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Loss of Estrogen Inactivation in Colonic Cancer

Division of Medical Sciences, The Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Martin Hewison, Department of Medicine, The Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, United Kingdom. E-mail: m.hewison{at}bham.ac.uk

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 17ß-hydroxysteroid dehydrogenase (17ß-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 17ß-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·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 17ß-HSD in normal colon; messenger RNA for 17ß-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 17ß-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.

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