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）下游的大型衔接蛋白，可调节正常生长、代谢、存活和分化。最近的研究表明，IRSs可以与许多癌基因相互作用，并且是许多癌基因转化能力所必需的功能，并且IRSs在许多人类肿瘤（包括乳腺癌）中升高和过度活跃。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，并确定它们是否可能在预测抗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，我们创建并研究了IRS作用的几种新型体外和体内模型。使用IRS-null小鼠，我们发现IRS是胚胎乳腺芽形成和最大泌乳所需的。使用人永生化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，我们产生了乳腺特异性过表达IRS-1或IRS-2的转基因小鼠，这两种小鼠都表现出进行性乳腺增生、肿瘤和转移。有趣的是，其他使用IRS-2缺失小鼠的研究表明，乳腺肿瘤转移仅需要IRS-2。 这些研究提出了三个基本问题：1）IRSs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都能引起转化，但只有IRS-2才能引起转移？3)IRSs在乳腺癌进展和预后中是否重要，其水平和/或活性能否预测抗IGF-IR抑制剂的反应？1）IRS-1和IRS-2是否都通过aPKC介导的极性复合物的破坏来破坏MCF-10A腺泡的形态发生，并促进IGF-1 R下游的增殖和存活？2)IRS-2是否利用NF-κ B的独特双向正调控？调节迁移、侵袭和转移的B活性？3)IRSs在乳腺癌进展和预后中是否重要？它们能否用作抗IGF-IR治疗反应的预测因子？ 这些研究的长期影响将是更好地理解IRS在乳腺癌中的作用，以及预测乳腺癌对IGF-IR抑制剂反应的可能的新生物标志物。 公共卫生相关性：本研究的目的是更好地了解信号转导适配器（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.