Gene expression network analysis reveals pathway interactions of the IGF axis in breast cancer

Background: Understanding crosstalk and feedback among oncogenic pathways is a critical challenge to overcoming resistance to targeted anticancer therapy. The topology of biological networks has increasingly been used to complement studies based on individual genes or gene collections. We apply network analysis to understand interactions among critical biological signaling pathways in breast cancer. Results: An overlapping clustering of the networks showed highly distinct patterns in patients with high IGF versus low IGF axis. We demonstrate through cluster comparison metrics and permutation studies that these differences are unlikely to occur by chance. IRS-1, an IGF adaptor protein, is shown to have a highly central place in the IGF high as compared to the IGF low networks. We further demonstrate that network connections reveal information about interactions of genes in TGF-beta, MAPK, and other pathways known to interact with IGF. Conclusions: Network analyses can provide novel insights and hypotheses about signaling pathways involved in feedback and crosstalk in breast cancer.