Loss of Estrogen Inactivation in Colonic Cancer

Abstract

Age and sex differences in the incidence of colonic cancer, together with epidemiological 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 C19 androgens to C18 estrogens) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) [responsible for interconversion of active estradiol (E2) to less potent estrone (E1)] in normal and neoplastic human colon from 24 patients undergoing tumor resection. Aromatase activity was similar in homogenates from normal mucosa, tissue adjacent to tumors, and the tumors themselves. Analysis of 17beta-HSD activity indicated that the predominant activity was oxidative (E2 to E1), and this conversion was significantly lower in colonic tumors [444 (90-1735); median (95% confidence interval) pmol/mg protein x 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 17beta-HSD in normal colon; messenger RNA for 17beta-HSD 4 was significantly lower in tumor tissue [0.75 +/- 0.22 (mean +/- SD) arbitrary 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 17beta-HSD oxidative activity and the rate of cell proliferation. In addition, E1, but not E2, was shown to significantly decrease proliferation when added exogenously to the colonic epithelial cell line, SW620 cells. Colonic mucosa can regulate estrogen hormone action in an intracrine fashion. The loss of estrogen inactivation may be an important mechanism in the pathogenesis of colonic cancer.

O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)

“…The mechanism for the protective effect of hormone replacement is unknown and in vitro studies show contradictory effects of estrogens on the proliferation of colorectal cancer cells [52][53][54]. Exogenous estrogens decrease secondary bile acid production in the colonic epithelium, which reduces chronic irritation of the colonic mucosa [55,56] and may protect against colorectal cancer [57].…”

Identification and localization of estrogen receptor a- and �-positive cells in adult male and female mouse intestine at various estrogen levels

“…This temporal difference could be due to tissue-specific responses to estrogen. In this regard, English et al (1999) reported that 17b-hydroxysteroid dehydrogenase is present in human colon mucosa, indicating that estrogen level in the colon tissues can be locally regulated by the enzyme.…”

Epistasis between the HSD17B4 and TG polymorphisms is associated with premature ovarian failure

“…The dehydrogenase domain is involved in the oxidative inactivation of E 2 , and all three domains are involved in peroxisomal b-oxidation of fatty acids (36,37). Abnormal expression of HSD17B4 has been associated with several cancers (38,39). In addition, mutations in HSD17B4 cause D-bifunctional protein deficiency (which is an autosomal-recessive disorder of peroxisomal fatty acid b-oxidation (40)(41)(42)) and are associated with Perrault syndrome, a feature of which is ovarian dysgenesis (11).…”