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.

项目摘要 这项提案的总体目标是调查肥胖对乳腺癌发生和发展的贡献。 胰岛素受体(IR)信号通路在调节血管紧张素转换酶中的作用 乳腺癌干细胞(CSC)。肥胖是一种日益严重的健康流行病，与患肥胖症的风险增加有关 都在发展和死于乳腺癌。高胰岛素水平是肥胖的结果，是一种 乳腺癌发生和复发的独立危险因素，这表明这一信号转导信号的作用 乳腺CSCs的调控途径。CSCs代表的是一群具有 自我更新并产生肿瘤异质性，足以引发原发和复发的肿瘤 成长。需要新的方法来针对这种侵袭性的肿瘤细胞亚群。尽管 IR在调节CSC功能中的作用已经在一些癌症背景下进行了研究，这是一个严格的 对该受体调节CSC功能的机制还没有进行分析。这是 临床上很重要，因为直接靶向IR用于癌症治疗是具有挑战性的，因为它具有重要的作用 该受体在调节正常代谢动态平衡方面发挥作用。胰岛素受体底物(IRS) 胞质接头蛋白在IR信号的功能结果中起着关键作用。在这项提案中， 申请人提出假设，IRS2通过IR调节乳腺CSCs，这一功能 不能由IRS1执行。申请人的初步数据确立了IRS2在胰岛素依赖型糖尿病中的作用 CSC自我更新的调节，并在IRS2中确定对该调节至关重要的结构域。这个 IRS2促进自我更新的能力还取决于它对PI3K的招募和激活。申请人 建议选择性地干扰IRS2促进CSC自我更新的功能，而不干扰其 正常代谢动态平衡的功能可能是抑制CSCs IR调节的新途径。 从本提案中概述的实验中获得的结果将为开发 可结合当前治疗方法靶向CSCs治疗原发肿瘤的靶向方法 和复发的乳房肿瘤。研究IRS2依赖信号在IR反应中的假说 激活促进CSC自我更新申请者将：1)研究胰岛素对乳房的调节 CSCS。胰岛素通过IR-A/IRS2信号调节乳腺CSC自我更新的假说是 研究；2)确定胰岛素信号调节乳腺CSC功能的机制。这个 假设IR信号通过IRS2通过招募因子(S)促进CSC的自我更新 将研究IRS2(SR)C-末端尾部中与PI3K/AKT信号协同的独特区域； 3)阐明高胰岛素血症促进乳腺肿瘤生长的机制。假设 IR/IRS2调控CSCs对高胰岛素状态下肿瘤生长的促进作用 将使用遗传和耐药模型进行检查。