Autophagy-independent function of Beclin 1 in Breast Cancer

描述(申请人提供)：在这项建议中要检验的新假设是Beclin 1通过调节内吞运输和促进IGF-1R信号在乳腺癌中发挥不依赖于自噬的作用。Beclin 1在包括乳腺癌在内的人类肿瘤中的表达经常降低，而在小鼠中的表达降低促进了肿瘤的发生，使Beclin 1成为单倍体不足的肿瘤抑制基因。虽然许多研究都集中在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的替代功能可能与其在癌症中的作用有关的关注较少。这一点意义重大，因为Beclin 1是核心复合体的重要组成部分，它不仅调节自噬，还调节内吞运输，这可能会影响生长因子受体信号转导。在这方面，申请人做出了新的发现，在乳腺癌细胞中，Beclin 1的缺失增强了IGF-1R的激活和AKT的下游信号，并且这些信号的变化与增加的生长和侵袭有关。IGF-1R磷酸化表达是患者生存率降低的一个预后指标，这一事实突显了IGF-1R信号通路在乳腺癌中的重要性。IGF-1R的临床重要性以及开发改进的方法来确定接受IGF-1R靶向治疗的患者的必要性突出了进一步研究申请人已经确定的调控IGF-1R信号的新型Beclin 1中介机制并破译其对乳腺癌的贡献的重要性。初步数据支持Beclin 1参与IGF-1R信号调节的自噬非依赖性机制，并指向涉及控制受体内吞运输的机制。有必要进行进一步的研究，以了解这一重要的膜转运途径对受体信号的空间和时间控制如何有助于肿瘤的进展。为了研究Beclin 1通过独立于自噬调节IGF-1R内吞运输来控制乳腺癌进展的假设，申请者将：1)确定Beclin 1在调节IGF-1R信号中的作用。2)研究Beclin 1通过控制IGF-1R信号通路抑制乳腺癌进展的假说。假设IGF-1R在失去Beclin 1表达后持续激活，可提高乳腺癌的生存、侵袭和转移能力。此外，还将评估Beclin 1在癌前病变乳腺和人类乳腺肿瘤中的表达与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.