IGF-1& its Cross-Talk with Estrogen in Breast Tumor Grow

描述(申请人提供)：IGF-I刺激正常和肿瘤的生长 乳腺，遗传学研究表明，IGF-I和IGF-IR信号是 完整的乳房发育。IGF是强大的乳腺癌细胞有丝分裂原，与正常乳腺相比，IGF-IR及其下游信号中间体IRS-1在乳腺肿瘤中过度活跃。IGF信号中间产物升高与乳腺癌预后不良有关。阻断IGF作用的策略在抑制乳腺癌生长方面取得了成功，为IGF-IR抑制剂的药物开发提供了原理证据。此外，IGF系统与ER途径有很强的正相互作用，已知ER途径在癌前病变与正常乳腺组织中升高。我们已经证明这种相互作用是双向的，ERα可以增加多种IGF信号中间产物的表达，并使细胞对IGFS敏感，而IGF-I即使在没有雌激素的情况下也可以特异性地激活ERα。尽管有大量文献表明IGFS与乳腺癌增殖有关，并证明了IGFS与ER系统的相互作用，但对于IGFS在乳腺癌前疾病发生和发展过程中的重要性几乎一无所知，尽管ERa？的升高明显参与了这一过程。我们假设IGF是乳腺组织癌前进展的重要驱动力，部分原因是雌激素上调了IGF信号和IGF介导的生长。我们将通过检验IGF是否 它的信号通路调节癌前进展，以及阻断IGF-IR作用的药物是否可以阻止这种进展。此外，我们还将调查ER？在这一过程中与IGF途径相互作用。需要解决的具体问题是：1)IGF-I信号的增加是否促进了乳腺的癌前进展？2)IGF途径的阻断能否防止或延缓小鼠乳腺癌模型的癌前疾病及其进展？3)ER和IGF-I之间的相互作用是否调节癌前疾病和乳腺癌的生长和发展？在这项提案中，我们将采取多学科的方法，利用PPG参与者和核心提供的专业知识和材料，并使用异种移植、细胞系、小鼠模型和人类乳腺标本，来研究IGFS在乳腺癌前疾病进展中的作用。

DESCRIPTION (provided by applicant): IGF-I stimulates growth of both normal and neoplastic mammary gland, and genetic studies have shown that IGF-I and IGF-IR signaling are needed for complete mammary development. IGFs are potent mitogens for breast cancer cells, and IGF-IR and its downstream signaling intermediate IRS-1 are hyperactive in breast tumors compared to normal breast. Elevated IGF signaling intermediates are associated with a poor prognosis in breast cancer. Strategies to block IGF action have been successful in inhibiting breast cancer growth, providing proof of principle for the pharmaceutical development of IGF-IR inhibitors. Furthermore, the IGF system has a strong positive interaction with the ER pathway, which is already known to be elevated in premalignant vs. normal breast tissue. We have shown that this interaction is bidirectional ERalpha can increase expression of multiple IGF signaling intermediates and sensitize cells to IGFs, while IGF-I can specifically activate ERalpha even in the absence of estrogen. Despite the wealth of literature implicating IGFs in breast cancer proliferation and demonstrating their interaction with the ER system, almost nothing is known about the importance of IGFs during onset and progression of premalignant breast disease, even though elevated ERalpha ?is clearly involved in this process. We hypothesize that IGFs are important drivers of premalignant progression in mammary tissue, due in part to upregulation of IGF signaling and IGF-mediated growth by estrogen. We will test this hypothesis by examining whether IGF and its signaling pathways regulate premalignant progression, and whether agents that block IGF-IR action can prevent this progression. Additionally, we will investigate how ER? interacts with IGF pathway in this progression. The specific questions to be addressed are: 1) Does increased IGF-I signaling promote premalignant progression in the mammary gland? 2) Can blockade of the IGF pathway prevent or delay premalignant disease and its progression to mammary cancer in mouse models? 3) Does cross-talk between ER and IGF-I regulate the growth and progression of premalignant disease and breast cancer? In this proposal we will take a multidisciplinary approach, making use of the expertise and materials available from the PPG participants and cores, and using xenografts, cell lines, mouse models, and human breast specimens, to address the role of IGFs in premalignant breast disease progression.