Tyrosine Kinase-Dependant and - Independent Pathways of EGFR in Breast Cancer Pro

乳腺癌中 EGFR 的酪氨酸激酶依赖性和非依赖性通路

• 批准号: 7962726
• 负责人: MIEN-CHIE HUNG
• 金额: $ 56.17万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962726
• 关键词: Antineoplastic Agents; Binding; Breast; Breast Cancer Cell; Cell Surface Receptors; Cell membrane; Cells; Cellular biology; Cessation of life; Complex; Development; Doctor of Philosophy; Energy Metabolism; Epidermal Growth Factor Receptor; Funding; GLUT4 gene; Glucose; Glucose Transporter; Goals; Grant; Human; Instruction; Light; Literature; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Nature; Outcome; Outcomes Research; Pathway interactions; Phosphotransferases; Play; Program Research Project Grants; Progress Reports; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Receptor Signaling; Regulation; Reporting; Reproduction spores; Resistance; Role; Signal Pathway; Signal Transduction; Sodium; TSC1/2 gene; Testing; Tyrosine Kinase Inhibitor; cancer cell; cancer therapy; chemotherapeutic agent; energy balance; glucose metabolism; glucose uptake; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; malignant phenotype; neoplastic cell; prevent; success; therapeutic target; tumor progression

PROJECT SUMMARY (See Instructions): The signaling pathway of epidermal growth factor receptor (EGFR), a cell membrane bound tyrosine kinase, plays an important role in breast cancer progression and regulates cell metabolism through kinasedependent and -independent mechanism. Additionally, accumulated evidence has demonstrated the close relationship between cancer progression and energy metabolism. Metabolic deregulation has even lately been considered as the seventh hallmark of cancers in addition to the well-established six hallmarks. Recently, we have demonstrated that EGFR, independent of its kinase activity, maintains the basal intracellular glucose level by associating with and stabilizing a sodium/glucose cotransporter (SGLT1), thereby preventing cells from undergoing autophagic death. The resulL together with those reported in the literature that AKT may activate another glucose transporter, GLLIT4 to enhance energy metabolism had stimulated us to hypothesize that EGFR may mediate glucose uptake through both tyrosine kinase dependent and independent pathways, which may contribute to the EGFR-mediated malignant phenotype in breast cancer cells. In addition, we and others have also shown that cell surface receptor-mediated kinases including ERK, AKT and IKK regulate TSC1/TSC2 complex and FoxoSa, both of which are known to involve in tumor progression and energy balance. These three kinases are frequently activated in human cancers including breast cancer and have served as therapeutic targets for the development on anti-cancer drugs. The long-term goal of this proposal is to understand molecular mechanism of breast cancer progression and metabolic regulation. Specifically, in the current proposal we propose three Specific Aims to fulfill the goals: Specific Aim 1: To elucidate the role of kinase-independent EGFR mediated glucose transporter signaling in mammary tumor progression. Specific Aim 2: To investigate energy metabolism regulated by the kinase-dependent EGFR signaling pathways. Specific Aim 3: To determine the role of kinase-dependent EGFR signaling in mammary tumor progression. The outcome of this project will advance an understanding on the effect of glucose metabolism on breast cancer progression and may shed light on new directions for breast cancer therapy.

项目总结(见说明)： 表皮生长因子受体(EGFR)是一种细胞膜结合的酪氨酸激酶， 在乳腺癌的进展中起着重要作用，并通过依赖于激酶来调节细胞代谢 和--独立的机制。此外，积累的证据表明， 癌症进展与能量代谢的关系。新陈代谢放松管制甚至最近 被认为是癌症的第七个标志，此外还有公认的六个标志。 最近，我们已经证明，EGFR不依赖于它的激酶活性，维持基础的 通过与钠/葡萄糖共转运体(SGLT1)结合并稳定细胞内血糖水平， 从而防止细胞发生自噬死亡。结果L与在 有关AKT可能激活另一种葡萄糖转运蛋白GLLIT4以增强能量代谢的文献 刺激我们假设EGFR可能通过两种酪氨酸激酶介导葡萄糖摄取 依赖和独立的途径，这可能有助于EGFR介导的恶性表型 乳腺癌细胞。此外，我们和其他人还表明，细胞表面受体介导的激酶 包括ERK，AKT和IKK调节TSC1/TSC2复合体和FoxoSa，这两个已知都涉及 在肿瘤进展和能量平衡方面的作用。这三种激酶在人类癌症中经常被激活。 包括乳腺癌，并已成为抗癌药物开发的治疗靶点。 这项建议的长期目标是了解乳腺癌进展的分子机制和 代谢调节。具体地说，在目前的提案中，我们提出了实现这些目标的三个具体目标： 特异性目标1：阐明非依赖性EGFR介导的葡萄糖转运体的作用 乳腺肿瘤进展中的信号转导。具体目标2：研究能量代谢 受依赖于激酶的EGFR信号通路调节。具体目标3：确定角色 激酶依赖的EGFR信号在乳腺肿瘤进展中的作用。这个项目的结果将是 进一步了解糖代谢在乳腺癌进展中的作用并可能减少 乳腺癌治疗的新方向。