CHARACTERIZATION OF APC FUNCTION IN THE MAMMARY GLAND

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Alteration of the APC tumor suppressor gene is an early genetic change in the development of colorectal tumors in humans. Interestingly, mice carrying an Apc mutation (ApcMin) are predisposed to mammary neoplasia in addition to intestinal polyposis. One function of APC is to facilitate the degradation of beta-catenin and down-regulate the Wnt signaling pathway and target gene transcription. We propose that APC plays an important role in growth control of the mammary epithelium, and that this role is dependent on the ability of APC to regulate beta-catenin and Wnt signaling. To test this hypothesis, we will use ApcMin mice to determine if there is an in vivo association between Apc mutation, beta-catenin nuclear accumulation and target gene transcription. Furthermore, we will determine if disruption of the Wnt signaling pathway is necessary for mammary tumorigenesis in ApcMin mice. Transgenic mice will be generated in which Wnt signaling is inhibited in the mammary gland by down- regulation of beta-catenin or by interruption of Tcf-mediate transcription. The ability of these transgenes to suppress tumorigenesis in ApcMin mice will be examined. These studies will elucidate the molecular mechanism by which APC suppresses tumorigenesis in the mammary gland and will be valuable in designing therapeutic and chemopreventive strategies for breast cancer.