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

描述（由申请人提供）：IGF-I刺激正常和肿瘤生长 乳腺，遗传研究表明，IGF-I和IGF-IR信号转导是必需的， 完全乳房发育。IGFs是乳腺癌细胞的有效有丝分裂原，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信号中间体升高与乳腺癌预后不良相关。阻断IGF作用的策略已经成功地抑制了乳腺癌的生长，为IGF-IR抑制剂的药物开发提供了原理证明。此外，IGF系统与ER途径具有强的正相互作用，已知ER途径在癌前病变组织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，ER α可以增加多种IGF信号中间体的表达，并使细胞对IGF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ER α。尽管大量的文献暗示IGFs在乳腺癌的增殖，并证明其与ER系统的相互作用，几乎没有什么是已知的重要性IGFs在发病和进展的癌前乳腺疾病，即使升高ER α？显然参与了这一过程。我们假设IGF是乳腺组织癌前病变进展的重要驱动因素，部分原因是IGF信号转导和IGF介导的雌激素生长的上调。我们将通过检查IGF是否 及其信号通路调节癌前病变的进展，以及阻断IGF-1 R作用的药物是否可以阻止这种进展。此外，我们将研究如何ER？在这个过程中与IGF途径相互作用。具体的问题是：1）增加IGF-I信号是否促进乳腺癌前病变进展？2)在小鼠模型中，阻断IGF通路能否预防或延迟癌前病变及其向乳腺癌的进展？3)ER和IGF-I之间的相互作用是否调节癌前病变和乳腺癌的生长和进展？在本提案中，我们将采取多学科方法，利用PPG参与者和核心的专业知识和材料，并使用异种移植物，细胞系，小鼠模型和人类乳腺标本，以解决IGF在癌前乳腺疾病进展中的作用。

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.