The soy isoflavone daidzein lowers the increased risk of endometrial cancer produced by tamoxifen in rats. Free

B222

Tamoxifen is an established effective chemopreventive agent against estrogen receptor positive breast cancer. Although the long term administration of tamoxifen substantially reduces the risk of breast cancer it significantly increases the risk of endometrial cancer as well as the incidence of benign endometrial pathologies. In a previous study (European J Cancer, 41: 647-654, 2005) we have found that the combination of tamoxifen with daidzein prevented 7,12, dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis in female Spraque-Dawley Rats more effectively than tamoxifen alone. Since daidzein is converted in the gut of the rats to equol and is found in the blood in this form we attributed the effect of daidzein to its metabolite equol. The objective of the present study is to determine if daidzein (or equol) diminishes the risk for endometrial cancer introduced by tamoxifen. Four groups of female rats were fed the basal AIN-76A diets supplemented with: 1) vehicle (control), 2) tamoxifen (0.125 mg/Kg diet), 3) daidzein (140 mg/Kg) diet, or 4) tamoxifen (0.125 mg/Kg diet) plus daidzein (140 mg/Kg diet) combination. Rats were sacrificed at either after 28 days (short term exposure) or 185 days (long-term exposure) and the endometrium removed and processed for immunohistochemical and biochemical evaluations. We determined that the most significant differences were within the glandular cells of the endometrium. In these cells, both short-term and long term exposure to the tamoxifen diet produced increased DNA damage, increased PCNA expression, and reduced PTEN expression. The combined tamoxifen/daidzein diet reversed to a large degree these effects. The daidzein diet alone did not effect the level of DNA damage when compared to the control diet whereas it increased PCNA and reduced PTEN exression. These data demonstrate for the first time that the soy isoflavone daidzein reduces the risk of endometrial cancer in female rats. Furthrmore, it seems that soy products (through daidzein and its end-metabolite equol) may abolish one of the most severe adverse effects of tamoxifen.