Background: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients.
Methods: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters.
Results: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035).
Conclusion: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.