Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology in breast cancer survivors with chronic paclitaxel-induced peripheral neuropathy

Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat breast cancer, is peripheral neuropathy (paclitaxel-induced peripheral neuropathy). Paclitaxel-induced peripheral neuropathy, which persists into survivorship, has a negative impact on patient’s mood, functional status, and quality of life. Currently, no interventions are available to treat paclitaxel-induced peripheral neuropathy. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie paclitaxel-induced peripheral neuropathy. While data from preclinical studies suggest that disrupting cytoskeleton- and axon morphology-related processes are a potential mechanism for paclitaxel-induced peripheral neuropathy, clinical evidence is limited. The purpose of this study in breast cancer survivors was to evaluate whether differential gene expression and co-expression patterns in these pathways are associated with paclitaxel-induced peripheral neuropathy. Methods Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology were identified between survivors who received paclitaxel and did (n = 25) or did not (n = 25) develop paclitaxel-induced peripheral neuropathy. Results Pathway impact analysis identified four significantly perturbed cytoskeleton- and axon morphology-related signaling pathways. Weighted gene co-expression network analysis identified three co-expression modules. One module was associated with paclitaxel-induced peripheral neuropathy group membership. Functional analysis found that this module was associated with four signaling pathways and two ontology annotations related to cytoskeleton and axon morphology. Conclusions This study, which is the first to apply systems biology approaches using circulating whole blood RNA-seq data in a sample of breast cancer survivors with and without chronic paclitaxel-induced peripheral neuropathy, provides molecular evidence that cytoskeleton- and axon morphology-related mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors and suggests pathways and a module of genes for validation and as potential therapeutic targets.