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Metastasis of breast cancer (BC) is the leading cause of mortality in American women. In particular, brain metastasis is a significant clinical problem present in 30-40% of triple receptor negative (TN) and epidermal growth factor receptor 2 (HER2) positive BC patients. These patients also have the worst prognosis of all breast cancers in women. Due to advances in clinical management at both the diagnostic and therapeutic levels, the lifespan or overall survival of these patients has increased, but the manifestation of brain metastasis at later stages of the disease remains an unfortunate burden for these patients. In addition, the blood-brain barrier (BBB) poses an additional hurdle for treatment of BC brain metastases, because the majority of chemotherapeutic drugs fail to cross the BBB. Furthermore, there is no single targeted therapy available for TNBC patients with brain metastasis, and thus there is an urgent requirement to discover novel biomarkers and therapeutics to address BC brain metastasis. In this regard, using a bioinformatics approach, we observed that several mucins, including MUC5AC, are significantly up-regulated in brain metastases of BC compared to primary tumors. However, we found the secretory mucin MUC5AC protein to be substantially high in brain-seeking BC (BSBC) cell lines and metastatic brain tissues. We also observed that knockdown of MUC5AC reduced proliferation and metastatic potential in these cell lines. Furthermore, we observed that MUC5AC colocalizes with activated MET receptor. MUC5AC knockdown in BSBC cell lines reduced MET activation and its downstream targets FAK and paxillin. Interestingly, MET and FAK inhibition using pharmacological inhibitors led to substantial decrease in MUC5AC expression. Overall, these studies suggest that MUC5AC-MET axis may regulate breast cancer brain metastasis. Understanding the MUC5AC-MET axis could be a novel approach for the development of better prognosis and prevention of life-threatening and treatment-resistant breast cancer brain metastasis. Citation Format: Mohd W. Nasser, Shailendra K. Gautam, Ranjana Kanchan, Pranita Atri, Jawed Siddiqui, Rakesh Bhatia, Joseph Carmicheal, Dario Ghersi, Sukhwinder Kaur, Siddharth Mahapatra, Maneesh Jain, Surinder K. Batra. Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 50.

Background and Aims Pancreatic Cancer (PC) is often discovered in late stages, which contributes to its extreme lethality. Early detection is key to improved curative response and increased survival. This study explored the potential of secretory mucin MUC5AC and its glycosylation (Sialyl-Lewis A and Disialyl-Lewis A) states in combination with carbohydrate antigen CA19.9 for early diagnosis of PC. Methods Sandwich ELISA and radioimmunoassay were utilized to measure patient serum for levels of MUC5AC and CA19.9, respectively. A blinded reference set was obtained from the NCI’s Early Detection Research Network Program (n=242): healthy control (HC, N=50), chronic pancreatitis (CP, N=59), acute biliary obstruction (ABO, N= 30), stage IA/IB/IIA (N=52), and stage IIB PC (N=41), to assess the diagnostic performance of MUC5AC. Further, glycans on MUC5AC (Disialyl Lewis A, Lewis A, Blood group H (BGH) antigen) were measured via Surface Enhanced Raman Spectroscopy (SERS). Results MUC5AC levels were significantly increased in patients with stage IA/IB/IIA/IIB PC in comparison to HC, ABO and CP. MUC5AC efficiently differentiated stage IA/IB/IIA PC from healthy controls [AUC- 0.707], ABO [AUC- 0.662], and CP [AUC- 0.745]. CA19.9 differentiated stage IA/IB/IIA PC from healthy controls [AUC- 0.727], ABO [AUC-0.537] and CP [AUC- 0.675]. The MUC5AC combination with CA19.9 significantly improved the performance of CA19.9 alone: healthy controls [AUC- 0.761], ABO [AUC-0 .679], and CP [AUC- 0.753]. Further, PC serum was shown to express MUC5AC with greater Sialyl-Lewis A glycosylation in comparison to Disialyl-Lewis A glycosylation. Further, the reverse trend for these glycosylation was observed in CP and BC group. Conclusions MUC5AC is an early-stage PC biomarker that offers improved performance with CA19.9 for the detection of PC. Also, measurement of MUC5AC glycan modification will aid in the better differentiation of PC from healthy controls and high risk groups (CP, ABO). Further, the ratio of disialyl to CA19.9 glycosylation of MUC5AC is a novel way to differentiate between PC and benign conditions. Citation Format: Chihiro Hayashi, Joseph Carmicheal, Alexey Krasnoslobodtsev, Ying Haung, Randall E. Brand,, Surinder K. Batra, Sukhwinder Kaur. Implication of secretory mucin MUC5AC and its glycan modification for detection of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2017-LB-244