Notch Signaling in Mammary Development and Tumorigenesis

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DESCRIPTION (provided by applicant): Notch signaling defines a fundamental cell signaling pathway controlling cell fate acquisition. Notch signals control the development of a very broad spectrum of tissues and experimental modulation of such signals results in cell fate changes throughout the development of multicellular organisms including man. Given the pleiotropy of Notch signals and their potency in controlling the developmental state of cells, as well as the established direct involvement of Notch in carcinogenesis, we wish to explore the consequences of Notch signal modulation in tumors and its potential to influence the fate of specific cell lineages. We will focus our attention to the mammary gland, a tissue with a well characterized developmental profile as well as established mouse cancer models. Our working hypothesis is that changes in Notch signaling activity will result in changes in cell fates, including the fate of specific oncogenic conditions. The aims proposed will examine the consequences of Notch signal modulation in the mouse mammary epithelium with the help of transgenic mice. We expect that these studies will provide a firm basis to analyze the action of Notch signals in mammary tissue, including the involvement of these signals in both the onset and maintenance of mammary tumors as well as evaluate the capacity of those signals to influence the kinetics of oncogenesis. In order to supplement our understanding of how Notch signaling influences oncogenesis, we will also study the involvement of Notch in proliferative events using cell culture systems.