Estrogen metabolism and malignancy: analysis of the expression and function of 17beta-hydroxysteroid dehydrogenases in colonic cancer.
Age and sex differences in the incidence of gastrointestinal cancers suggest the involvement of sex steroids. Post-menopausal loss of estrogen in women appears to be associated with a lower risk of colonic cancer, and studies in vitro have shown that estradiol (E2) stimulates the growth of colonic cancer cell lines. Paradoxically more recent epidemiological data have shown that hormone replacement therapy (HRT) is associated with a lower risk of colonic cancer, although this may reflect differences in the composition and route of administration of HRT regimes. The precise mechanism by which estrogens influence colonic cancer in vivo remains unclear, although E2-induced growth of colonic cancer cells in vitro appears to be dependent on estrogen receptor (ER) expression. We have previously demonstrated differential responses to E2 in pre-malignant and malignant colonic cancer cell lines, without any apparent difference in ER expression. Analogous to well documented studies in breast cancer, we have postulated that local steroid metabolism in the colon may play a key role in modulating the effects of oestrogens by determining the tissue availability of active E2. Using biopsy material we have shown that the normal colonic mucosa has a high level of 17beta-hydroxysteroid dehydrogenase (17beta-HSD)-mediated E2 metabolism. Furthermore, the predominant enzyme activity, inactivation of E2 to estrone (E1), was significantly decreased in paired tumor biopsies. The presence of 17beta-HSD activity in the colon appears to be due to expression of the type 2 and 4 isozymes of 17beta-HSD (17beta-HSD2 and 4), and expression of mRNA for the latter was shown to be significantly decreased in tumours compared to normal mucosa. Further studies have characterised the expression of 17beta-HSD2 and 4 in colonic epithelial cells and in colonic cancer cell lines, and have suggested a link between estrogen metabolism and colonic cell proliferation. Data reviewed here provide evidence for the importance of 17beta-HSD isozymes as attenuators of E2 bioavailability in the colon, and emphasise a possible role for 17beta-HSD2 and 4 in the pathogenesis of colon cancer.
English
M A
MA
Division of Medical Sciences, Queen Elizabeth Hospital, The University of Birmingham, Edgbaston, B15 2TH, Birmingham, UK.
Stewart
P M
PM
Hewison
M
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000502:physiology*; D003106:Colon / Q000201:enzymology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D011960:Receptors, Estrogen / Q000502:physiology
D004967:Estrogens; D007527:Isoenzymes; D011960:Receptors, Estrogen; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases