|Rahal, Omar -|
|Simmen, Rosalia -|
Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 7, 2010
Publication Date: August 1, 2010
Citation: Rahal, O., Simmen, R.C. 2010. PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation. Carcinogenesis. 31(8):1491-1500. Interpretive Summary: The risk of breast cancer can be highly modified by lifestyle habits such as nutrition. Studies have shown a lower occurrence of breast cancer in women who consume large amounts of soy foods early in life. Our research team has shown that dietary intake of soy foods or its main component, the isoflavone genistein, can protect against breast cancer induced by chemicals in rats. These effects were shown to be mediated in part by the increased of tumor suppressors such as PTEN and p53 in the mammary glands of those animals before they were administered the carcinogens. Therefore, in the present study, we will further expand our initial observation and examine what is the functional outcome of the increased expression of PTEN and p53 in the mammary epithelial cells. Our data shows that the isoflavone genistein increases the expression and nuclear levels of PTEN and p53 in mammary epithelial cells, coincident with decreased cell proliferation, making these cells more resistant against future damage. We also showed that PTEN is necessary to maintain stable levels of p53, which in turn, will increase the expression of PTEN. This suggests that dietary induction of PTEN can sustain its anticarcinogenic effects by interacting and stabilizing p53.
Technical Abstract: The tumor suppressors PTEN and p53 are closely related to the pathogenesis of breast cancer, yet pathway-specific mechanisms underlying their participation in mediating the protective actions of dietary bioactive components on breast cancer risk are poorly understood. We recently showed that dietary exposure to the soy isoflavone geinistein induced PTEN expression in mammary epithelial cells in vivo and in vitro, consistent with the breast cancer preventive effects of soy food consumption. Here we evaluated PTEN and p53 functional interactions in the nuclear compartment of mammary epithelial cells as a mechanism for mammary tumor protection by genistein. Using the non-tumorigenic human mammary epithelial cells MCF10-A, we demonstrate that genistein increased PTEN expression and nuclear localization. We show that increased nuclear PTEN levels initiated an autoregulatory loop involving PTEN-dependent increases in p53 nuclear localization, PTEN/p53 physical association, PTEN/p53 co-recruitment to the PTEN promoter region, and p53 transactivation of PTEN promoter activity. The PTEN/p53 cross-talk induced by genistein resulted in increased cell cycle arrest; decreased pro-proliferative cyclin D1 and pleiotrophin gene expression; and the early formation of mammary acini, indicative of genistein promotion of lobuloalveolar differentiation. Our findings provide support to genistein-induced PTEN as both a target and regulator of p53 action and offer a mechanistic basis for PTEN pathway activation to underlie the anti-tumorigenic properties of dietary factors, with important clinical applications.