Browsing by Author "Grönman, Jasmin"

High-grade serous ovarian cancer (HGSOC) is the most common histological type of epithelial ovarian cancer with the five-year survival rate of approximately only 40%. Platinum-based chemotherapy together with surgical cytoreduction is the standard of care in HGSOC. Platinum compounds bind to DNA causing intra- and interstrand cross-links ultimately leading to severe DNA damage in the form of DNA double-strand breaks. Functional DNA repair mechanisms, most importantly homologous recombination (HR), are crucial in repairing these double-strand breaks and maintaining genomic integrity. HR deficiency is found in approximately 50% of HGSOC tumours making these tumours sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. The androgen receptor (AR) has been reported to be expressed widely in the normal ovarian surface epithelium as well as in malignant ovarian cancer cells. With the current evidence pointing towards the involvement of AR signalling in the maintenance of HR as well as driving radiation resistance, combined or sequential use of anti-androgen therapies together with platinum-based compounds might function as a novel therapeutic approach and lead to the accumulation of DNA damage within HGSOC tumours. Blocking AR signalling in prostate cancer cells receiving androgen deprivation therapy has already been shown to functionally impair HR and result in the upregulation of PARP mediated pathways. To investigate the expression levels of AR within the human primary HGSOC tumour specimens, immunofluorescent immunohistochemistry together with reverse transcriptase polymerase chain reaction were performed. The androgen receptor was found to be expressed in approximately 75% of the patient samples with ≥10% nuclear AR staining. Intriguingly, the AR expression did not differ between primary and metastatic tumours or between chemo-naïve and chemotherapy treated samples. Moreover, the effects of AR inhibition and stimulation on the functional HR capacity of HGSOC cells was examined to elucidate the role of AR signalling in the homologous recombination DNA repair pathway. Receptor manipulation with an antagonist enzalutamide prior to gamma radiation led to a significant decrease in the HR capacity of HR- proficient and AR positive commercial HGSOC cell line OAW28. Furthermore, agonist treatment with dihydrotestosterone increased the HR capacity within these cells. A deeper understanding on the interactions between HR and AR signalling can be utilized in the development of future therapeutic strategies against platinum resistant HGSOC. Pharmaceutically induced HR deficiency has the potential to provide opportunities for a wide range of combination treatment strategies using standard of care chemotherapy in conjunction with molecularly targeted agents towards DNA damage response proteins as well as widen the therapeutic possibilities for the use of PARP inhibitors.