Loss of estrogen inactivation in colonic cancer

Age and sex differences in the incidence of colonic cancer, together with e pidemiological data on patients taking hormone replacement therapy, suggest the involvement of estrogens. Analogous to the role of aromatase in breast cancer, we postulated that steroid metabolism within the colon itself may be a crucial mechanism in regulating tissue exposure to estrogens. We have characterized expression of aromatase (responsible for converting C-19 andr ogens to C-18 estrogens) and 17 beta-hydroxysteroid dehydrogenase (17 beta- HSD) [responsible for interconversion of active estradiol (E-2) to less pot ent estrone (E-1)] in normal and neoplastic human colon from 24 patients un dergoing tumor resection. Aromatase activity was similar in homogenates fro m normal mucosa, tissue adjacent to tumors, and the tumors themselves. Anal ysis of 17 beta-HSD activity indicated that the predominant activity was ox idative (E-2 to E-1), and this conversion was significantly lower in coloni c tumors [444 (90-1735); median (95% confidence interval) pmol/mg protein-h ], compared with normal mucosa [1709 (415-13828), P < 0.001]. Northern blot analyses indicated expression of messenger RNAs (mRNAs) for the type 2 and 4 isozymes of 17 beta-HSD in normal colon; messenger RNA for 17 beta-HSD 4 was significantly lower in tumor tissue [0.75 +/- 0.22 (mean +/- SD) arbit rary U vs. 0.43 +/- 0.17, P < 0.01]. Studies in vitro, using three colonic cancer cell lines, indicated that there was an inverse correlation between 17 beta-HSD oxidative activity and the rate of cell proliferation. In addit ion, E-1, but not E-2, was shown to significantly decrease proliferation wh en added exogenously to the colonic epithelial cell line. SW620 cells. Colo nic mucosa can regulate estrogen hormone action in an intracrine fashion. T he loss of estrogen inactivation may be an important mechanism in the patho genesis of colonic cancer.