Selective oestrogen receptor modulators : mechanisms of action in the reproductive tract

The increased incidence of endometrial cancers in women treated with tamoxifen, an adjuvant treatment for breast cancer, has led to the search for more tissue selective oestrogen agonists. The potential of the oestrogen receptor to regulate the response to oestrogen, tamoxifen and related compounds in the uterus has been investigated. The control of oestrogen receptor degradation was investigated in Ishikawa (endometrial) and MCF-7 (breast) cell lines. Results show that proteasome-mediated oestrogen receptor alpha and oestrogen receptor beta degradation was ligand dependent. The effects of selective oestrogen receptor modulators on the expression of oestrogen receptor alpha or oestrogen receptor beta were investigated in the uterus of ovariectomised Wistar (Han) rats and CD-1 mice using in situ hybridisation and immunohistochemistry. Results showed that both mRNA and protein were localised in the epithelial cells of the lumen and glands for both species. Treatment with oestradiol and tamoxifen caused an increase in expression of oestrogen receptor alpha and oestrogen receptor beta mRNA and protein throughout many cell types, compared to ovariectomised controls. The increase in oestrogen receptor expression, in combination with uterotrophic effects, suggests a role in cell proliferation. To further investigate the mechanisms of endometrial tumours, a neonate mouse model was used. It was shown for the first time that oral dosing of neonate CD-1 mice on days 2 to 5 after birth with tamoxifen or toremifene gave rise to adenomyosis by 3 months of age. An investigation into the accompanying changes of gene expression, by cDNA microarray analysis suggested nerve growth fact alpha, insulin-like growth factor 2 and preadipocyte factor 1 as candidate genes associated with the development of this condition.