Autophagy-independent function of Beclin 1 in Breast Cancer

描述（由申请人提供）：本提案中要检验的新假设是Beclin 1通过调节内吞运输和促进IGF-1R信号传导在乳腺癌中发挥自噬独立作用。Beclin 1在包括乳腺癌在内的人类肿瘤中表达经常降低，而在小鼠中表达降低促进肿瘤发生，这表明Beclin 1是一个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的其他功能可能有助于其在癌症中的作用，但很少受到关注。这很重要，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，申请人提出了新的发现，Beclin 1的缺失增强了乳腺癌细胞中IGF-1R的激活和AKT的下游信号传导，这些信号传导的变化与生长和侵袭增加有关。磷酸化IGF-1R的表达是降低患者生存率的一个预后指标，这一事实强调了IGF-1R信号通路在乳腺癌中的重要性。IGF-1R的临床重要性，以及需要开发改进的方法来识别需要使用IGF-1R靶向治疗的患者，这突出了进一步研究新的Beclin 1介导的调节IGF-1R信号的机制的重要性，申请人已经确定并解读了其对乳腺癌的贡献。初步数据支持Beclin 1参与IGF-1R信号调节的自噬独立机制，并指出了涉及控制受体内吞运输的机制。进一步的研究是有必要的，以了解受体信号的时空控制是如何通过这一重要的膜运输途径促进肿瘤进展的。为了研究Beclin 1通过独立于自噬的调节IGF-1R内吞运输来控制乳腺癌进展的假设，申请人将：1)建立Beclin 1在调节IGF-1R信号传导中的作用。Beclin 1的缺失通过阻止早期核内体成熟和随后溶酶体降解激活受体的下调来维持IGF-1R/IRS-2信号传导的假设将被检验；2)探讨Beclin 1通过控制IGF-1R信号传导抑制乳腺癌进展的假说。在Beclin 1表达缺失的情况下，IGF-1R的持续激活会提高乳腺癌的存活、侵袭和转移，这一假设将被检验。我们还将评估Beclin 1表达与乳腺癌前组织和乳腺肿瘤中IGF-1R/IRS-2/AKT信号的相关性。

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.