IRS1 and 2 Signaling in Mammary Development and Cancer

IRS1 和 2 信号在乳房发育和癌症中的作用

• 批准号: 6620551
• 负责人: Adrian V Lee
• 金额: $ 26.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620551
• 关键词: breast neoplasms; enzyme inhibitors; gene targeting; genetically modified animals; histogenesis; hormone regulation /control mechanism; insulin; insulin receptor; laboratory mouse; lactation; mammary epithelium; mammary gland; phosphatidylinositol 3 kinase; receptor expression; steroid hormone

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.

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 (IRS) 的功能和重要性 乳腺发育和肿瘤发生。 IRS，一个蛋白质家族， 整合和协调来自生长因子、细胞因子和 整合素，在乳腺癌细胞系中受到激素调节，并且具有 对乳腺癌的预后意义。但人们对此几乎一无所知 IRSs 在正常乳房发育和复旧阶段的作用， 可以帮助我们解释它们在癌症发生中的作用。因此我们有 选择研究小鼠乳腺发育过程中的 IRS，因为该系统 已被很好地表征并且可以进行基因操纵。 我们发现国税局的本地化、级别和管理方式发生了巨大变化。 在怀孕、哺乳和复旧期间激活。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。具体来说， 我们假设 IRS 在处女发育过程中受到激素调节， 提供增殖和生存信号。 IRS 表达增加 怀孕期间提供进一步的增殖和生存信号 促进小叶肺泡发育。然而，哺乳期后，IRS 产生的 生存信号必须关闭，让乳腺经历 细胞凋亡介导的退化。我们将在三个具体方面测试这些假设 目标。 1) 类固醇激素如何调节不同的定位模式 乳腺导管上皮中的IRS-1和-2，是乳腺导管上皮的水平或模式 IRS-1 或 -2 对导管和小叶肺泡发育至关重要？ 2) 国税局 (IRS) 在哺乳期间提供生存信号，该信号会被快速关闭 退化开始时泛素介导的 IRS 降解？ 3）意志 IRS-1 或 -2 的强制过度表达导致 IRS 信号异常并导致 乳腺增生或明显的肿瘤发生，或促进致癌物质诱发 肿瘤发生？ IRSs 在整合生长因子和类固醇中的作用 正常和恶性乳腺细胞中的激素信号使得 了解它们在两种环境下的工作原理。了解它们在正常情况下的功能 发展可能使了解异常的功能障碍成为可能 发展，甚至可能制定干预措施来阻止或逆转 完全恶性肿瘤的发作。