Abstract 3398: Reciprocal regulation of MYB and CXCR4 in pancreatic cancer cells: Potential pathobiological implications

Abstract

Abstract Pancreatic cancer remains one of the most lethal malignancies with a median post-diagnosis survival of 3-8 months, and a 5 year survival of ∼6%. The poor outcome from pancreatic cancer is largely due to the presence of locally advanced or metastatic disease at the time of diagnosis. Therefore, it is imperative to identify novel molecular targets driving aggressive and metastatic progression of pancreatic cancer, and build up a better understanding of the underlying molecular mechanisms. In this regard, we have identified that MYB, encoding for an oncogenic transcription factor (a cellular progenitor of v-Myb oncogenes), is overexpressed in majority of pancreatic cancer cases and cell lines. Furthermore, our data from gain and loss of function studies (in BxPC3 and MiaPaCa cells, respectively) show that MYB overexpression is associated with pancreatic tumor growth and metastasis. From the mechanistic standpoint, we observe that MYB regulates the expression of CXCR4 through direct binding to its promoter. MYB-overexpressing BxPC3 cells exhibit significantly enhanced migration and invasion against a CXCL12 (sole ligand for CXCR4) gradient, whereas it is suppressed in MYB-silenced MiaPaCa cells as compared to their respective control cells. Furthermore, MYB-overexpressing cells exhibit greater resistance to serum-deprivation in CXCL12-supplemeted media, an effect that is abrogated upon CXCR4 silencing. Interestingly, in parallel studies, we have observed that treatment with CXCL12 also leads to MYB upregulation in pancreatic cancer cells in a CXCR4 dependent manner. Together, these data are suggestive of a novel positive feedback regulatory loop between CXCR4 and MYB and hold important significance for pancreatic cancer pathobiology. Citation Format: Sanjeev K. Srivastava, Arun Bhardwaj, Sumit Arora, Seema Singh, William E. Grizzle, Ajay P. Singh. Reciprocal regulation of MYB and CXCR4 in pancreatic cancer cells: Potential pathobiological implications. [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 3398. doi:10.1158/1538-7445.AM2014-3398