Highly Expressed Progesterone Receptor B Isoform Increases Platinum Sensitivity and Survival of Ovarian High-Grade Serous Carcinoma

SIMPLE SUMMARY: Ovarian high-grade serous carcinoma is the deadliest ovarian cancer. Cancer cells develop resistance to anti-cancer regimens leading to poor prognosis. Previous studies showed that the progesterone receptor was associated with better rates of survival of ovarian cancer patients. We aimed to investigate the association between the progesterone receptor and its isoform-B and platinum sensitivity of ovarian high-grade serous carcinoma. We found that strong progesterone receptor-B expression was associated with better platinum sensitivity and better survival in high-grade serous ovarian cancer patients. Our clinical data also showed that a high expression of progesterone receptor-B and optimal debulking were the independent factors associated with better platinum sensitivity. In a cell model, enhancing progesterone receptor-B expression and progesterone treatment increased platinum sensitivity and platinum-related apoptosis of the ovarian cancer cells. These might be potential therapeutic targets of ovarian high-grade serous carcinoma. ABSTRACT: Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms’ expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson’s correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated.