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 ?-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 ?-Catenin-mediated biological functions and in breast-cancer biology. We add a novel arm of regulatory mechanism for WNT/?-Cat activation in the context of breast-cancer progression.
The proposed research aims to establish CD177 as a novel breast-cancer suppressor. We identified CD177 as an excellent predictor for relapse free survival in patients and a suppressor for breast-cancer growth and metastasis. CD177 forms a functions complex with syntaxin 4 and its binding protein STXBP2, together to sequester beta-catenin to the plasma membrane and prevent its activation by WNT signaling.
|Janowski, Ann M; Colegio, Oscar R; Hornick, Emma E et al. (2016) NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. J Clin Invest 126:3917-3928|
|Kolb, Ryan; Phan, Liem; Borcherding, Nicholas et al. (2016) Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun 7:13007|
|Li, Ying; Zhang, Weizhou; Chang, Liang et al. (2016) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell 7:478-88|
|Yuan, Fang; Kolb, Ryan; Pandey, Gaurav et al. (2016) Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy. PLoS One 11:e0164135|