IRS1 and 2 Signaling in Mammary Development and Cancer

描述：（由申请人提供）这些研究的长期目标是 了解胰岛素受体底物（IRSs）的功能和重要性， 乳腺发育和肿瘤发生。IRSs是一个蛋白质家族， 整合和协调来自生长因子、细胞因子 整合素，在乳腺癌细胞系中受到神经调节， 乳腺癌的预后意义。但几乎没有人知道 IRS在正常乳房发育和退化阶段的作用， 可以帮助我们解释它们在癌症发病中的作用。我们因此 选择在小鼠乳房发育期间研究IRSs，因为该系统 已经被很好地描述并且可以被基因操纵。 我们发现，IRS的定位、水平和 在妊娠、哺乳和退化期间激活。我们建议，这些 这些变化反映了IRS在乳腺发育中的关键作用。具体地说， 我们假设IRSs在处女发育期间是受免疫调节的， 提供增殖和存活信号。IRS表达增加 在怀孕期间提供进一步的增殖和存活信号， 促进小叶肺泡发育。然而，哺乳后，IRS产生的 必须关闭生存信号，让乳腺经历 退化介导的退化。我们将在三个具体的测试这些假设 目标。1)类固醇激素是如何调节 IRS-1和IRS-2在乳腺导管上皮中的表达，是IRS-1和IRS-2在乳腺导管上皮中的水平或模式。 IRS-1或-2对导管和小叶肺泡发育至关重要？2)做IRS 在哺乳期间提供生存信号，这些信号被快速的 泛素介导的退化的IRS开始退化？3)将 IRS-1或-2的强制过表达导致IRS信号传导异常并导致 乳腺增生或明显的肿瘤发生，或促进致癌物质诱导 肿瘤发生胰岛素抵抗系统在整合生长因子和激素中的作用 正常和恶性乳腺细胞中的激素信号使得 了解它们在这两种环境中的工作原理。了解它们在正常情况下的功能 发展可能使我们有可能了解异常的功能障碍， 发展，甚至可能制定干预措施，以阻止或扭转 完全恶性肿瘤的发病。

DESCRIPTION: (provided by applicant) 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.