INSULIN-LIKE GROWTH FACTOR ACTION IN BREAST CANCER CELLS

该提案的目标是调查 胰岛素样生长因子（IGFs）在乳腺癌生物学中的作用 以及这些因子刺激有丝分裂的机制， 系统 长期目标是利用这些研究来确定 这种疾病中肿瘤进展的生化事件， 确定治疗干预的新靶点。 先前的工作已经 显示IGF-I和IGF-II在某些细胞中引起显著促有丝分裂反应， 乳腺癌细胞系通过结合IGF-I受体。 此外，委员会认为， 在雌激素依赖性细胞系中IGF-II的过表达赋予一些 雌激素的独立性。 此外，乳腺中的基质细胞 肿瘤表达IGF-II，而肿瘤细胞仅在少数肿瘤细胞中表达IGF-II。 例 综上所述，这些数据表明IGFs是潜在的旁分泌 乳腺癌细胞生长的调节因子和IGF-II的表达， 肿瘤细胞可能是肿瘤进展中的一个事件，使细胞 变得不依赖于基质因子。 目前的建议旨在确定胰岛素样生长因子对乳腺癌的影响 细胞生长的更详细，探索IGFs的相互作用， 激素剂和视黄酸以及与生长相关的作用， IGF-I受体表达、酪氨酸激酶活性和 自磷酸化 然后将该系统用作模型， 研究增殖性细胞因子转导的机制细节， IGFs信号。 初步结果显示IGFs激活IGF-I 受体酪氨酸激酶，随后磷酸化其β- 亚基和几种其他底物，包括pp 185（IRS 1）、GAP和 GAP相关pp 62. 目前的研究重点是进一步界定这些 事件，并确定其功能后果。 相互作用 pp 185和GAP与其他蛋白质的特性和评估 在IGF-应答和无应答细胞系、IGF-II转染子中， 用抗雌激素和分化剂处理的细胞。 具体 事件和互动将与 增殖和转化表型。 GAP转染 将进行表达载体以评估GAP-ras的作用， 复杂的调解这些事件。

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.