Impact of Beclin 1 Loss on Breast Cancer Progression

 描述(申请人提供)：这项建议的目标是了解Beclin 1/Vps34复合体如何促进乳腺癌的进展，并确定如何使Beclin 1/Vps34功能缺陷的肿瘤细胞对促进肿瘤细胞死亡的药物敏感。乳腺癌是全世界女性中最常见的癌症，也是癌症相关死亡的第二大原因。尽管有靶向治疗，但I期转移性疾病的总体存活率仍为23%。因此，有必要开发治疗晚期乳腺癌的新方法。申请人假设，其中一种方法可以利用Beclin 1/Vps34在乳腺癌进展中的作用。在40%的乳腺癌中，Beclin 1单等位基因缺失，在ER阴性的乳腺癌亚型中，Beclin 1的表达与不良预后呈负相关。此外，Beclin 1的低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Vps34相互作用并激活，从而调节多种膜转运途径，包括自噬、生长因子受体转运和胞质分裂。这些转运途径中的每一个对癌症的个体贡献尚不清楚，需要进行调查，以了解Beclin 1缺失对乳腺癌进展的影响。申请人实验室以前的研究表明，Beclin 1表达的丧失与IGF和EGF受体下游AKT和ERK信号的持续增加有关。此外，Beclin 1在乳腺癌细胞中的表达缺失会导致侵袭性增加。这些初步发现表明，目前处于临床试验中的Vps34抑制剂可能会对肿瘤治疗产生负面影响。申请人在这里提出的工作将探索Beclin 1/Vps34复合体如何促进乳腺癌的进展。申请人假设，抑制Beclin1/Vps34复合体将导致促进肿瘤生长和进展的特定途径的上调，并且在Beclin 1低表达的肿瘤中靶向这些途径或与Vps34抑制联合使用将抑制肿瘤细胞的活力。这项建议的目标是剖析每个Beclin 1/Vps34复合体在乳腺癌进展中与肿瘤生长、转移和肿瘤体内代谢有关的ROE(目标1)。此外，抑制Beclin 1/Vps34使乳腺癌细胞死亡的机制将被确定为靶向Beclin 1缺陷肿瘤和优化Vps34抑制剂作为潜在治疗剂的一种手段(目标2)。该提案中的研究将增强我们对Beclin 1在乳腺癌中的作用的理解，并可以为晚期乳腺癌疾病的新疗法提供洞察力。

 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.