Aim: Serous epithelial ovarian cancer often presents at late stage and survival rates for high-grade disease have improved little over recent decades, despite introduction of experimental treatment regimes. ABC transporters mediate the active transport of a variety of chemotherapeutic agents, but also control efflux of important endogenous substrates.
Methods: We examined the impact of ABC transporter gene expression on clinical outcome in epithelial ovarian cancer in 150 serous ovarian cancer patients recruited to the Australian Ovarian Cancer Study using real-time PCR and determined associations with clinical outcome using Kaplan-Meier survival analysis and Cox regression. Associations were further examined in The Cancer Genome Atlas, using expression microarray data.
Results: High-level expression of ABCA1, ABCA6, ABCA8 and ABCA9 in primary tumours was significantly associated with reduced survival in serous ovarian cancer patients in two independent datasets. Expression of each of these genes was particularly high in tumours characterised by a desmoplastic phenotype. By contrast, low levels of ABCA5 were associated with shorter overall survival (OS). The effects of ABCA1, ABCA5 and ABCA9 remained significant in multivariate analysis and their combined expression was associated with particularly poor outcome. Studies in vitro demonstrated that suppression of ABCA1 expression leads to reduced ovarian cancer cell growth and migration and that statin treatment inhibits ovarian cancer cell migration.
Conclusion: Aberrant expression of several ABCA family transporter genes was observed in poor-outcome cases of epithelial ovarian cancer. In light of the role of ABCA genes in lipid biosynthesis, trafficking and homeostasis, together with accumulating evidence for the importance of such substrates to the inflammatory microenvironment, our data highlight the potential of these transporters, particularly ABCA1, as therapeutic targets for the treatment of ovarian cancer.