Abstract 2003: C-terminal binding protein (CtBP): An emerging oncogene and small molecule drug target in solid tumors

C-terminal binding proteins 1 and 2 (CtBP) are transcriptional coregulators whose overexpression has been linked to poor prognosis and/or chemoresistance in most common solid tumor types. CtBP exerts oncogenic activities through modulation of gene expression programs governing cell survival, epithelial/mesenchymal transitions, migration/invasion, and cell cycle, and is also required for colon cancer tumor initiating cell function. CtBP, however, has never been formally characterized as an oncogene. We now show that Ctbp2 exhibits transforming activity in immortalized NIH 3T3 as well as mouse and human primary cells. Ctbp2 alone, or in cooperation with SV40 large T antigen (LT) transformed NIH 3T3 cells and MEF’s, respectively, to anchorage independence with similar efficiency to mutant H-Ras. Human BJ foreskin fibroblasts were also transformed to anchorage independence by CtBP2 in cooperation with LT, SV40 small T antigen, and h-TERT with efficiency similar to H-Ras, indicating that CtBP overexpression, as found in the majority of human colon, ovary, breast, and prostate cancers, may be a key oncogenic driver gene. To confirm the physiologic role of Ctbp2 in a mouse tumor model with Ctbp overexpression, we bred Apcmin/+ mice to Ctbp2 hemizygote (Ctbp2+/-) mice, which are otherwise healthy. CtBP is a known target of the APC E3 ligase and is thus stabilized in APC mutated human colon cancers and is found in high levels in APCmin polyps. Remarkably, survival to humane endpoint at 37 weeks for Apcmin/+ vs. Apcmin/+-Ctbp2+/- mice was 0% vs. 100% (p Citation Format: Evan T. Sumner, Sudha Korwar, Benjamin L. Morris, Martin M. Dcona, Brendan J. Hilbert, William E. Royer, Keith C. Ellis, Steven Grossman. C-terminal binding protein (CtBP): An emerging oncogene and small molecule drug target in solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2003.