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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: 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.

Authors: Byrns, Michael C; Duan, Ling; Lee, Seon Hwa; Blair, Ian A; Penning, Trevor M

Published In J Steroid Biochem Mol Biol, (2010 Feb 15)

Abstract: 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)).

PubMed ID: 20036328 Exiting the NIEHS site

MeSH Terms: 20-alpha-Dihydroprogesterone/metabolism; 3-Hydroxysteroid Dehydrogenases/genetics; 3-Hydroxysteroid Dehydrogenases/metabolism*; 5-alpha-Dihydroprogesterone/metabolism; Aldo-Keto Reductase Family 1 Member C3; Androstenedione/metabolism; Androsterone/metabolism; Biocatalysis; Breast Neoplasms/enzymology; Breast Neoplasms/genetics; Breast Neoplasms/metabolism*; Cell Line, Tumor; Cell Proliferation/drug effects; Dihydrotestosterone/metabolism; Dinoprost/metabolism; Dinoprost/pharmacology; Estradiol/metabolism; Estradiol/pharmacology; Estrone/metabolism; Estrone/pharmacology; Etiocholanolone/analogs & derivatives; Etiocholanolone/metabolism; Female; Gene Expression Regulation, Neoplastic*; Gonadal Steroid Hormones/metabolism*; Gonadal Steroid Hormones/pharmacology; Humans; Hydroxyprostaglandin Dehydrogenases/genetics; Hydroxyprostaglandin Dehydrogenases/metabolism*; Ketosteroids/metabolism; Kinetics; Progesterone/analogs & derivatives; Progesterone/metabolism; Prostaglandin D2/analogs & derivatives; Prostaglandin D2/metabolism; Prostaglandin D2/pharmacology; Prostaglandins/metabolism*; Prostaglandins/pharmacology; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Testosterone/metabolism; Transfection; Up-Regulation*

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