Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer.

Endometrial cancer is related to estrogen stimulation not opposed by progesterone. We have examined expression of the pre-receptor regulatory enzymes aromatase, 17beta-hydroxysteroid dehydrogenases (17beta-HSDs), 20alpha-hydroxysteroid dehydrogenases (20alpha-HSDs), sulfatase and sulfotransferase, and estrogen (ERs) and progesterone (PRs) receptors in samples of endometrial cancer and adjacent normal endometrium. No significant gene up-regulation was seen, although aromatase, AKR1C3, a 17beta-HSD and 20alpha-HSD, and AKR1C1, the major 20alpha-HSD, were up-regulated in 50% of samples. Significant down-regulation was seen for 17beta-HSD types 1 and 7, sulfotransferase, ERalpha, ERbeta, PR-AB. Western blotting revealed higher levels of AKR1C3 and PR-B and lower levels of ERalpha in cancerous endometrium, and immunohistochemistry confirmed expression of AKR1C3, PR-B and ERalpha at the cellular level. Up-regulation of aromatase in concert with AKR1C3 can lead to increased levels of estradiol, which acts via ERalpha. Up-regulation of AKR1C1 and AKR1C3 can result in lower levels of the protective progesterone, which acts mainly via PR-B.