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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
Open accessAbstract
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)).
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“In MCF-7 cells stably transfected with AKR1C3 it was found that the enzyme converts 0.1 μM estrone to 17β-estradiol faster than it catalyzes either the conversion of Δ4-androstene-3,17-dione to testosterone or the conversion of progesterone to 20α-hydroxy-pregn-4-ene-3-one”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [37]
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The aldo-keto reductases (AKRs): Overview
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Metadata
- Authors
- Byrns, M. C., Duan, L., Lee, S. H., Blair, I. A., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 118
- Issue
- 3
- Pages
- 177-187
- ISSN
- 0960-0760 (ISSN-L)
- PMC
- PMC2819162
- OpenAlex
- W1984703484
- Cited by
- 116
- References
- 45
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 11 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 5 · 2015: 7 · 2014: 14 · 2013: 5 · 2012: 11
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (22590130)
- National Cancer Institute (R01CA090744)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007314)
- National Institute of Environmental Health Sciences (U01ES016004, P30ES013508)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007305)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
- Keywords
- AKR1C3, MCF-7 cells, breast cancer, steroid hormone metabolism, prostaglandin metabolism, prostaglandin F2alpha, estrogen metabolism, estrone, estradiol, cell proliferation, estrogen receptor alpha, PPARγ signaling
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Androstenedione, Androsterone, Breast Neoplasms, 20-alpha-Dihydroprogesterone, Estradiol, Estrone, Etiocholanolone, Female, Humans, Hydroxyprostaglandin Dehydrogenases, Ketosteroids, Kinetics, Progesterone, Prostaglandins, Recombinant Proteins, Gonadal Steroid Hormones, Dihydrotestosterone, Testosterone, Transfection, 3-Hydroxysteroid Dehydrogenases, Prostaglandin D2, Dinoprost, Up-Regulation, Gene Expression Regulation, Neoplastic, 5-alpha-Dihydroprogesterone, Cell Line, Tumor, Cell Proliferation, Biocatalysis
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