TARGETING THE IGF SYSTEM IN BREAST CANCER

针对乳腺癌的 IGF 系统

• 批准号: 6489199
• 负责人: Douglas Yee
• 金额: $ 28.54万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2003-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489199
• 关键词: MCF7 cell; Retroviridae; antisense nucleic acid; athymic mouse; binding proteins; biological signal transduction; breast neoplasms; cell growth regulation; cell proliferation; disease /disorder model; epithelium; growth factor receptors; insulinlike growth factor; mutant; neoplastic cell; neoplastic transformation; polyethylene glycols; protein structure function; receptor coupling; receptor expression; recombinant proteins; tissue /cell culture; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) Several model systems have shown that the insulin-like growth factors (IGFs) are potent regulators of breast cancer growth. The applicant has demonstrated that neutralization of IGF action by IGF binding protein-1 (IGFBP-1), or interruption of type I IGF receptor (IGFR1) signaling by dominant-negative receptor constructs, inhibit breast cancer proliferation in vitro. The applicant has also identified the insulin-receptor substrate-1 (IRS-1) adaptor protein as a key molecule activated by IGFR1. Thus, IGF stimulation of breast cancer could be prevented at three levels: blockade of ligand/receptor interaction, interruption of IGFR1 autoactivation, and uncoupling of IGFR1 from downstream signaling pathways. Most of this work has thus far been based on human breast cancer cells in culture. The applicant now proposes to show that these anti-IGF strategies will effectively inhibit breast cancer growth in vivo in the more complex xenograft model system, as a prelude to designing new therapeutic strategies for clinical breast cancer. His aims are: 1) to interfere with IGF ligand-receptor interactions by neutralizing IGF action by administering recombinant IGFBP-1 and by expressing IGFBP-1 in breast cancer cells; 2) to inhibit breast cancer growth by disrupting IGFR1 activation with the inducible expression and gene transfer of dominant negative receptor constructs, and 3) to inhibit function of the key IGFR1 substrate, IRS-1, by expressing an inducible anti-sense IRS-1 construct and by overexpressing an inhibitory adaptor protein (grb-IR), to uncouple the receptor from downstream signaling pathways. Identification of the key growth regulatory pathways in breast cancer cells has already proved to have enormous clinical value. For example, discovering the function of the estrogen receptor in the breast cancer cells has led to major advances in both prognosis and treatment. The IGF system appears to be at least equally important in stimulating breast cancer growth, and demonstrating targetable points in its functional pathway could well have an equally valuable impact on overall breast cancer treatment.

描述：（申请人的摘要）几个模型系统表明 胰岛素样生长因子（IGF）是乳房的有效调节剂 癌症生长。 申请人证明了IGF的中和 IGF结合蛋白-1（IGFBP-1）的作用或I型IGF的中断 受体（IGFR1）通过显性阴性受体构建体的信号传导，抑制 体外乳腺癌增殖。 申请人还确定了 胰岛素受体底物-1（IRS-1）衔接蛋白作为关键分子 由IGFR1激活。 因此，IGF刺激乳腺癌可能是 在三个级别上预防：封锁配体/受体相互作用， IGFR1自动活化的中断和IGFR1的解偶联 下游信号通路。 到目前为止，这项工作的大部分是基于 培养中的人类乳腺癌细胞。 申请人现在建议显示 这些抗IGF策略将有效抑制乳腺癌的生长 在更复杂的异种移植模型系统中的体内，作为前奏 为临床乳腺癌设计新的治疗策略。 他的目标 是：1）通过中和来干扰IGF配体 - 受体相互作用 通过管理重组IGFBP-1和表达IGFBP-1的IGF作用 乳腺癌细胞； 2）通过破坏IGFR1抑制乳腺癌的生长 用诱导表达和基因转移的激活 负受体构建体，3）抑制密钥IGFR1的功能 底物IRS-1，通过表达诱导的抗渗透IRS-1构建体和 通过过表达抑制衔接子蛋白（GRB-IR），使其脱离 来自下游信号通路的受体。 钥匙的识别 乳腺癌细胞中的生长调节途径已经证明 巨大的临床价值。 例如，发现 乳腺癌细胞中的雌激素受体已导致 预后和治疗。 IGF系统似乎至少是平等的 对于刺激乳腺癌生长和证明可靶向的重要 其功能途径的点很可能会产生同样有价值的影响 关于整体乳腺癌治疗。