Insulin regulation of breast cancer stem cells

乳腺癌干细胞的胰岛素调节

• 批准号: 10227661
• 负责人: LESLIE M SHAW
• 金额: $ 16.75万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227661
• 关键词: Adaptor Signaling Protein; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; C-terminal; Cells; Clinical; Data; Data Set; Drug resistance; Epidemic; Gene Expression; Goals; Health; Homeostasis; Hyperinsulinism; IRS1 gene; IRS2 gene; Informal Social Control; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Lead; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammospheres; Mediating; Metabolic; Modeling; Obesity; Outcome; PI3K/AKT; Pathway interactions; Play; Population; Primary Neoplasm; Protein Isoforms; RNA Splicing; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recurrence; Recurrent tumor; Regulation; Reporting; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Tail; Testing; Variant; cancer initiation; cancer recurrence; cancer risk; cancer stem cell; cancer therapy; experimental study; functional outcomes; genetic resistance; glucose uptake; in vivo; insulin regulation; insulin signaling; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; receptor; receptor expression; receptor function; recruit; response; self-renewal; side effect; stem cell function; stem cell genes; stem cell population; stem cell self renewal; stemness; targeted treatment; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression

Project Summary The overall goal of this proposal is to investigate the contribution of obesity to breast cancer initiation and progression by establishing the contribution of the insulin receptor (IR) signaling pathway to the regulation of breast cancer stem cells (CSCs). Obesity is a growing health epidemic that is associated with increased risk of both developing and dying from breast cancer. High insulin levels, which are a consequence of obesity, are an independent risk factor for breast cancer initiation and recurrence, which suggests a role for this signaling pathway in the regulation of breast CSCs. CSCs represent a sub-population of tumor cells that have the ability to self-renew and generate tumor heterogeneity and they are sufficient to initiate primary and recurrent tumor growth. Novel approaches are needed to target this aggressive tumor cell subpopulation. Although the involvement of the IR in regulating CSC function has been investigated in some cancer contexts, a rigorous analysis of the mechanism by which this receptor regulates CSC function has not been performed. This is clinically important because directly targeting the IR for cancer therapy is challenging given the essential role that this receptor plays in regulating normal metabolic homeostasis. The insulin receptor substrate (IRS) cytoplasmic adaptor proteins play key roles in the functional outcomes of IR signaling. In this proposal, the applicant advances the hypothesis that IRS2 mediates the regulation of breast CSCs by the IR, a function that cannot be executed by IRS1. The applicant’s preliminary data establish a role for IRS2 in the insulin-dependent regulation of CSC self-renewal and they identify a domain within IRS2 that is essential for this regulation. The ability of IRS2 to promote self-renewal also depends upon its recruitment and activation of PI3K. The applicant proposes that selectively disrupting functions of IRS2 that promote CSC self-renewal without interfering with its functions in normal metabolic homeostasis would be a novel approach for inhibiting IR regulation of CSCs. The results obtained from the experiments outlined in this proposal will lay the groundwork for developing targeted approaches that could be used in combination with current therapies to target CSCs to treat primary and recurrent breast tumors. To investigate the hypothesis that IRS2-dependent signaling in response to IR activation enhances CSC self-renewal the applicant will: 1) Investigate insulin-dependent regulation of breast CSCs. The hypothesis that insulin signaling through IR-A/IRS2 regulates breast CSC self-renewal will be examined; 2) Determine the mechanism by which insulin signaling regulates breast CSC function. The hypothesis that IR signaling through IRS2 enhances CSC self-renewal through the recruitment of factor(s) to a unique region within the C-terminal tail of IRS2 (SR) that cooperate with PI3K/AKT signaling will be examined; 3) Elucidate the mechanism by which hyperinsulinemia promotes breast tumor growth. The hypothesis that IR/IRS2 regulation of CSCs is required for enhancing tumor growth in response to hyperinsulinemic conditions will be examined using both genetic and drug resistance models.

项目概要 该提案的总体目标是调查肥胖对乳腺癌发生和发生的影响。 通过建立胰岛素受体（IR）信号通路对调节的贡献来进展 乳腺癌干细胞（CSC）。肥胖是一种日益严重的健康流行病，与肥胖风险增加有关 都死于乳腺癌。高胰岛素水平是肥胖的后果之一 乳腺癌发生和复发的独立危险因素，这表明该信号传导的作用 乳腺 CSC 的调节途径。 CSC 代表肿瘤细胞的一个亚群，具有以下能力： 自我更新并产生肿瘤异质性，足以引发原发性和复发性肿瘤 生长。需要新的方法来针对这种侵袭性肿瘤细胞亚群。虽然 IR 参与调节 CSC 功能已在某些癌症背景下进行了研究，严格的 尚未对该受体调节 CSC 功能的机制进行分析。这是 临床上很重要，因为鉴于其重要作用，直接靶向 IR 进行癌症治疗具有挑战性 该受体在调节正常代谢稳态中发挥作用。胰岛素受体底物 (IRS) 细胞质接头蛋白在 IR 信号传导的功能结果中发挥着关键作用。在该提案中， 申请人提出了这样的假设：IRS2 通过 IR 介导乳腺 CSC 的调节，该功能 IRS1 不能执行。申请人的初步数据确定了 IRS2 在胰岛素依赖型糖尿病中的作用 CSC 自我更新的调节，他们在 IRS2 中确定了一个对于这种调节至关重要的域。这 IRS2 促进自我更新的能力还取决于其招募和激活 PI3K。申请人 提出选择性地破坏 IRS2 促进 CSC 自我更新的功能，而不干扰其功能 正常代谢稳态中的功能将是抑制 CSC IR 调节的新方法。 从本提案中概述的实验中获得的结果将为开发奠定基础 可以与当前针对 CSC 的疗法结合使用的靶向方法来治疗原发性 和复发性乳腺肿瘤。调查 IRS2 依赖性信号传导响应 IR 的假设 激活增强 CSC 自我更新 申请人将： 1) 研究乳房的胰岛素依赖性调节 CSC。胰岛素信号通过 IR-A/IRS2 调节乳腺 CSC 自我更新的假设将是 检查； 2) 确定胰岛素信号调节乳腺CSC功能的机制。这 假设通过 IRS2 的 IR 信号传导通过招募因子来增强 CSC 的自我更新 将检查 IRS2 (SR) C 端尾部内与 PI3K/AKT 信号传导合作的独特区域； 3）阐明高胰岛素血症促进乳腺肿瘤生长的机制。假设 IR/IRS2 对 CSC 的调节是增强肿瘤生长以应对高胰岛素血症所必需的 将使用遗传和耐药性模型进行检查。