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Use of P63 expression to define a lethal subset of muscle-invasive bladder cancers.

4653 Background: Previous studies implicate p63 as an epithelial marker in epithelial-to-mesenchymal transition (EMT) and in the maintenance of epithelial stem cell compartments. While known to be downregulated in the transition from superficial to muscle-invasive bladder cancer (MIBC), the relationship between p63 expression and survival in MIBC is not clear.


METHODS
Using real-time PCR and whole genome expression profiling, we characterized p63 expression and several genes implicated in EMT in 15 human bladder cancer cell lines and 101 primary tumors. We correlated marker expression with stage, disease-specific (DSS), and overall survival (OS), and then validated these markers at the protein level by immunohistochemistry (IHC) in an independent set of tissue from 57 patients with MIBC.


RESULTS
Expression of epithelial markers E-cadherin and p63 correlated directly with one another and inversely with expression of mesenchymal markers Zeb-1, Zeb-2, and vimentin. EMT marker expression was associated with muscle invasion with non-MIBC expressing high levels of E-cadherin (p<0.0001) and p63 (p=0.01), and MIBC expressing high levels of mesenchymal markers (p<0.0001 for Zeb-1, Zeb-2, and vimentin). Interestingly, a subset of MIBC maintained high levels of E-cadherin and p63 expression. Patients with MIBC that retained p63 had a significantly worse OS (p=0.007) and DSS (p=0.004). In an independent validation set, p63 expression by IHC was restricted to the nucleus of tumor cells, with higher percent expression associated with adverse OS (p=0.03) and DSS (p=0.046). Using multivariate analysis, both p63 and MMP9, which has been previously associated with adverse outcome, remained independent predictors of survival (DSS p63: HR1.63, p=0.022; log-MMP9: HR 1.35, p = 0.003).


CONCLUSIONS
Molecular markers of EMT are elevated in muscle-invasive bladder cancers; however, retention of the "epithelial" marker p63 in muscle-invasive tumors is associated with a worse outcome. MMP9 and p63 expression appeared independent in predicting adverse outcomes in MIBC. Mechanisms driving MIBC displaying an "epithelial" phenotype and the role of EMT in chemotherapy response and cancer metastases need to be more fully explored in future studies.