Steroid hormone transforming aldo-keto reductases and cancer.

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 17beta-HSD) reduces Delta(4)-androstene-3,17-dione to yield testosterone while AKR1C2 (type 3 3alpha-HSD) eliminates 5alpha-dihydrotestosterone (5alpha-DHT), and AKR1C1 forms 3beta-androstanediol (a ligand for ERbeta). In the breast, AKR1C3 forms testosterone, which is converted to 17beta-estradiol by aromatase or reduces estrone to 17beta-estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF(2alpha) and 11beta-PGF(2alpha), which stimulate the FP receptor and prevent the activation of PPARgamma by PGJ(2) ligands. This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer.