Abstract 2431: A novel role of MUC5AC/CD44v6/c-Met axis in breast cancer brain metastasis

Abstract

Abstract Brain metastasis (BrM) is one of the leading causes of mortality in breast cancer (BC). Although BrM is associated with all BC subtypes, but it is more prevalent in triple-negative and HER2+ BC patients. Recent advancements in the multimodality treatment of primary BC have prolonged patient survival, which has in turn increased the incidence of BrM. Due to the lack of understanding of BC-BrM, there is no reliable biomarker and effective therapeutic strategy. In this regard, using publicly available databases and RNA-Seq analysis, we observed that secretory mucin MUC5AC is significantly upregulated in BC brain metastatic cell lines and tissues compared to their respective control. We validated these observations in brain-seeking BC (BSBC) cell lines and brain metastatic tissues at protein levels. Interestingly, we found that the MUC5AC levels were significantly increased in the serum of CNS metastatic patients relative to healthy donors and BC patients. Our functional studies revealed that silencing of MUC5AC in BSBC cell lines showed a significant decrease in cell adhesion, migration, brain metastatic potential, and increased survival of mice. Exploring the molecular mechanism further revealed that MUC5AC interacts with CD44v6 and c-Met and deletion of MUC5AC demonstrated a decrease in the expression of c-MET and CD44v6. Furthermore, pharmacological targeting of MUC5AC through c-Met inhibitor reduces the expression of CD44v6 and MUC5AC, suggesting that c-Met inhibitors could be used as a novel therapeutics for targeting MUC5AC and thereby attenuating BC brain metastasis. Altogether, our study demonstrates that MUC5AC/CD44v6/c-Met axis could be used as a novel approach to prevent breast cancer brain metastasis. Citation Format: Shailendra Kumar Maurya, Jawed A. Siddiqui, Shailendra K. Gautama, Ranjana K. Kanchan, Ramesh Pothuraju, Gopalakrishnan Natarajan, Pranita Atri, Ramakanth C. Venkata, Rakesh Bhatia, Parvez Khan, Asad Ur Rehmana, Sanjib Chaudhary, Naveenkumar Perumal, Sidharth Mahapatra, Hitendra S. Chand, Maneesh Jain, Juan A. Santamaria-Barriab, Diana M. Cittelly, Surinder K. Batra, Mohd W. Nasser. A novel role of MUC5AC/CD44v6/c-Met axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2431.