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Abstract

Despite recent advances in breast cancer therapeutics, mortality of highly metastatic triple negative breast cancer (TNBC) subtype remains high; due to their lack of hormone receptors expression for targeted therapy. Therefore, there is a pressing need to identify new prognostic markers and therapeutic targets for this group of breast cancers. Aberrant activation of Wnt/�²- catenin signaling has been associated with breast cancers; where 40% of total breast cancers have elevated �²-catenin levels and/ or Wnt activity. Herein, we identify DEAD-box RNA helicase DP103 as a novel driver of Wnt/�²-catenin pathway in TNBC. The link between DP103 and Wnt/beta-catenin signaling was further validated using in vivo Zebrafish models, where disruption in DDX20 gene splicing mechanisms resulted in severe early embryonic developmental defects which phenocopies loss of Wnt/ beta-catenin signaling during gastrulation. Interestingly, we also show DP103 drives breast cancer stem cell (CSC) formation, a process regulated by the Wnt/beta-catenin pathway. Depletion of DP103 led to a marked reduction in the percentage of CSC-enriched mammospheres with reduced tumor-initiating ability. Mechanistically, we show DP103â��s role in driving Wnt/ beta-catenin pathway is independent of casein kinase I activity but highly dependent on GSK3�² activity. More interestingly, from molecular docking data, we found DP103 protein has to be phosphorylated at threonine residue 552, when it interacts with GSK3�². Surprisingly, induction of Wnt/�²-catenin signaling also significantly increased DP103 expression, indicating a possible positive feedback loop. Collectively, our data suggest a novel regulatory role of DP103 in the Wnt/�²-catenin signaling pathway in parental and CSC derived TNBC.

Biography

Email: csiapk@nus.edu.sg