CD177 suppresses breast-cancer development by inhibiting beta-catenin

 描述（由申请人提供）：乳腺癌是最常见的癌症类型（约1，383，500例新发病例/年），是全球女性癌症相关死亡的主要原因（约458，400例死亡/年），也是美国第二大致死性癌症。乳房X线摄影的一个不可预见的后果是原位导管癌（DCIS）和早期乳腺癌的检测显着增加，导致对此类癌症的过度治疗。准确预测和了解复发的原因是非常重要的，这对于为早期乳腺癌患者制定化疗方案至关重要。使用一个系统的方法，我们确定了CD 177作为一个很好的预测乳腺癌复发使用已发表的元数据集，包括3554例患者标本。CD 177最初是在中性粒细胞中研究的，其在癌症进展和复发中的功能尚不清楚。本文通过多种方法研究CD 177在乳腺癌发生、发展和转移中的作用，并试图了解CD 177调控乳腺癌发生、发展和转移的分子机制。我们发现，CD 177将β-连环蛋白隔离在细胞质膜上，并阻止β-连环蛋白活化。β-连环蛋白是一种具有多种功能的蛋白质，其中最重要的是粘附连接的结构蛋白，并且是介导WNT信号通路的重要信号分子。已知后者在乳腺癌发展的不同阶段至关重要。由于CD 177是一种细胞外蛋白，并通过修饰与质膜连接，我们假设CD 177通过跨膜蛋白间接与细胞内β-连环蛋白相互作用。因此，我们发现了一种蛋白质复合物，它介导β-连环蛋白与质膜的隔离，这与β-连环蛋白向粘附连接的募集和隔离类似。我们建议研究这种隔离如何在细胞中和癌症发展过程中发生的分子机制。目的1：探讨CD 177-STX 4-STXBP 2蛋白复合物调控β-Catenin的分子机制。目的2：确定CD 177在乳腺癌发展中的作用。除了提出的目标之外，我们还确定了CD 177-STX 4-STXBP 2基因签名可以预测无转移生存期，突出了开发作为乳腺癌复发和转移预测工具的潜力。总的来说，我们希望了解CD 177如何抑制肿瘤生长和/或复发/转移。积极的影响是鉴定了一种新的CD 177-STXBP 2-STX 4蛋白复合物，用于控制β-连环蛋白介导的生物学功能和乳腺癌生物学。我们在乳腺癌进展的背景下为WNT/β-Cat激活增加了一种新的调节机制。

 DESCRIPTION (provided by applicant): Breast cancer is the most prevalent cancer type (~1,383,500 new cases/year), the leading cause of cancer-associated death among woman worldwide (~458,400 death/year), and the 2nd most lethal cancer in the United States. One of the unforeseen consequences of mammography is the marked increase in detection of ductal carcinoma in situ (DCIS) and early-stage breast cancer, resulting in the overtreatment for such cancers. It is important for the accurate prediction and understanding the cause of relapse, which is vital for tailoring chemotherapy for early breast-cancer patients. Using a systems approach, we identified CD177 as an excellent predictor for breast-cancer relapse using a published meta-dataset including 3554 patient specimens. CD177 was initially studied in neutrophils and its function in cancer progression and relapse is unknown. Here we use various approaches to study the role of CD177 in breast-cancer development and metastasis, and try to understand the molecular mechanism of how CD177 regulates such process. We identified that CD177 sequesters beta-catenin to the plasma membrane of cells and prevents beta-catenin from activation. beta-catenin is a protein with several roles, the most important ones being a structural protein for adherens junctions and being an important signaling molecule to mediate WNT signaling pathway. The latter is known to be critically involved in different stages of breast-cancer development. Since CD177 is an extracellular protein and linked to plasma membrane via modification, we hypothesize that CD177 indirectly interacts with intracellular beta-catenin via transmembrane proteins. As such, we found a protein complex that mediates the sequestration of beta-catenin to the plasma membrane, a similar process as the recruitment and sequestration of beta-catenin to adherens junctions. We propose to examine the molecular mechanism how this sequestration happens in cells and during cancer development. Here are specific aims in this study: Aim 1: Examine the molecular mechanism how CD177-STX4-STXBP2 protein complex regulate β-Catenin. Aim 2: Determine the role of CD177 in breast-cancer development. In addition to the proposed aims, we identified that the CD177-STX4-STXBP2 gene signature can predict metastasis-free survival, highlighting the potential to be developed as a prediction tool for breast cancer relapse and metastasis. Overall, we expect to understand how CD177 suppresses tumor growth and/or relapse/metastasis. The positive impact is the identification of a novel CD177-STXBP2-STX4 protein complex in controlling β-Catenin-mediated biological functions and in breast-cancer biology. We add a novel arm of regulatory mechanism for WNT/β-Cat activation in the context of breast-cancer progression.