Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention.

摘要

In the present grant, I demonstrated a linear pathway by which soy isoflavone genistein (GEN)-mediated increase in PTEN nuclear localization initiates an autoregulatory loop involving PTEN-dependent increases in p53 nuclear localization and PTEN/p53 functional interactions to enhance PTEN expression resulting in mammary epithelial cell differentiation. I also investigated the effect of lifetime intake of soy protein (SPI) diet relative to casein (CAS) diet on mammary stem cell (MaSC) population and tumor formation in MMTV-Wnt1- Transgenic (Wnt1-Tg) female mice. We report that mammary tumor incidence was lower in the SPI-fed group by age 8 months. Mammary epithelial cells from SPI-fed Wnt1-Tg mice exhibited fewer MaSCs; decreased ability to form mammospheres in culture, lower mammary outgrowth potential when transplanted into cleared fat pads, and reduced accumulation of cancer stem cells. Gene array of the MaSC-enriched population demonstrated a stem cell-like expression pattern and markedly suppressed expression of inflammatory and metastasis-associated genes with dietary SPI exposure. SPI effects on MaSCs and tumor formation in Wnt1-Tg mice were recapitulated by dietary GEN. Our findings suggest an association between dietary regulation of mammary stem/progenitor cells and inhibition of tumor susceptibility and highlight diet-regulated, stem cell-associated genes for potential application in breast cancer therapy.