727: Stage-dependent sensory neuropeptide remodeling and neuropathic transition in breast cancer

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Omics (Proteomics/Metabolomics/Transcriptomics/Genomics)

Background and Aims: Triple-negative breast cancer (TNBC), defined by the absence of hormone receptors and HER2 expression, represents a highly aggressive subtype with limited therapeutic options, underscoring the urgent need to elucidate novel mechanisms governing its progression. Accumulating evidence suggests that sensory neurons innervating the tumor microenvironment exert functions beyond nociception, actively modulating cancer cell behavior and immune landscapes through activity-dependent release of neuropeptides. However, the temporal dynamics of neuron-derived molecular changes during TNBC progression, and their stage-specific functional implications, remain entirely undefined. This study aimed to evaluate time-dependent changes in sensory neuronal remodeling during breast cancer progression.

Methods: An orthotopic breast cancer model was established by implanting 4T1 murine TNBC cells into the left fourth mammary fat pad of BALB/c mice. Gene expression changes in dorsal root ganglia (DRG) were then systematically analyzed at multiple time points during tumor progression.

Results: In the early phase following tumor implantation, DRG exhibited marked upregulation of nociceptive neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P, accompanied by a concomitant reduction in prodynorphin (Pdyn), the precursor of dynorphin. Given that excessive CGRP and substance P release promotes tumor aggressiveness and fosters an immunosuppressive microenvironment, whereas dynorphin exerts counter-regulatory effects, this imbalance indicates the establishment of a pro-tumorigenic sensory neural milieu at tumor initiation. In contrast, during the tumor expansion phase, neuropeptide-associated alterations were attenuated, while genes associated with neuronal injury and demyelination were prominently upregulated. This shift reflects a transition from a functionally hyperactive state to a structurally compromised, neuropathic-like condition. Notably, molecules released from degenerating sensory neurons may further potentiate tumor malignancy in a stage-dependent manner.

Conclusions: These findings reveal a dynamic and staged remodeling of sensory neurons in TNBC, wherein early neuropeptide imbalance facilitates tumor progression, followed by neurodegenerative processes that may exacerbate disease severity. Targeting sensory neuron–derived signaling, including axon reflex mechanisms and demyelination pathways, represents a promising therapeutic avenue for TNBC.

References: No references are cited in this abstract.

Presenting Author: Takumi Yoshizawa
Submitting Author: Takumi Yoshizawa

Senior Author: Minoru Narita

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Hitoshi Makabe: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Jion Takise - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Michiko Narita - Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Yusuke Hamada: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Yukari Suda: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Kazumi Yoshizawa: Ph.D. - Laboratory of Pharmacology and Therapeutics, Tokyo University of Science
• Naoko Kuzumaki: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Minoru Narita: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute