Genistein alone and in combination with the mammalian lignans enterolactone and enterodiol induce estrogenic effects on bone and uterus in a postmenopausal breast cancer mouse model

Abstract

The use of phytoestrogens, such as isoflavones and lignans, for treatment of postmenopausal breast cancer is increasing, but their effects on bone and other major organs are not clear. While the isoflavone genistein (GEN) has been shown to prevent or slow the loss of bone mineral density (BMD), the effect of lignans enterodiol (END) and enterolactone (ENL) are unknown. In this study, we determined in ovariectomized mice with human MCF-7 breast tumor xenografts the effects of the lignans, and GEN, alone and in combination, on bone and uterus. Mice with established MCF-7 tumors were fed a basal diet (AIN-93G), divided into 5 groups, and given daily subcutaneous injections (10 mg/kg body weight) of either ENL, END, GEN, a mixture of these compounds (MIX), or vehicle as a negative control for 22 weeks. Results showed that GEN acts estrogenically in both the uterus and bone by increasing the uterus weight, femur BMD, and femur biomechanical strength (yield load), while the lignans do not. However, treatment with MIX induced minimal effects on femur biomechanical strength parameters but significantly increased uterus weight. A significant positive correlation was observed between MCF-7 tumor volume and femur BMD and biomechanical strength parameters (femur peak load and yield load) but not with uterus weight, suggesting that the uterus may respond differently to phytoestrogens compared to MCF-7 tumors and bone. It is concluded that GEN induces beneficial effects on bone but has adverse effects on tumors and uterus in this model of postmenopausal breast cancer. The lignans do not exert adverse effects on any tissue, however, when combined with GEN, they exert an adverse effect on the uterus.