Role of Progesterone Receptor A and B Isoforms in Lung Neuroendocrine Tumors

Abstract

Lung neuroendocrine tumors (NETs) incidences are increasing in recent years. Women with lung NETs have significantly better survival rates as compared to men suggesting the involvement of sex steroids and their receptors in the progression of lung NETs. Recent data suggested that progesterone receptor (PR) may play a role in the survival of lung NET patients. PR exists as two major isoforms, PRA and PRB. How expression of PR isoforms affects proliferation of lung NETs and patient’s survival is not known. To determine the role of PR isoforms in lung NETs, we constructed H727 lung NET cell models expressing PRB or PRA. PR expressions, transcriptional activities and localization in these cell models were similar to endogenous PR in breast cancer cells. PR expression inhibited H727 cell proliferation in the absence of progestin. A monoclonal antibody specific to the N-terminus unique to PRB (250H11 mAb) was developed to specifically detect PRB, but not PRA, by immunoblots and immunostaining. Immunohistochemistry staining with 250H11 and 1294 mAb, detecting PRB and PRB&PRA, respectively, were performed on 198 cases of lung NETs tissue sections. Comparing with PR negative cases, PR-positive lung NETs showed significantly lower mitotic index and were found mostly in lower grade lung NETs. Interestingly, PRB expressions in lung NETs were associated with longer disease-free survival. Using these PR specific antibodies, we showed PR expression in pulmonary neuroendocrine cells of normal fetal and adult lung suggesting a role of PR in the development of neuroendocrine cells. Together, these data demonstrate that PRB expression is associated more differentiated less proliferative tumors and longer disease-free survival of patients with lung NETs. Better understanding of molecular mechanism of how PR or PR isoform signals in lung NET cells may help us to develop novel therapeutic strategies that will be beneficial for lung NET patients in the future.