Background: Targeting the type 1 insulin-like growth factor receptor (IGF1R) in breast cancer remains an ongoing clinical challenge. Oncogenic IGF1R-signaling occurs via activation of PI3K/AKT/MAPK downstream mediators which regulate cell proliferation and protein synthesis. To further understand IGF1R signaling we have investigated the involvement of the oncogenic IGF1R-related sphingosine kinase (SphK) pathway.
Methods: The prognostic (overall survival, OS) and therapeutic (anti-endocrine therapy) co-contribution of IGF1R and SphK1 were investigated using breast cancer patient samples (n = 236) for immunohistochemistry to measure total and phosphorylated IGF1R and SphK1. Kaplan-Meier and correlation analyses were performed to determine the contribution of high versus low IGF1R and/or SphK1 expression to OS in patients treated with anti-endocrine therapy. Cell viability and colony formation in vitro studies were completed using estrogen receptor (ER) positive and negative breast cancer cell-lines to determine the benefit of IGF1R inhibitor (OSI-906) and SphK inhibitor (SKI-II) co-therapy. Repeated measures and 1-way ANOVA were performed to compare drug treatments groups and the Chou-Talalay combination index (CI) was calculated to estimate drug synergism in vitro (CI < 1).
Results: High IGF1R and SphK1 protein co-expression in tumor tissue was associated with improved OS specifically in ER-positive disease and stratified for anti-endocrine therapy. A significant synergistic inhibition of cell viability and/or colony formation following OSI-906 and SKI-II co-treatment in vitro was evident (p < 0.05, CI < 1).
Conclusion: We conclude that high IGF1R and SphK1 co-expression act together as prognostic indicators and are potentially, dual therapeutic targets for the development of a more effective IGF1R-directed combination breast cancer therapy.
Keywords: Breast cancer; Insulin-like growth factor receptor; Targeted-therapies and sphingosine kinase.