Androgen receptor expression is a biological marker for androgen sensitivity in high grade serous epithelial ovarian cancer

Objectives

In the present study we explore the effects of androgens and anti-androgens on primary cultures of EOC cells. We also investigate the effects of chemotherapy on AR expression. Epithelial ovarian cancer (EOC) arises from ovarian surface epithelial cells (OSE), which express the androgen receptor (AR). Androgen stimulation of OSE cells results in increased proliferation and protection from apoptosis. Nevertheless, in clinical trials anti-androgens have had a low objective response rate in relapsed ovarian cancer.

Methods

1. Androgen receptor (AR) expression and response to androgenic stimulation were correlated in primary ovarian cancer cells derived from ascitic fluid from patients with advanced ovarian cancer,2. AR expression in primary epithelial ovarian cancer was investigated before and after chemotherapy using paired histological samples which had been incorporated into a tissue microarray.

Results

Eleven primary ovarian cancer cultures were established from ascitic fluid. There was wide variation of expression of androgen receptor mRNA between cultures. Cell division increased after dihydro-testosterone (DHT) stimulation in 6 out of 11 primary cultures. The fraction of cells in S-phase increased from 4.4% in cells grown in serum-free medium to 8.3% in cells stimulated with 100 nM of DHT (P < 0.001). The increase in S-phase fraction was abrogated after treatment with the anti-androgen, bicalutamide in 4 out of 5 responsive cultures. There was a strong correlation (r² = 0.7) between nuclear AR expression by immunohistochemistry and S-phase fraction changes in primary cultures.Paired pre- and post-chemotherapy histological samples from 29 patients were incorporated into a tissue microarray (TMA). Nuclear and cytoplasmic AR expression by immunohistochemistry (IHC) decreased significantly after chemotherapy (P < 0.01).

Conclusion

AR expression correlates with increased S-phase fraction in response to androgenic stimulation. Immunohistochemical analysis of AR expression needs to be further tested in clinical trials to select AR positive EOC for anti-androgen therapy. Anti-androgen use early in the course of ovarian cancer is more likely to be effective as these data suggest that androgen receptor expression decreases with exposure to chemotherapy and this may explain the low response rates seen in clinical trials of patients heavily pre-treated with multiple courses of chemotherapy.