IRS-1 and -2 signaling in mammary development and cancer

描述（由申请人提供）：胰岛素受体底物 1 和 2 (IRS) 是胰岛素样生长因子-I 受体 (IGF-IR) 下游的大衔接蛋白，调节正常生长、代谢、存活和分化。最近的研究表明，IRS 可以与许多癌基因相互作用，并且是其转化能力所必需的，并且 IRS 在包括乳腺癌在内的许多人类肿瘤中升高且过度活跃。这些研究的长期目标是了解胰岛素受体底物 (IRS) 在乳腺癌中的作用，并确定它们是否在预测抗 IGF-IR 抑制剂的反应中发挥作用。 为了更好地了解 IRS 在乳腺发育和乳腺癌中的作用，在上一个资助期间，我们创建并研究了几种新颖的 IRS 作用的体外和体内模型。使用IRS缺失小鼠，我们发现IRS是胚胎乳芽形成和最大泌乳所必需的。使用人类永生化 MCF-10A 细胞，我们发现 IRS 的过度表达通过改变极性、增殖和存活来破坏腺泡的形成。最后，我们培育了乳腺特异性过度表达 IRS-1 或 IRS-2 的转基因小鼠，这两个品系的小鼠均表现出进行性乳腺增生、肿瘤和转移。有趣的是，其他人使用 IRS-2 缺失小鼠进行的研究表明，乳腺肿瘤转移只需要 IRS-2。 这些研究提出了三个基本问题：1）IRS 如何调节乳腺细胞极性、转化和肿瘤发生？ 2）为什么IRS-1和IRS-2都引起转化，但转移只需要IRS-2？ 3) IRS 对乳腺癌进展和预后重要吗？其水平和/或活性可以预测对抗 IGF-IR 抑制剂的反应吗？我们将通过以下具体目标来解决这些问题：1）IRS-1和IRS-2是否都通过aPKC介导的极性复合物破坏来破坏MCF-10A腺泡的形态发生，并促进IGF-IR下游的增殖和存活？ 2) IRS-2是否利用NF-κB活性的独特双向正向调节来调节迁移、侵袭和转移？ 3) IRS 在乳腺癌进展和预后中重要吗？它们可以用作抗 IGF-IR 治疗反应的预测因子吗？ 这些研究的长期影响将是更好地了解 IRS 在乳腺癌中的作用，并可能成为预测乳腺癌中 IGF-IR 抑制剂反应的新生物标志物。 公共健康相关性：本研究的目的是更好地了解信号适配器 (IRS) 在乳腺癌中的作用。该研究将阐明 IRS 的功能，然后将其转化为人类乳腺癌，以测试它们是否影响患者预后并预测对抗 IGF-IR 抑制剂的反应。

DESCRIPTION (provided by applicant): Insulin receptor substrates 1 and 2 (IRSs) are large adaptor proteins downstream of insulin-like growth factor-I receptor (IGF-IR) which modulate normal growth, metabolism, survival, and differentiation. Recent studies have shown that IRSs can interact with, and are functionally required for the transforming ability of many oncogenes, and IRSs are elevated and hyperactive in many human tumors including breast cancer. The long-term goal of these studies is to understand the role of inuslin receptor substrates (IRSs) in breast cancer, and determine if they may have a role in predicting response to anti-IGF-IR inhibitors. To better understand the role of IRSs in mammary gland development and breast cancer, in the last funding period, we created and studied several novel in vitro and in vivo models of IRS action. Using IRS-null mice we found that IRSs are required for embryonic mammary bud formation and for maximal lactation. Using human immortalized MCF-10A cells we showed that overexpression of IRSs disrupted formation of acini by altering polarity, proliferation, and survival. Finally, we generated transgenic mice with mammary-specific overexpression of either IRS-1 or IRS-2 with both lines of mice displaying progressive mammary hyperplasia, tumors, and metastasis. Intriguingly, studies from others using IRS-2-null mice have shown that only IRS-2 is required for mammary tumor metastasis. These studies have raised three fundamental questions: 1) How do IRSs modulate mammary cell polarity, transformation, and tumorigenesis? 2) Why do both IRS-1 and IRS-2 cause transformation, but only IRS-2 is required for metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can levels and/or activity predict response to anti-IGF-IR inhibitors? We will address these questions with the following specific aims: 1) Do both IRS-1 and IRS-2 disrupt morphogenesis of MCF-10A acini via aPKC mediated disruption of the polarity complex, and promote proliferation and survival downstream of IGF-IR? 2) Does IRS-2 utilize a unique bi-directional positive regulation of NF-?B activity to modulate migration, invasion, and metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can they be used as predictors of response to anti-IGF-IR therapy? The long-term impact of these studies will be a better understanidng of IRS action in breast cancer, and a possible new biomarker for predicting response to IGF-IR inhibitors in breast cancer. PUBLIC HEALTH RELEVANCE: The goal of this study is to better understand the role of signaling adaptors (IRSs) in breast cancer. The study will elucidate IRS function, and then translate this into human breast cancer to test if they affect patient prognosis and predict response to anti-IGF-IR inhibitors.