Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology in breast cancer survivors with chronic paclitaxel-induced peripheral neuropathy. (September 2019)

• Record Type: Journal Article
• Authors: Kober, Kord M; Schumacher, Mark; Conley, Yvette P; Topp, Kimberly; Mazor, Melissa; Hammer, Marilynn J; Paul, Steven M; Levine, Jon D; Miaskowski, Christine
• Is Part Of: Molecular pain. Volume 15(2019)
• Publication Date: 2019-09
• Subjects: Chemotherapy -- peripheral neuropathy -- breast cancer -- survivor -- paclitaxel -- gene expression -- axon morphology -- cytoskeleton -- signaling pathway -- pathway impact analysis -- gene co-expression network analysis; Pain -- Molecular aspects -- Periodicals; Pain -- Pathophysiology -- Periodicals; Pain -- Physiological aspects -- Periodicals; 616.0472
• DOI: 10.1177/1744806919878088
• Languages: English
• ISSNs: 1744-8069

Abstract

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.