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

Michael C. Byrns, Ling Duan, Seon Hwa Lee, Ian A. Blair, Trevor M. Penning

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

Abstract

Aldo-keto reductase (AKR) 1C3 (type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase), may stimulate proliferation via steroid hormone and prostaglandin (PG) metabolism in the breast. Purified recombinant AKR1C3 reduces PGD2 to 9α,11β-PGF2, Δ4-androstenedione to testosterone, progesterone to 20α-hydroxyprogesterone, and to a lesser extent, estrone to 17β-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 0.1 μM. MCF-7-AKR1C3 cells proliferated three times faster than parental cells in response to estrone and 17β-estradiol. AKR1C3 therefore represents a potential target for attenuating estrogen receptor α induced proliferation. MCF-7-AKR1C3 cells also reduced PGD2, limiting its dehydration to form PGJ2 products. The AKR1C3 product was confirmed as 9α,11β-PGF2 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 PGD2 on MCF-7 cells, suggesting that AKR1C3 limits peroxisome proliferator activated receptor γ (PPARγ) signaling by reducing formation of 15-deoxy-Δ12,14-PGJ2 (15dPGJ2).

Original languageEnglish
Pages (from-to)177-187
Number of pages11
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume118
Issue number3
DOIs
Publication statusPublished - 2010 Feb 15
Externally publishedYes

Keywords

  • 17β-Hydroxysteroid dehydrogenase
  • Estrogen receptor
  • Peroxisome proliferator activated receptor γ
  • Prostaglandin D
  • Prostaglandin F synthase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this