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

Kord M. Kober, Mark Schumacher, Yvette P. Conley, Kimberly Topp, Melissa Mazor, Marilynn J. Hammer, Steven M. Paul, Jon D. Levine, Christine Miaskowski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalMolecular Pain
Volume15
DOIs
StatePublished - 2019

Keywords

  • Chemotherapy
  • axon morphology
  • breast cancer
  • cytoskeleton
  • gene co-expression network analysis
  • gene expression
  • paclitaxel
  • pathway impact analysis
  • peripheral neuropathy
  • signaling pathway
  • survivor

ASJC Scopus subject areas

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

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