Location: Arkansas Children's Nutrition CenterTitle: Tumor suppressor pten signaling is up-regulated in mammary epithelial cells by soy isoflavone genistein: implications for breast cancer protection) Author
Submitted to: Meeting Abstract
Publication Type: Abstract only
Publication Acceptance Date: 8/31/2009
Publication Date: N/A
Citation: 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 increase of tumor suppressors such as PTEN 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 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 genistein enhances differentiation of mammary epithelial cells. This suggests that dietary induction of PTEN might be responsible for the anticarcinogenic effects of soy components.
Technical Abstract: Epidemiological studies have shown lower occurrence of breast cancer in Asian women whose early intake of soy products is higher than their American counterparts. In a previous work, we showed protection against NMU-induced mammary tumors in rats exposed to dietary soy protein isolate (SPI) or casein (CAS) supplemented with the major soy isoflavone genistein (GEN) when compared to those fed the control CAS diet. Here, we test the hypothesis that GEN induction of tumor suppressor PTEN expression and nuclear localization in mammary epithelial cells result in decreased cellular proliferation and enhanced cellular differentiation, to confer protection from mammary tumorigenesis. Using the human non-tumor mammary epithelial cell line MCF-10A, we show that GEN at physiological relevant concentrations (40 nM and 2 microM) increased PTEN mRNA and protein levels and enhanced nuclear accumulation of PTEN. Further, cells treated with GEN had lower cell viability when compared to control cells, concomitant with decreased expression of cyclin D1 and of the PTEN regulated gene pleiotrophin. Interestingly, GEN up-regulation of PTEN expression was accompanied by similar effects on another tumor suppressor p53, which co-localized with PTEN in nuclei of GEN-treated cells. PTEN siRNA targeting, which decreased basal PTEN expression by 60%, significantly increased cyclin D1 and pleiotrophin expression. Our findings provide support to the hypothesis that the protective effects of GEN in the mammary epithelium may be mediated by PTEN to enhance differentiation and inhibit cellular proliferation, and suggest the participation of another key tumor suppressor p53.