Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention
Annual summary rept. 1 Jan 2010-31 Jul 2012
ARKANSAS CHILDREN'S HOSPITAL LITTLE ROCK AR
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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 PTENp53 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 stemprogenitor cells and inhibition of tumor susceptibility and highlight diet-regulated, stem cell-associated genes for potential application in breast cancer therapy.
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