Molecular actions of phytoestrogens in human breast cancer MCF-7 cells and osteoblastic SaOS-2 cells

Estrogens are among the most ubiquitous and important hormones in the female body. After menopause, estradiol levels drop significantly. The goals of estrogen replacement therapy (ERT)/hormone replacement therapy (HRT) are to replace estrogen in a manner that alleviates menopausal symptoms. However, women are reluctant to use ERT/HRT mainly due to the undesirable side-effects. Postmenopausal women are more inclined to use natural remedies. Of all the natural alternatives, phytoestrogens appear to offer the greatest potential. In the present study, we used two in vitro cell model systems to characterize the molecular actions of isoflavones genistein and ginsenoside Rg1. Biphasic effects of genistein have been demonstrated on the growth of ER positive human breast cancer MCF-7 cells. In the absence of endogenous estrogens, physiological concentrations of genistein stimulate the cell growth, whereas high concentrations of genistein have inhibitory effect. Using cDNA microarray technology, genes differentially regulated by high concentrations of genistein were identified. The result suggested that the inhibitory action of genistein on breast cancer cells appears to be complex and is only partially mediated by the alteration of ER-dependent pathway. Our results also indicated both genistein (1muM) and Rg1 (1pM) mimic the action of estradiol in stimulation of human breast cancer MCF-7 cell growth by inducing IGF-IR and IRS-1 expression. These effects were ER dependent and accompanied by an enhancement of IGF-I mediated signaling. Thus, caution is warranted for the consumption of soy products containing genistein or ginseng products amongst pre- and post-menopausal women who suffered from ER-positive breast cancer. In SaOS-2 cell model system, we attempted to investigate if genistein and Rg1 have anabolic effects on osteoblastic cells. Our results showed that genistein could induce ALP activity and OPG expression in a dose-dependent manner. Genistein pretreatment significantly attenuated PTH-induced decrease in OPG expression and increase in RANKL expression. However there is no significant effect of Rg1 on SaOS-2 cells, suggesting not all phytoestrogen can have anabolic effect on bone. These results help to elucidate the detailed mechanism of phytoestrogens on different cell types and provide information to assess the potential risk and benefit of phytoestrogens consumption in postmenopausal women.