Biocatalysis
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
Female
Gene Expression Regulation, Neoplastic*
Gonadal Steroid Hormones / metabolism*,  pharmacology
Humans
Hydroxyprostaglandin Dehydrogenases / genetics,  metabolism*
Ketosteroids / metabolism
Kinetics
Progesterone / analogs & derivatives,  metabolism
Prostaglandin D2 / analogs & derivatives,  metabolism,  pharmacology
Prostaglandins / metabolism*,  pharmacology
Recombinant Proteins / genetics,  metabolism
Testosterone / metabolism
Transfection
Up-Regulation*
Grant Support
ID/Acronym/Agency:
P30 ES013508/ES/NIEHS NIH HHS; P30 ES013508-04/ES/NIEHS NIH HHS; R01 CA090744/CA/NCI NIH HHS; R01 CA090744-08/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/15-deoxyprostaglandin J2; 0/Gonadal Steroid Hormones; 0/Ketosteroids; 0/Prostaglandins; 0/Recombinant Proteins; 08J2K08A3Y/Dihydrotestosterone; 145-14-2/20-alpha-Dihydroprogesterone; 2DI9HA706A/Estrone; 3XMK78S47O/Testosterone; 409J2J96VR/Androstenedione; 4G7DS2Q64Y/Progesterone; 4TI98Z838E/Estradiol; 5982-99-0/androstane-3,17-dione; 97CGB1M48I/Etiocholanolone; 98G4S1OH0Z/5-alpha-Dihydroprogesterone; B7IN85G1HY/Dinoprost; C24W7J5D5R/Androsterone; EC 1.1.-/3-Hydroxysteroid Dehydrogenases; EC 1.1.1.-/AKR1C3 protein, human; EC 1.1.1.-/Hydroxyprostaglandin Dehydrogenases; RXY07S6CZ2/Prostaglandin D2
Comments/Corrections

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