Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local horm one metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the exp ression and regulation of isozymes of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in vitro and in situ. Immunohistochemistry was used to confir m expression of the type 2 and 4 isozymes of 17 beta-HSD (17 beta-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirm ed by Western blot analyses. Abnormal expression of 17 beta-HSD2 and 4 prot eins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines , although the overall pattern of oestrogen metabolism in these cells was s imilar to that seen in primary colonic mucosal tissue. The predominant acti vity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT- 29, which correlated inversely with the rate of proliferation of the cell l ines. Regulatory studies using SW620 cells indicated that the most potent s timulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D-3 (1,25D(3)), whilst oestradiol itself inhibi ted 17 beta-HSD activity. Both oestradiol and 1,25D(3) decreased mRNA for 1 7 beta-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17 beta-HSD2 an d 4 in epithelial cells. Abnormal expression of both isozymes in colonic ca ncer cells and the stimulation of oestrogen inactivation by the antiprolife rative agent 1,25D(3) highlights a possible role for 17 beta-HSD isozymes a s modulators of colonic cell proliferation. (C) 2000 Cancer Research Campai gn.