Insulin-like growth factor receptor and sphingosine kinase are prognostic and therapeutic targets in breast cancer

Aleksandra M Ochnik,Robert C Baxter

doi:10.1186/s12885-017-3809-0

Aleksandra M Ochnik, Robert C Baxter

Open Access

https://doi.org/10.1186/s12885-017-3809-0

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Abstract

BackgroundTargeting 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.MethodsThe 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).ResultsHigh 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).ConclusionWe 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.

Highlights

Targeting the type 1 insulin-like growth factor receptor (IGF1R) in breast cancer remains an ongoing clinical challenge
IGF1R expression is positively associated with overall survival in breast cancer In formalin-fixed paraffin embedded (FFPE) tissue sections, high total IGF1R protein expression, in isolation or combined with sphingosine kinase 1 (SphK1), was associated with a better overall survival (OS) rate when analyzed across all patients suggesting IGF1R, alone or together with SphK1, acts as a positive prognostic indicator (Table 3, p = 0.018, Fig. 2a and p = 0.028,; Fig. 2b, respectively)
IGF1R and SphK1 co-expression is associated with improved disease outcome in anti-endocrine therapy treated breast cancer patients Given that we identified a relationship between high IGF1R protein expression alone and combined with high SphK1 expression, and overall patient survival, that was most evident for estrogen receptor (ER)-positive breast cancers, we undertook further analysis to determine whether a similar relationship existed when samples were stratified for anti-endocrine therapy

Summary

Introduction

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. Given the heterogeneity that exists among breast cancer molecular subtypes based on the ER, progesterone receptor (PR) and HER2 status, which modulate many growth factor signaling pathways such as the IGF1R signaling pathway has been shown to play an oncogenic role in both ER-positive and ER-negative breast cancer via the activation of downstream PI3K/AKT/MAPK/FAK signaling mediators to effectively regulate cell proliferation, migration and protein synthesis (i.e. mRNA translation) [6, 7]. High phosphorylated IGF1R (p-IGF1R) expression in luminal, triple-negative, and HER2 subtypes combined has been shown to be associated with a poorer survival outcome suggesting that IGF1R activation compared to expression may be more important as a prognostic factor [10]. There is still conflicting prognostic vs. preclinical data in relation to the benefits of IGF1R targeted therapies in breast cancer which highlights the need for a better understanding of IGF1R signaling [12]

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