Interactive effects of low-dose estradiol and tamoxifen on the postmenopausal primate endometrium and mammary gland.

Abstract

Abstract Abstract #3047 Background: Long-term use of combined estrogen+progestin hormone therapies increases breast cancer risk in postmenopausal women. Selective estrogen receptor modulators (SERMs) are promising alternatives to progestins, particularly for breast cancer survivors and other women at high-risk for breast cancer considering hormone therapy. The purpose of this study was to evaluate interactive effects of low-dose estradiol (E2) and the SERM tamoxifen on the postmenopausal endometrium and mammary gland.
 Materials and Methods: Ovariectomized adult female cynomolgus monkeys were given placebo (n=6), oral estradiol (E2, 0.25 mg/1800 kcal) (n=6), tamoxifen (TAM, 20 mg/1800 kcal) (n=5), or E2+TAM (n=6) for 4 months. Doses of E2 and TAM were scaled to approximate those given to women.
 Results: Endometrial thickness and uterine weight were significantly higher in E2, TAM, and E2+TAM groups compared to placebo (P < 0.01 for all). In contrast, endometrial gland and stromal proliferation determined by Ki67 immunolabeling was significantly greater only in the E2 group (P < 0.01 for both). Endometrial Ki67 gene expression was also higher only in the E2 group (P < 0.01). Gene markers of estrogen receptor alpha (ER) activity such as TFF1 and STC2 were significantly increased in E2, TAM, and E2+TAM groups (P < 0.01 for all). On endometrial histology TAM and E2+TAM induced stromal fibrosis and occasional simple glandular hyperplasia with cystic change. In the mammary gland, TFF1 gene expression was increased by all treatments (P < 0.05 for all), while no statistically significant treatment effects were seen for epithelial proliferation or progesterone receptor expression.
 Discussion: Previous studies have suggested that the weak estrogen-like effects of tamoxifen in the uterus contribute to increased endometrial cancer risk. Our findings reveal a more complex pattern of tamoxifen action involving increased ER activity, antagonism of E2-induced proliferation, and distinctive stromal remodeling. These results suggest that tamoxifen does not exhibit simple weak estrogen agonist / antagonist effects in the primate endometrium but instead acts through pathways independent of classical ER signaling to alter cancer risk. Future gene profiling should aid in the identification of these alternative pathways. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3047.