INSULIN-LIKE GROWTH FACTOR ACTION IN BREAST CANCER CELLS

乳腺癌细胞中胰岛素样生长因子的作用

• 批准号: 2099395
• 负责人: NEAL ROSEN
• 金额: $ 25.45万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099395
• 关键词: MCF7 cell; biological signal transduction; breast neoplasms; cell cycle; cell growth regulation; enzyme activity; enzyme substrate; estrogen inhibitor; estrogens; growth factor receptors; guanosinetriphosphatases; hormone regulation /control mechanism; human genetic material tag; insulinlike growth factor; monoclonal antibody; neoplastic cell; neoplastic growth; northern blottings; nucleic acid probes; phosphorylation; protein structure function; protein tyrosine kinase; receptor binding; receptor expression; retinoate; transfection /expression vector; western blottings

The goals of the proposal are the investigation of the role played by insulin-like growth factors (IGFs) in the biology of human breast cancer and of the mechanism by which these factors stimulate mitogenesis in this system. the long term aim is to use these studies to define the biochemical events underlying tumor progression in this disease and to identify new targets for therapeutic intervention. Previous work has shown that IGF-I and IGF-II elicit a marked mitogenic response in some breast cancer cell lines by binding to the IGF-I receptor. Moreover, overexpression of IGF-II in an estrogen-dependent cell line confers some aspects of estrogen independence. In addition, stromal cells in breast tumors express IGF-II, whereas tumor cells do in only a minority of cases. Taken together, the data imply that IGFs are potential paracrine regulators of breast tumor cell growth and that expression of IGF-II by the tumor cell may be an event in tumor progression that allows the cell to become independent of stromal factors. The current proposal aims to define the effects of IGFs on breast cancer cell growth in more detail, exploring the interactions of IGFs with hormonal agents and retinoic acid and correlating growth effects with IGF-I receptor expression, tyrosine kinase activity and autophosphorylation. The system will be then used as a model with which to study the mechanistic details of the transduction of the proliferative signal by IGFs. Preliminary results reveal that IGFs activate the IGF-I receptor tyrosine kinase with subsequent phosphorylation of its beta- subunit and several other substrates, including pp185 (IRS1), GAP, and GAP-associated pp62. Current studies focus on further defining these events and in identifying their functional consequences. Interactions of pp185 and GAP with other proteins will be characterized and assessed in IGF-responsive and unresponsive cell lines, IGF-II transfectants, and cells treated with antiestrogens and differentiation agents. Specific events and interactions will be correlated with aspects of the proliferative and transformed phenotype. Transfections with GAP expression vectors will be performed to evaluate the role of the GAP-ras complex in mediating these events.

该提案的目标是调查对角色的调查 人类乳腺癌生物学中的胰岛素样生长因子（IGF） 以及这些因素在此刺激有丝分裂发生的机制 系统。 长期目的是使用这些研究来定义 该疾病中肿瘤进展的生化事件和 确定治疗干预的新目标。 以前的工作有 表明IGF-I和IGF-II在某些人中引起了明显的有丝分裂反应 乳腺癌细胞系与IGF-I受体结合。 而且， 雌激素依赖性细胞系中IGF-II的过表达赋予了一些 雌激素独立性的各个方面。 另外，乳房中的基质细胞 肿瘤表达IGF-II，而肿瘤细胞仅在少数中进行 案例。 综上所述，数据表明IGF是潜在的旁分泌 乳腺肿瘤细胞生长的调节剂以及IGF-II的表达 肿瘤细胞可能是肿瘤进展中的事件 独立于基质因素。 当前的提案旨在定义IGF对乳腺癌的影响 细胞生长更详细，探索IGF与 激素剂和视黄酸以及将生长效应与 IGF-I受体表达，酪氨酸激酶活性和 自磷酸化。 然后将系统用作模型 研究增生性转导的机械细节 IGF的信号。 初步结果表明，IGFS激活IGF-I 受体酪氨酸激酶，随后其β-的磷酸化 亚基和其他几个底物，包括PP185（IRS1），GAP和 间隙相关的PP62。 当前的研究重点是进一步定义这些 事件并确定其功能后果。 互动 PP185和其他蛋白质的间隙将被表征和评估 在IGF反应性和无反应性细胞系中，IGF-II转染剂和 用抗雌激素和分化剂处理的细胞。 具体的 事件和互动将与 增殖和转化的表型。 带有间隙的转染 表达向量将进行评估GAP-RAS的作用 复杂的调解这些事件。