Wnt5a and TGF-beta in mammary development and cancer

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DESCRIPTION (provided by applicant): The TGF-? family of polypeptides consists of multifunctional factors that control many aspects of growth and development. It has been shown that TGF-?s are critical for normal mammary development and that dysregulation of TGF-? signaling has a biphasic effect on tumor progression and metastasis. Previously, we generated transgenic mice that express a dominant-negative form of the TGF-? type II receptor (DNIIR). Mice expressing the DNIIR transgene in the mammary gland demonstrated increased ductal elongation and lateral branching during puberty and alterations in tumor formation relative to wild type mice. To identify genes in the mammary gland that are regulated by TGF-? and mediate these effects, we performed cDNA based microarrays comparing gene expression in wild type and DNIIR transgenic mammary glands. Wnt5a was identified in the screen and regulation of Wnt5a expression by TGF-? was verified in vivo and in primary cell culture. Wnt5a is of special interest because, like TGF-?, it has been suggested to act as a tumor suppressor. Furthermore, preliminary data suggest that, like TGF-?, Wnt5a limits growth, ductal extension, and lateral branching in the mammary gland. Nevertheless, very little is known about the role or mechanism of Wnt5a action in normal mammary gland development or tumor progression in vivo. We hypothesize that TGF-? regulates the expression of Wnt5a, which in turn mediates at least a subset of TGF-?'s developmental and tumor suppressive effects. Analysis of the functional interactions of TGF-? and Wnt5a as well as the role and mechanism of Wnt5a action in normal mammary gland development and tumor progression will be undertaken in the following specific aims: 1) To test the hypothesis that TGF-? and Wnt5a signaling are coordinated to regulate ductal elongation and branching during puberty. 2) To determine the signaling pathways used by Wnt5a to regulate mammary development, and 3) To test the hypothesis that Wnt5a inhibits tumor growth and invasion using in vivo and explant tumor models. Since it has been suggested that the response to Wnt5a relies on intercellular interactions, it is important to use models in which cell-cell and cell-ECM interactions are intact. It is anticipated that a better understanding of the genes that regulate mammary development will promote advances in breast cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most common type of cancer among women in this country. Each year, more than 211,000 American women learn they have this disease. The TGF-? family of polypeptides consists of multifunctional factors that control many aspects of growth and development. It has been shown that deregulation of TGF-? signaling has a biphasic effect on tumor progression and metastasis. We have identified another factor, Wnt5a, which is regulated by TGF-? and may mediate some of its effects. We propose to characterize functional interactions between TGF-? and Wnt5a in normal mammary development and tumor progression. We also propose to determine the role and mechanism of Wnt5a action in normal breast physiology and pathology. It is anticipated that a better understanding of the genes that regulate mammary development will promote advances in breast cancer treatment. Completion of these studies will yield valuable information regarding a novel and highly relevant tumor-suppressor signaling pathway.