Abstract 4429: Loss of function Cbl-c mutations in solid tumors

Abstract

Listen

Translate article

Abstract Receptor Tyrosine Kinase (RTK) signaling is essential for normal biological processes and disruption of this regulation can lead to tumor initiation and progression. Cbl proteins are a family of RING finger ubiquitin ligases that negatively regulate a variety of RTKs, including EGFR, MET, RET and components of the TCR pathway. Recent studies have identified a growing number of Cbl mutations associated with human myeloid neoplasias and epithelial tumors. Cbl-c is the most recently identified human Cbl protein and is expressed exclusively in epithelial cells. Recently, a novel cDNA has been isolated from the ductal carcinoma of a mouse mammary cancer model. This mutant has a deletion in the catalytic domain of Cbl-c, thereby resembling known Cbl family mutations associated with myeoloid neoplasias. Genomic analysis of both parental and transgenic lines shows no evidence of germline mutation indicating that this mutation is likely a somatic mutation. In overexpression studies, this mutant cDNA fails to mediate ubiquitination and degradation of activated EGFR and, acting as a dominant negative, enhances cell transformation. Furthermore, data mining reveals several Cbl family mutations associated with solid tumors in humans. Subsequent cell-based analysis demonstrates a similar loss of E3 function in some of these human mutations. Through subsequent analysis of transforming capacity and signal pathway regulation, we are assessing interacting partners of Cbl-c and the potential role of these mutations in tumorigenesis. Citation Format: Stephen C. Kales, Philip E. Ryan, Marion M. Nau, Jeffrey E. Green, Stanley Lipkowitz. Loss of function Cbl-c mutations in solid tumors. [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 4429. doi:10.1158/1538-7445.AM2014-4429