The role of estrogen receptor beta (ER-β) expression in ductal pancreatic adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-β may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-β, phosphorylated ER-β (pER-β), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. Methods: We

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... dentified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of ER-β and pER-β was evaluated using the immunoreactive score (IRS) by Remmele. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. Results: More than half of the tumor samples showed high expression of all the five markers. Univariate survival analysis showed that higher UICC stage, tumor grade, residual tumor (R1) and expression of pER-β were correlated to shorter overall and disease- free survival. All the other markers investigated showed no prognostic relevance. Cox multivariate analysis revealed that pER-β expression was an independent factor correlating with a shorter overall survival (hazard ratio 1.9; P= 0.021) and disease-free survival (hazard ratio 1.9; P= 0.033). Conclusions: Expression of pER-β constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. The underlying molecular mechanisms require further investigation. These data may help in identifying patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.