Ethanol-Extracted Cameroonian Propolis Counteracts Tamoxifen-Induced Endometrial Hyperplasia by Modulating Apoptosis and Proliferation-Regulating Proteins in the Ovaries of Intact Wistar Rats

Abstract

Tamoxifen is the most common adjuvant that has been widely used in the treatment of positive estrogen receptor (ER+) breast cancer for over 20 years. However, long term exposure to tamoxifen doubles the risk of endometrial cancer. The association of tamoxifen with antiproliferative substances could abrogate its side effects on the endometrium. Recently, we demonstrated that ethanol-extracted Cameroonian propolis (EECP) has chemopreventive effects on ER+ breast cancer in rats. This study evaluated the capability of EECP to counteract tamoxifen-induced endometrial hyperplasia, without altering its effect on the breast. Thirty-six rats of ∼2 months were coadministered either EECP (16.5, 50, and 150 mg/kg BW) or fulvestrant (300 μg/kg BW) and tamoxifen (10 mg/kg BW) for 8 weeks. Afterward, the relative weights and histomorphometry of the uterus, vagina, ovaries, and mammary gland were assessed. The expression of some proteins of proliferation (PCNA), angiogenesis (VEGF), and apoptosis (Bax, Bcl-2, and caspase-3) was measured by immunohistochemistry. Rats that received only tamoxifen had endometrial hyperplasia compared to normal rats. EECP and fulvestrant protected the rats against tamoxifen-induced endometrial hyperplasia. A significant decrease in uterine wet weight ( $p<0.01$ ); endometrial height ( $p<0.001$ ); and expression of PCNA, Bcl-2, and VEGF proteins as well as a significant increase in the expression of Bax and caspase-3 proteins was observed in the EECP group compared to the Tamox group. EECP did not change the effects of tamoxifen on the breast. In summary, Cameroonian propolis which is efficacious in preventing breast cancer can also be a good complementary medicine to prevent tamoxifen-induced endometrial cancer in tamoxifen users.