Use of the androgen signalling pathway to identify ovarian cancer patients suitable for hormonal therapy

Abstract

Background Despite confirmed AR expression in epithelial ovarian cancer (EOC), clinical response to anti-androgen treatment is poor. Stratification of susceptible individuals with a specific biomarker, such as the previously described Rab35, might enable more effective treatment strategies. Abiraterone, a steroid synthesis inhibitor, might be of therapeutic benefit in specific EOC subgroups. Methods Primary cell cultures (PCO) generated from ascites were used as a representative model for the heterogeneity of EOC. PCOs were examined for AR and Rab35 expression at mRNA and protein level and were stimulated with androgens to evaluate subsequent Rab35 expression. CYP17 expression was measured in ovarian cancer cell lines and PCOs and the effect of abiraterone on proliferation was assessed in two ovarian cancer cell lines. Results The AR expression was widely different when examined with qRT-PCR, Western blotting and immunohistochemistry. No correlations were found between the modalities for either AR or Rab35 expression. In contrast, AR and Rab35 expression showed a positive correlation at the protein and mRNA level. However, androgen treatment of PCOs showed >50% increase in Rab35 mRNA expression in only 40% of PCOs. CYP17 expression was confirmed in all examined cell cultures and PCOs at both, the protein and mRNA level. Abiraterone treatment of the ovarian cancer cell lines led to significant inhibitory effects on proliferation. On protein level however, abiraterone exposure resulted in increased expression of AR and CYP17. Conclusion Although AR expression was confirmed in POCs, it remains unclear which technique would be most suitable to stratify for androgen expressing tumours. Rab35 in PCOs appeared to be androgen-related and hence may not be a suitable biomarker in EOC for AR. The inhibitory effect of abiraterone on proliferation that was observed in ovarian cultures is suggestive of a dual action of the compound. Response to abiraterone exposure in PCOs might help to determine potential treatment effects.