Estrogen metabolism and malignancy: analysis of the expression and function of 17 beta-hydroxysteroid dehydrogenases in colonic cancer

Age and sex differences in the incidence of gastrointestinal cancers sugges t the involvement of sex steroids. Post-menopausal loss of estrogen in wome n appears to be associated with a lower risk of colonic cancer. and studies in vitro have shown that estradiol (E-2) stimulates the growth of colonic cancer cell lines. Paradoxically more recent epidemiological data have show n that hormone replacement therapy (HRT) is associated with a lower risk of colonic cancer, although this may reflect differences in the composition a nd route of administration of HRT regimes. The precise mechanism by which e strogens influence colonic cancer in vivo remains unclear, although E-2-ind uced growth of colonic cancer cells in vitro appears to be dependent on est rogen receptor (ER) expression. We have previously demonstrated differentia l responses to E-2 in pre-malignant and malignant colonic cancer cell lines , without any apparent difference in ER expression. Analogous to well docum ented studies in breast cancer, we have postulated that local steroid metab olism in the colon may play a key role in modulating the effects of oestrog ens by determining the tissue availability of active E-2. Using biopsy mate rial we have shown that the normal colonic mucosa has a high level of 17 be ta -hydroxysteroid dehydrogenase (17 beta -HSD)-mediated E-2 metabolism Fur thermore, the predominant enzyme activity, inactivation of E-2 to estrone ( E-1), was significantly decreased in paired tumor biopsies. The presence of 17 beta -HSD activity in the colon appears to be due to expression of the type 2 and 4 isozymes of 17 beta -HSD (17 beta -HSD2 acid 4), and expressio n of mRNA for the latter was shown to be significantly decreased in tumours compared to normal mucosa. Further studies have characterised the expressi on of 17 beta -HSD2 and 4 in colonic epithelial cells and in colonic cancer cell lines, and have suggested a link between estrogen metabolism and colo nic cell proliferation. Data reviewed here provide evidence Tor the importa nce of 17 beta -HSD isozymes as attenuators of E-2 bioavailability in the c olon, and emphasise a possible role for 17 beta -HSD2 and 4 in the pathogen esis of colon cancer. (C) 2001 Elsevier Science Ireland Ltd. All rights res erved.