Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/4/2008
Publication Date: 3/15/2009
Citation: Su, Y., Simmen, R.C. 2009. Soy isoflavone genistein upregulates epithelial adhesion molecule e-cadherin expression and attenuates beta-catenin signaling in mammary epithelial cells. Carcinogenesis. 30(2):331-339.
Interpretive Summary: The linkage between nutrition and cancer prevention has been widely studied. We have shown that lifetime consumption of soy-containing diets is protective in a rat carcinogen-induced breast cancer model. Genistein is a phytochemical component in the soybean, and it has been has been shown to be protective against mammary cancers. In the present study, we found that genistein increased cell-cell adhesion molecules-E-cadherin and enhanced inhibition of basal or stimulated proliferation. Also genistein is anti-proliferation in normal epithelial cells, but acts as a pro-proliferation agent in the absence of E-cadherin. Together, these data provide important information about the mechanisms by which consumption of soy foods are protective against breast cancer.
Technical Abstract: Enhanced Wnt/beta -catenin signaling and loss of E-cadherin expression are considered hallmarks of mammary tumorigenesis. Mammary tumor protection by dietary intake of soy-rich foods and the soy isoflavone genistein (Gen) is widely regarded based on numerous epidemiological and animal studies; however, it remains unknown if dietary Gen supplementation can be used as therapy against breast cancer. Here we show that Gen up-regulation of the cell adhesion molecule E-cadherin in mammary epithelial cells mediates cellular response to oncogene Wnt signaling and proliferation status. In mammary glands of rats exposed to dietary Gen, levels of E-cadherin protein, but not transcript, were higher, concurrent with increased beta-catenin protein and induction of the differentiation-associated beta-casein gene. Gen inhibited basal and Wnt-1-mediated cell proliferation and abolished Wnt-1 targets c-Myc and Cyclin D1 expression in mouse mammary epithelial cells. This effect of Gen was reversed by the estrogen receptor (ER) antagonist ICI 182,780 and mimicked by the ER beta specific agonist diarylpropionitrile. The abundance of membrane E-cadherin protein and of epithelial E-cadherin/beta-catenin adhesion complex were increased by Gen, attendant with its down-regulation of Wnt-1-induced accumulation of beta-catenin in cytosol and nucleus. E-cadherin siRNA targeting eliminated Gen repression of Wnt-1-stimulated c-Myc expression and promoted Gen induction of basal c-Myc transcript, leading to reversal of proliferation status from that observed with higher E-cadherin levels. Our studies identify E-cadherin as a cellular target of Gen and provide a novel mechanism linking this dietary isoflavone with the negative regulation of the oncogene Wnt pathway for mammary tumor protection.