Autophagy-independent function of Beclin 1 in Breast Cancer

描述（由申请人提供）：本提案中待检验的新假设是Beclin 1通过调节内吞运输和促进IGF-1 R信号传导在乳腺癌中发挥自噬独立作用。Beclin 1在人类肿瘤（包括乳腺癌）中的表达经常降低，而在小鼠中的表达降低促进肿瘤发生，从而确立Beclin 1为单倍不足的肿瘤抑制基因。尽管许多研究都集中在Beclin 1在自噬中的作用，作为其发挥肿瘤抑制作用的机制，但Beclin 1的替代功能可能有助于其在癌症中的作用，但很少受到关注。这是重要的，因为Beclin 1是核心复合物的重要组成部分，不仅调节自噬，还调节内吞运输，这可以影响生长因子受体信号传导。在这方面，申请人做出了新的发现，即Beclin 1的缺失增强了乳腺癌细胞中IGF-1 R活化和下游AKT信号传导，并且这些信号传导的变化与增加的生长和侵袭相关。磷酸化IGF-1 R的表达是患者生存率降低的预后指标，这一事实强调了IGF-1 R信号通路对乳腺癌的重要性。IGF-1 R的临床重要性以及开发用于鉴定待用IGF-1 R靶向疗法治疗的患者的改进方法的需要突出了进一步研究申请人已经鉴定并破译其对乳腺癌的贡献的用于调节IGF-1 R信号传导的新型Beclin 1介导的机制的重要性。初步数据支持Beclin 1参与调节IGF-1 R信号传导的自噬独立机制，并指向涉及控制受体内吞运输的机制。进一步的研究是必要的，以了解受体信号的空间和时间控制这一重要的膜运输途径有助于肿瘤的进展。为了研究Beclin 1通过IGF-1 R内吞运输的自噬非依赖性调节来控制乳腺癌进展的假设，申请人将：1）确定Beclin 1在调节IGF-1 R信号传导中的作用。将检查Beclin 1的缺失通过阻止早期内体成熟和随后通过溶酶体降解下调活化受体来维持IGF-1 R/IRS-2信号传导的假设; 2）研究Beclin 1通过其控制IGF-1 R信号传导来抑制乳腺癌进展的假设。Beclin 1表达丧失后IGF-1 R的持续激活增强乳腺癌的存活、侵袭和转移的假设将被检验。还将评估癌前乳腺和人乳腺肿瘤中Beclin 1表达与IGF-1 R/IRS-2/AKT信号传导之间的相关性。

DESCRIPTION (provided by applicant): The novel hypothesis to be examined in this proposal is that Beclin 1 plays an autophagy-independent role in breast cancer through the regulation of endocytic trafficking and the promotion of IGF-1R signaling. Beclin 1 expression is frequently decreased in human tumors, including breast cancer, and decreased expression in mice promotes tumorigenesis, establishing Beclin 1 as a haploinsufficient tumor suppressor gene. Although much research has focused on the role of Beclin 1 in autophagy as the mechanism by which it exerts its tumor suppressor action, alternative functions of Beclin 1 that could contribut to its role in cancer have received less attention. This is significant because Beclin 1 is an essential component of the core complex that regulates not only autophagy, but also endocytic trafficking, which can impact growth factor receptor signaling. In this regard, the applicant made the novel discovery that loss of Beclin 1 enhances IGF-1R activation and downstream signaling to AKT in breast carcinoma cells and that these changes in signaling are associated with increased growth and invasion. The significance of the IGF-1R signaling pathway for breast cancer is underscored by the fact that expression of phosphorylated IGF-1R is a prognostic indicator of reduced patient survival. The clinical importance of the IGF-1R and the need to develop improved approaches for identifying patients to be treated with IGF-1R-targeted therapies highlight the importance of investigating further the novel Beclin 1-mediated mechanism for regulating IGF-1R signaling that the applicant has identified and deciphering its contribution to breast cancer. Preliminary data support an autophagy-independent mechanism for the involvement of Beclin 1 in the regulation of IGF-1R signaling and point toward a mechanism involving the control of endocytic trafficking of the receptor. Further investigation is warranted to understand how the spatial and temporal control of receptor signaling by this essential membrane trafficking pathway contributes to tumor progression. To investigate the hypothesis that Beclin 1 controls breast cancer progression through the autophagy- independent regulation of IGF-1R endocytic trafficking, the applicant will: 1) Establish the role o Beclin 1 in the regulation IGF-1R signaling. The hypothesis that loss of Beclin 1 sustains IGF-1R/IRS-2 signaling by preventing early endosome maturation and subsequent downregulation of the activated receptor by lysosomal degradation will be examined; 2) Investigate the hypothesis that Beclin 1 suppresses breast carcinoma progression through its control of IGF-1R signaling. The hypothesis that sustained activation of the IGF-1R upon loss of Beclin 1 expression enhances survival, invasion and metastasis of breast carcinomas will be examined. The correlation between Beclin 1 expression and IGF-1R/IRS-2/AKT signaling in the pre-malignant mammary gland and human breast tumors will also be assessed.