Clinical and epidemiological studies demonstrate reduced breast cancer risk with soy food consumption; however the underlying mechanisms remain poorly understood. The present studies explored novel mechanisms for dietary prevention of breast cancer. First, we showed a linear pathway by which 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 cell differentiation. Mammary stem cells (MaSC) are required for tissue homeostasis; however, dysregulation of MaSC self-renewal such as by Wnt1 overexpression leads to neoplastic transformation. We investigated the effect of lifetime intake of soy protein (SPI) diet relative to the control casein (CAS) diet on the MaSC population and its correlation to tumor formation in MMTV-Wnt1-Transgenic (Wnt1-Tg) female mice. Tumor incidence was lower in SPI fed Wnt1-Tg mice relative to those fed CAS. FACS analysis of freshly isolated MECs revealed that the MaSC-enriched and tumor initiating populations were decreased in preneoplastic mammary glands of Wnt1-Tg mice fed SPI. Microarray analysis of the MaSC-enriched cell population from Wnt1-Tg mice fed CAS or SPI identified a list of diet-regulated genes associated with inflammatory response, cell proliferation, and protein metabolic pathways. We also investigated how the mammary stromal compartment participates in the promotion of mammary epithelial differentiation by SPI. We showed that local adiponectin synthesis/secretion induced by SPI in mammary tissues in vivo results in increased differentiation of mammary epithelial cells. Mechanistically, we showed that in estrogen receptor (ER) negative MCF-10A cells, adiponectin (APN) induces early lobuloalveolar differentiation by inhibition of STAT3. In ER-positive HC11 cells, a novel mechanism was delineated where APN, in synergy with soy isoflavone GEN, promotes the pro-apoptotic, anti-proliferative effects of ERβ. In summary, results from these studies demonstrate that the dietary regulation of breast cancer by soy/GEN, the latter a paradigm for good nutrition, involves many cellular (mammary stromal, mammary epithelial, mammary stem cells) and molecular (tumor suppressors PTEN and p53, oncogene Wnt) targets. The end-point of this complex regulation is the enhancement of epithelial differentiation leading to increased resistance to oncogenic insults.
|Advisor:||Simmen, Rosalia C.M.|
|Commitee:||Kelly, Thomas J., McGehee Jr., Robert E., Price, Peter M., Simmen, Frank A.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/06(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Nutrition, Oncology|
|Keywords:||Breast cancer, Epithelial-stromal interactions, Genistein, Mammary stem cells, Pten, Soy foods|
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