The long-term goal of these studies is to understand the function and importance of insulin receptor substrates (IRSs) in mammary development and tumorigenesis. IRSs, a family of proteins that integrate and co-ordinate signals from growth factors, cytokines, and integrins, are hormonally regulated in breast cancer cell lines, and have prognostic significance in breast cancer. But almost nothing is known about the roles of IRSs in the stages of normal breast development and involution, which could help us interpret their role in the onset of cancer. We have therefore chosen to study IRSs during mammary development in the mouse, as this system has been well characterized and can be genetically manipulated. We find that there are dramatic changes in IRS localization, levels, and activation during pregnancy, lactation, and involution. We propose that these changes reflect a critical role for IRSs in mammary development. Specifically, we hypothesize that IRSs are hormone-regulated during virgin development, providing both proliferative and survival signals. Increased expression of IRSs during pregnancy supplies further proliferative and survival signals that promote lobuloalveolar development. However, following lactation, IRS-generated survival signals must be turned off, to allow the mammary gland to undergo apoptosis-mediated involution. We will test these hypotheses in three Specific Aims. 1) How do steroid hormones regulate the distinct localization patterns of IRS-1 and -2 in ductal mammary epithelium, and are the levels or patterns of IRS-1 or -2 critical for ductal and lobuloalveolar development? 2) Do IRSs provide survival signals during lactation that are turned off by rapid ubiquitin-mediated degradation of IRSs at the onset of involution? 3) Will forced overexpression of IRS-1 or -2 result in aberrant IRS signaling and cause mammary hyperplasia or overt tumorigenesis, or promote carcinogen-induced tumorigenesis? The role of IRSs in integrating growth factor and steroid hormone signals in both normal and malignant breast cells makes it essential to understand how they work in both settings. Knowing their function in normal development may make it possible to understand the dysfunction in abnormal development, and perhaps even to devise interventions to block or reverse the onset of full malignancy.
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