Abstract
Originally identified as Trop1, epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that received great attention because of its putative involvement in metastatic spread of several solid tumors including breast cancer. Experimental evidence indicated that EpCAM is a key transcriptional target of p53 tumor suppressor, due to the presence of specific p53 response elements within EPCAM gene promoter. Aim of present study was to investigate the joined prognostic significance of p53 and EpCAM in a cases series of 640 breast cancers with long-term follow-up. In addition, considering the role of EpCAM in modulating cell-cell interaction by decreasing the cytoskeleton-anchored fraction of E-cadherin, when feasible, we evaluated also E-cadherin expression. Results indicated that EpCAM overexpression was associated with a high incidence of relapse and that, when in association with p53 status, EpCAM was able to identify, within p53-positive cases, those with the highest incidence of relapse. Conversely, E-cadherin overexpression was associated with a low incidence of relapse. Overall, these findings are of particular clinical relevance taking into account the biological link between p53 activity and EPCAM gene expression and the functional relationship between EpCAM and E-cadherin in mediating cell-to-cell adhesion.
Highlights
Since its discovery in 1979, an intensive investigation has clearly proved that p53 is a pivotal tumor suppressor playing a central role in cell growth control by induction of apoptosis, cell-cycle arrest and senescence in response to a plethora of cellular stress signals (Levine & Oren, 2009; Suzuki, 2011)
The finding supports the clinical evidence that high epithelial cell adhesion molecule (EpCAM) expression is generally found in tumors potentially more aggressive
When we analyzed the joined effect of EpCAM expression and p53 status, we found that the subgroups EpCAM-negative/p53-positive, EpCAM-positive/p53-negative and EpCAM-negative/p53-negative had similar incidence of relapse, while the subgroup EpCAM-positive/p53-positive had a highest incidence of relapse
Summary
Since its discovery in 1979, an intensive investigation has clearly proved that p53 is a pivotal tumor suppressor playing a central role in cell growth control by induction of apoptosis, cell-cycle arrest and senescence in response to a plethora of cellular stress signals (Levine & Oren, 2009; Suzuki, 2011). TP53 gene is mutated in more than half of human cancers, and mutation frequently results in the expression/accumulation of an inactive protein, which hampers the correct cell cycle control and apoptosis activation (Olivier, 2010). P53 is mutated in about 30-40% of cases (Olivier, 2006), with a high frequency in some tumor subtypes including the pathologic class of triple-negative breast cancers (TNBCs). These tumors are characterized by a negative estrogen (ER) and progesterone receptor (PR) status, a negative HER2 expression, and the immunohistochemical expression of basal cytokeratin and epidermal growth factor receptor (EGFR) (Di Leo, 2007; Langerod, 2007; Chae, 2009). We found that p53 protein expression is able to subdivide this so critical pathologic class of breast tumors into two distinct subsets with a different outcome, being p53-expressing tumors associated with short overall and event-free survival (Biganzoli, 2011)
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