Steroid Hormone Transforming Aldo-Keto Reductases and Cancer


Address for correspondence: Trevor M. Penning, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, Pennsylvania, USA 19104-6084. Voice: +215-898-9445; fax: +215-573-2336.


Prostate and breast cancer are hormone-dependent malignancies of the aging male and female and require the local production of androgens and estrogens to stimulate cell proliferation. Aldo-keto reductases (AKR) play key roles in this process. In the prostate, AKR1C3 (type 5 17β-HSD) reduces Δ4-androstene-3,17-dione to yield testosterone while AKR1C2 (type 3 3α-HSD) eliminates 5α-dihydrotestosterone (5α-DHT), and AKR1C1 forms 3β-androstanediol (a ligand for ERβ). In the breast, AKR1C3 forms testosterone, which is converted to 17β-estradiol by aromatase or reduces estrone to 17β-estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF and 11β-PGF, which stimulate the FP receptor and prevent the activation of PPARγ by PGJ2 ligands. This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer.