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.
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)).
Byrns
Michael C
MC
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.
Duan
Ling
L
Lee
Seon Hwa
SH
Blair
Ian A
IA
Penning
Trevor M
TM
D004092:20-alpha-Dihydroprogesterone / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D043582:5-alpha-Dihydroprogesterone / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000735:Androstenedione / Q000378:metabolism; D000738:Androsterone / Q000378:metabolism; D055162:Biocatalysis; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004970:Estrone / Q000378:metabolism / Q000494:pharmacology; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D012739:Gonadal Steroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007664:Ketosteroids / Q000378:metabolism; D007700:Kinetics; D011374:Progesterone / Q000031:analogs & derivatives / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
C477819:15-deoxyprostaglandin J2; D012739:Gonadal Steroid Hormones; D007664:Ketosteroids; D011453:Prostaglandins; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D004092:20-alpha-Dihydroprogesterone; D004970:Estrone; D013739:Testosterone; D000735:Androstenedione; D011374:Progesterone; D004958:Estradiol; C006576:androstane-3,17-dione; D005043:Etiocholanolone; D043582:5-alpha-Dihydroprogesterone; D015237:Dinoprost; D000738:Androsterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D015230:Prostaglandin D2