Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: Evidence for a cyclin D1-dependent cell cycle progression

Introduction: We recently showed that cyclin D1 is overexpressed in human p ancreatic carcinoma cells, and that this overexpression correlates signific antly with a poor prognosis. Aims: To assess the interrelations of epidermal growth factor (EGF), EGF re ceptor (EGFR), and cyclin D1 in human pancreatic carcinoma. Methodology and Results: In pancreatic carcinoma cell lines (BxPC-3, AsPC-1 ), cell cycle analysis revealed an increase in cells in the S/G1 phase betw een 18 and 30 hours after stimulation with 50 ng/mL EGF. Cyclin D1 mRNA inc reased after 2 hours, corresponding to an increase in cyclin D1 protein, wi th the maximum level between 7.5 and 10 hours after stimulation, as demonst rated by Western blot analysis. We performed immunohistochemical analysis o n 61 adenocarcinoma tissues for the expression of EGF, EGFR, and cyclin D1 and demonstrated an overexpression in the tumor cells in 51%, 54%, and 62.3 %, respectively, whereas normal human pancreas stained negative for all of the three factors. Interestingly, EGF and EGFR expression correlated signif icantly with the cyclin D1 expression in human pancreatic tumor cells (p < 0.001 and p < 0.01, respectively). Conclusion: These results demonstrate that cyclin D1 overexpression in the tumor cells of pancreatic carcinoma tissue is at least partly dependent on the mitogenic effects of EGF signaling through the EGFR.