In a recent study published in Genes & Diseases, researchers from Nanjing Medical University, East China Normal University, and Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine investigated the role of the adipokine neuregulin 4 (NRG4), a member of the neurotrophic factor family, in suppressing metastatic dissemination and delineated the underlying molecular mechanisms involving ERBB4–YAP1 signaling.

Utilizing MMTV-PyMT and 4T1 breast cancer models, the researchers demonstrated that while obesity typically facilitates metastatic progression, NRG4—an adipokine secreted by inguinal white adipose tissue (iWAT)—functions as a potent suppressor of cancer cell migration and epithelial–mesenchymal transition (EMT). Proteomic analysis of the adipocyte secretome revealed that NRG4 expression is markedly reduced in the iWAT of obese subjects, highlighting the crucial role of adipose-derived factors in modulating the tumor microenvironment through paracrine signaling.

Single-cell transcriptomic data further corroborated these findings, showing a notable inverse association between NRG4 expression in circulating tumor cells and cellular invasion. Clinical data from TCGA and breast cancer tissue microarrays revealed that NRG4 levels are significantly lower in tumor tissues compared to adjacent healthy tissues, and that higher expression levels correlate with improved patient survival outcomes.

Mechanistically, the study highlights a pivotal regulatory role for the NRG4–ERBB4 signaling axis; NRG4 exerts its effects through binding to and activating the receptor tyrosine kinase ERBB4, leading to the generation of a cleaved intracellular domain that interacts with phosphorylated YAP1, thereby inhibiting its nuclear translocation and preventing its association with TEAD transcription factors that drive pro-metastatic gene expression programs.

In the absence of NRG4 signaling, active YAP1 translocates into the nucleus and binds to the transcription factor TEAD1, subsequently activating the transcription of matrix metalloproteinases, specifically MMP9 and MMP12, which facilitate extracellular matrix degradation and enhance tumor invasiveness. Conversely, NRG4-mediated inhibition of YAP1 activity results in their downregulation, effectively impairing the cellular machinery required for metastasis. Results from transcriptomic analyses, promoter activity assays, and protein interaction studies further confirm that the ERBB4–YAP1–TEAD axis serves as a central regulatory pathway controlling MMP expression and metastatic competence, while pharmacological or genetic inhibition of MMPs recapitulates the anti-metastatic effects observed with NRG4, reinforcing the functional importance of this signaling cascade.

Experimental validation using recombinant NRG4 (rNRG4) and patient-derived breast cancer organoids revealed that rNRG4 inhibits lung metastasis, angiogenesis, and migration, underscoring how metabolic dysfunction in adipose tissue facilitates tumor progression by diminishing the protective effects of NRG4.
Although the study demonstrates that NRG4 suppresses breast cancer metastasis via ERBB4–YAP1 signaling, the authors acknowledge that further investigation is needed to clarify the precise molecular interactions and post-translational modifications within this pathway, and to validate its prognostic and therapeutic potential through larger clinical cohorts and preclinical studies.

In conclusion, this study shows that NRG4, by inhibiting the ERBB4–YAP1–MMP signaling cascade, suppresses breast cancer metastasis, thereby highlighting the therapeutic potential of targeting the NRG4–ERBB4 axis in metastatic breast cancer, particularly in obesity-associated disease contexts.

Reference

Title of the original paper: NRG4 suppresses breast cancer metastasis via ERBB4-YAP1-mediated down-regulation of MMPs

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101691

Funding Information:

1. National Natural Science Foundation of China (No. 82473051, 82273232)
2. Natural Science Foundation of Jiangsu Province, China (No. BK20241775)
3. Changzhou Medical Center of Nanjing Medical University Program (Jiangsu, China) (No. CZKY102RC202301, CMC2024PY06, CMCM202403)
4. Changzhou Sci&Tech Program (Jiangsu, China) (No. LCQYBS202309, LC2024LCQYBS202309, 2024CZBJ020, 2022CZLJ017, LC20242022CZLJ017, QY202306)

Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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