Abstract 1396: Musashi 1 stabilizes TAC1 transcript in breast cancer cells to increase the production of onco-substance P

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Abstract Despite improved education and aggressive treatments, the mortality of breast cancer (BC) remains high. The TAC1 gene exerts oncogenic effects partly due to its major peptide, substance P, inducing the production of cytokines, which facilitate expression of the tumor-promoting truncated neurokinin-1 receptor. In turn, TAC1 facilitates metastasis to bone marrow and brain. TAC1 expression in BC cells (BCCs) occurs partly through increased translation of its mRNA. Cytosolic extracts from TAC1-expressing cells (BCCs and ectopic expression in non-tumorigenic breast cells) were analyzed for the candidate RNA-binding protein. In vitro translational, RNA stabilization, RNA shift and proteomic analyses identified a 40 kDa binding protein, which interacted with Exon 7 of the 3′ UTR of TAC1. Western blots and RNA supershift assay identified musashi 1 (Msi1) as the TAC1 mRNA binding protein. The data also indicated that TAC1 expression was sufficient for an increase in Msi1. A reporter gene system utilizing the TAC1 3′ UTR indicated that Msi1 competed with the endogenous translational suppressors, miR-130a and -206 for the same interacting site. Use of anti-miRs, Msi1 shRNA and the reporter gene system confirmed Msi1 as the stabilizer of TAC1 mRNA to increase the production of substance P. In vivo studies with nude mice showed reduced tumor growth with Msi1 knockdown BCCs compared to control. Msi1 knockdown retracted the tumor, indicating a role in tumor initiation. These findings correlated with a loss of two stem cell genes, REST and Oct4. In summary, this study identified Msi1 as a central RNA binding protein, which enhanced expression of the oncogenic TAC1 in BCCs. The data also suggested that Msi1, through TAC1 might be important in tumor initiation. These findings have clinical implications as a new drug target to reverse the oncogenic effects of TAC1. Furthermore, the feasibility of targeting TAC1 is evident since its receptor antagonist such as aprepitant are already approved by the FDA. Citation Format: George R. Nahas, Raghav G. Murthy, Shyam A. Patel, Steven J. Greco, Pranela Rameshwar. Musashi 1 stabilizes TAC1 transcript in breast cancer cells to increase the production of onco-substance P. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1396. doi:10.1158/1538-7445.AM2014-1396