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.
1) 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 β-catenin to the plasma membrane of cells and prevents β-catenin from activation. β-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 β-catenin to the plasma membrane, a similar process as the recruitment and sequestration of β-catenin to adherens junctions.
2) In addition to the suppressive role of CD177 in breast cancer, we also found that CD177 is important for normal mammary gland development when using the knockout mouse model we have recently developed. We found that CD177 could be an important metabolism regulator for glycolysis, which contributes to the overproliferation mammary stem cells in aged mammary glands and leads to its exhaustion. This is a novel project that leads to a combined project related to the role of metabolism, stem cell aging and the predisposition for carcinogenesis.
This project is currently supported by an NIH R01 grant.
- Qing Xie, Julia Klesney-Tait, Kathy Keck, Corey Parlet, Nicholas Borcherding, Ryan Kolb, Wei Li, Lorraine Tygrett, Thomas Waldschmidt, Alicia Olivier, Songhai Chen, Guang-hui Liu, Xiangri Li, Weizhou Zhang. Characterization of a novel mouse model with genetic deletion of CD177. Protein Cell. 2015 Feb;6(2):117-26. PMCID: PMC4312768.