Impact of Beclin 1 Loss on Breast Cancer Progression

Beclin 1 缺失对乳腺癌进展的影响

• 批准号: 9126141
• 负责人: Asia Matthew
• 金额: $ 3.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-07 至 2020-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126141
• 关键词: 1-Phosphatidylinositol 3-Kinase; Autophagocytosis; Breast Cancer Cell; Breast Cancer therapy; Breast Carcinoma; Cancer Etiology; Cancer Prognosis; Cause of Death; Cell Death; Cell Survival; Cells; Cessation of life; Clinical Treatment; Clinical Trials; Complex; Cytokinesis; Data; Development; Diagnosis; Disease; Distant Metastasis; ERBB2 gene; Endocytosis; Epidermal Growth Factor Receptor; Estrogen receptor negative; Event; Gene Expression; Goals; Growth; Growth Factor Receptors; Human; Hypoxia; In Vitro; Individual; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Lead; Link; Lipids; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Membrane Fusion; Membrane Protein Traffic; Metabolism; Metastatic breast cancer; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphatidylinositols; Process; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Role; Signal Pathway; Signal Transduction; Staging; Stress; Survival Rate; Testing; Therapeutic Agents; Time; Tumor Suppressor Proteins; United States; Up-Regulation; Vacuolar Protein Sorting; Woman; Work; cancer diagnosis; cancer therapy; effective therapy; improved; in vivo; inhibitor/antagonist; insight; interest; loss of function; malignant breast neoplasm; mortality; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; nutrient deprivation; outcome forecast; phosphatidylinositol 3-phosphate; public health relevance; receptor; targeted treatment; trafficking; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): The goal of this proposal is to understand how the Beclin 1/vacuolar protein sorting-associated protein 34 (VPS34) complex contributes to breast cancer progression and to determine how to sensitize tumor cells that are deficient in Beclin 1/VPS34 function to drugs that promote tumor cell death. Breast cancer is the most commonly diagnosed cancer among women worldwide and the second leading cause of cancer related mortality. Despite the availability of targeted therapeutics, the overall survival rate for stage I metastatic disease remains 23%. Therefore, there is a need to develop novel approaches for the treatment of advanced stage breast cancer. The applicant hypothesizes that one such approach could exploit Beclin 1/VPS34 function in breast cancer progression. Beclin 1 is monoallelically deleted in 40% of human breast cancer and there is an inverse correlation between Beclin 1 expression and poor prognosis in ER negative subtypes of breast cancer. In addition, low Beclin 1 expression serves as an independent predictor of patient survival. Beclin 1 interacts with and activates VPS34, the mammalian Class III phosphatidylinositol, to regulate multiple membrane trafficking pathways including autophagy, growth factor receptor trafficking and cytokinesis. The individual contribution of each of these trafficking pathways to cancer is unknown and needs to be investigated to understand the impact of Beclin 1 loss on breast cancer progression. Previous studies in the applicant's lab have shown that loss of Beclin 1 expression is associated with a sustained increase in AKT and ERK signaling downstream of the IGF and EGF receptors. In addition, loss of Beclin 1 expression in breast carcinoma cells leads to increased invasion. These preliminary findings suggest that VPS34 inhibitors, which are currently in clinical trials, may negatively impact tumor treatment. The work that the applicant proposes here will explore how the Beclin 1/VPS34 complex contributes to breast cancer progression. The applicant hypothesizes that inhibiting the Beclin1/VPS34 complex will lead to the upregulation of specific pathways that promote tumor growth and progression and that targeting these pathways in tumors with low Beclin 1 expression or in combination with VPS34 inhibition will suppress tumor cell viability. The goal with this proposal is to dissect out the roe of each Beclin 1/VPS34 complex in breast cancer progression with respect to tumor growth, metastasis, and tumor metabolism both in vitro and in vivo (Aim 1). Furthermore, mechanisms that sensitize breast cancer cells to death upon Beclin 1/VPS34 inhibition will be identified as a means to target Beclin 1 deficient tumors and optimize VPS34 inhibitors as potential therapeutic agents (Aim 2). The studies in this proposal will enhance our understanding of the role of Beclin 1 in breast cancer and can give insight into novel therapies for advanced stage breast cancer disease.

 描述（由申请人提供）：本提案的目的是了解Beclin 1/空泡蛋白分选相关蛋白34（VPS 34）复合物如何促进乳腺癌进展，并确定如何使Beclin 1/VPS 34功能缺陷的肿瘤细胞对促进肿瘤细胞死亡的药物敏感。乳腺癌是全世界妇女中最常诊断的癌症，也是癌症相关死亡的第二大原因。尽管靶向治疗的可用性，I期转移性疾病的总生存率仍为23%。因此，需要开发用于治疗晚期乳腺癌的新方法。申请人假设一种这样的方法可以利用Beclin 1/VPS 34在乳腺癌进展中的功能。Beclin 1在40%的人乳腺癌中是单等位基因缺失的，并且在乳腺癌的ER阴性亚型中Beclin 1表达与不良预后之间存在负相关。此外，低Beclin 1表达可作为患者生存的独立预测因子。Beclin 1与哺乳动物III类磷脂酰肌醇VPS 34相互作用并激活VPS 34，以调节多种膜运输途径，包括自噬、生长因子受体运输和胞质分裂。这些贩运途径中的每一种对癌症的单独贡献是未知的，需要进行调查以了解Beclin 1丢失对乳腺癌进展的影响。申请人实验室的先前研究已经表明，Beclin 1表达的丧失与IGF和EGF受体下游的AKT和ERK信号传导的持续增加相关。此外，乳腺癌细胞中Beclin 1表达的缺失导致侵袭增加。这些初步研究结果表明，目前正在临床试验中的VPS 34抑制剂可能会对肿瘤治疗产生负面影响。申请人在此提出的工作将探索Beclin 1/VPS 34复合物如何促进乳腺癌进展。申请人假设，抑制Beclin 1/VPS 34复合物将导致促进肿瘤生长和进展的特定途径上调，并且在Beclin 1表达低的肿瘤中靶向这些途径或与VPS 34抑制剂组合将抑制肿瘤细胞活力。该提议的目标是在体外和体内就肿瘤生长、转移和肿瘤代谢分析乳腺癌进展中每种Beclin 1/VPS 34复合物的roe（目的1）。此外，Beclin 1/VPS 34抑制后使乳腺癌细胞对死亡敏感的机制将被鉴定为靶向Beclin 1缺陷型肿瘤和优化VPS 34抑制剂作为潜在治疗剂的手段（目的2）。该提案中的研究将增强我们对Beclin 1在乳腺癌中作用的理解，并可以深入了解晚期乳腺癌疾病的新疗法。