WILD TYPE RAS AND FARNESYL TRANSFERASE INHIBITORS IN BREAST CANCER

乳腺癌中的野生型 RAS 和法尼基转移酶抑制剂

• 批准号: 5209471
• 负责人: NEAL X ROSEN
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5209471
• 关键词: apoptosis; biological signal transduction; cell cycle; cell growth regulation; cell sorting; clone cells; cytoskeleton; drug resistance; electron microscopy; enzyme inhibitors; gene induction /repression; gene mutation; growth factor receptors; hormone regulation /control mechanism; mammary epithelium; mass spectrometry; molecular oncology; neoplastic transformation; oncogenes; protein tyrosine kinase; transfection

Whether p21ras plays a role in regulating the transformed phenotype of breast cancer cells is not clear. Mutations in the ras gene are almost never detected in breast cancer. On the other hand, activated tyrosine kinases play an important role in breast cancer pathogenesis and, in other systems, exert some of their effects by activating wild type p2lras. If this is so in breast cancer, inhibition of p2lras function with drugs such as farnesyl transferase inhibitors (FTIs) could be an important therapeutic strategy. We have shown that polypeptide growth factors activate the ras-regulated signal transduction pathway in breast cancer cells and that introduction of the Nl7-ras dominant negative into a breast cancer cell line does not alter proliferation but reverses transformation. We conclude that activation of wild type p2lras is necessary for maintenance of transformation in at least some breast cancer cells. Furthermore, we have shown that these tumor cell lines are sensitive to farnesylation inhibitors. We propose in this grant to use dominant negative ras vectors to determine the role ras-regulated pathways play in the biology of breast cancer. We further plan to investigate the mechanism by which FTIs suppress breast cancer cell growth, to explore whether they work by inhibiting ras processing or whether they have other targets as well, and to determine mechanisms underlying cellular resistance to these drugs. The main goals of the work are to develop the possibility of using FTIs clinically and to use our knowledge of signal transduction pathways to design new therapies that combine such inhibitors with traditional chemohormonal therapy.

p21 ras是否在转化表型中起调节作用 乳腺癌细胞是不清楚的。ras基因的突变是 几乎从未在乳腺癌中发现。另一方面，激活 酪氨酸激酶在乳腺癌的发病机制中起重要作用 而在其他系统中，通过激活野生动物， p2 lras型。如果在乳腺癌中是这样，抑制p2 lras 与法尼基转移酶抑制剂（FTIs）等药物一起发挥作用 可能是一种重要的治疗策略。我们已经证明 多肽生长因子激活ras调节信号 乳腺癌细胞中的信号转导途径以及 将N17-ras显性阴性导入乳腺癌细胞系不 改变增殖但逆转转化。我们的结论是 野生型p2 Lras的激活对于维持 在至少一些乳腺癌细胞中的转化。而且我们 这些肿瘤细胞系对法尼基化敏感 抑制剂的 我们建议在本补助金中使用显性负ras载体， 确定ras调节途径在生物学中的作用， 乳腺癌我们计划进一步研究 FTI抑制乳腺癌细胞生长，以探索它们是否起作用 通过抑制RAS加工或它们是否有其他靶点， 以及确定细胞抵抗的机制， 这些药物。这项工作的主要目标是开发一种可能性， 在临床上使用FTI，并利用我们对信号的了解， 设计新的治疗方法，结合联合收割机， 抑制剂与传统的化学激素治疗。