Despite the loss of Adenomatous Polyposis Coli (APC) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl's mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.

The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Background While racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood. Methods We examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record and the survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated. Results Black patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.7, CI 1.01-2.9, p = 0.0467) for death. Though the response to therapy emerged as a strong predictor of survival (HR = 0.4, CI = 0.2-0.7, p = 0.0021), it was comparable between Blacks and Whites. Conclusions Despite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce the findings from previous studies regarding lower colorectal cancer survival in Black patients, and point to the importance of investigating other risk factors including genetic and pathogenic differences.

The 2008 recommendation appeared to reduce PSA screening rates in older men in 2009 and 2010; there was a substantial reduction in men aged 75 and older and a more modest reduction in men aged 65 to 74.