Proteomic Adaptations in the Spinal Cord of a Breast Cancer Model of Paclitaxel-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of taxane-based chemotherapy used in breast cancer treatment. Despite its prevalence, no FDA-approved therapies exist for CIPN prevention or treatment, highlighting the need for target prioritzation studies. Using label-free liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we examined the effects of four doses of paclitaxel (8 mg/kg) on the lumbar (L4-L6) spinal cord proteome in MMTV-PyMT-derived breast cancer bearing C57BL/6J mice. Breast cancer altered the expression of 551 proteins relative to naïve mice, while paclitaxel treatment in tumor-bearing mice altered 112 proteins relative to vehicle-treated cancer controls. Thirty-eight proteins were commonly affected by both conditions. Gene ontology enrichment and STRING protein-protein interaction analyses identified pathways linked to mitochondrial metabolism, ion transport, and neurotransmitter signaling. Pathway mapping further revealed convergent effects of breast cancer and paclitaxel on neuronal activation, neurotransmitter uptake, and mitochondrial dysfunction. Together, these findings define spinal cord proteomic alterations associated with acute paclitaxel-induced peripheral neuropathy and identify pain-relevant pathways for future mechanistic studies.