In a groundbreaking study recently 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 have uncovered a pivotal role of the adipokine neuregulin 4 (NRG4) in suppressing breast cancer metastasis. The investigation elucidates a complex molecular mechanism centered on the ERBB4–YAP1 signaling axis, revealing new avenues for understanding how obesity-driven metabolic alterations influence cancer progression and offering promising therapeutic implications for metastatic breast cancer.
Breast cancer metastasis remains a principal cause of mortality worldwide, with obesity recognized as a significant factor that exacerbates tumor aggressiveness and metastatic potential. The study leverages two established breast cancer mouse models, MMTV-PyMT and 4T1, subjecting them to high-fat diet (HFD) conditions to simulate obesity-induced cancer progression. Notably, while obesity promoted primary tumor growth and the number of lung metastatic nodules in these models, the secreted protein NRG4, predominantly expressed by inguinal white adipose tissue (iWAT), emerged as a robust suppressor of epithelial–mesenchymal transition (EMT) and cancer cell migration.
Proteomic profiling of the adipocyte secretome revealed a marked decrease in NRG4 expression in the iWAT of obese subjects, signifying a disruption of the protective adipokine milieu conducive to tumor containment. This downregulation underscores the functional importance of adipose tissue not only as an energy reservoir but also as a critical endocrine organ capable of modulating the tumor microenvironment via paracrine signaling pathways. Such findings add a nuanced layer to the obesity-cancer nexus, emphasizing the molecular crosstalk between adipose-derived factors and tumor cells.
Expanding on the mechanistic insights, single-cell transcriptomic analyses demonstrated an inverse correlation between NRG4 expression and the invasiveness of circulating tumor cells. This finding was further corroborated by clinical data derived from The Cancer Genome Atlas (TCGA) and breast cancer tissue microarrays, which showed significantly reduced NRG4 levels in malignant tissues compared to adjacent normal breast tissue. Importantly, elevated NRG4 expression correlated strongly with improved patient survival outcomes, positioning this adipokine as a potential prognostic biomarker.
At the heart of the molecular mechanism lies the ERBB4 receptor tyrosine kinase, a prominent member of the epidermal growth factor receptor family. NRG4 binds to ERBB4, activating the receptor and triggering proteolytic cleavage that releases an intracellular domain. This cleaved product forms a complex with phosphorylated Yes-associated protein 1 (YAP1), a transcriptional coactivator implicated in oncogenic EMT programs. Crucially, this interaction inhibits YAP1’s nuclear translocation, thereby preventing its association with TEA domain (TEAD) transcription factors which otherwise drive the expression of genes critical for metastasis.
In pathophysiological conditions characterized by reduced NRG4—such as obesity—YAP1 escapes ERBB4-mediated regulation and translocates into the nucleus. Once nuclear, YAP1 partners with TEAD1 to initiate transcriptional upregulation of matrix metalloproteinases MMP9 and MMP12. These proteases facilitate extracellular matrix degradation, a hallmark of invasive and metastatic cancer cells. By repressing YAP1 activity, NRG4 effectively downregulates MMP expression, curtailing the cell’s invasive machinery and metastatic potential.
Comprehensive transcriptomic analyses, promoter activity assays, and protein interaction studies reinforce the functional significance of this regulatory cascade. The ERBB4–YAP1–TEAD axis emerges as a crucial signaling pathway dictating metastatic competency via modulation of MMP levels. Moreover, pharmacological and genetic inhibition of MMPs phenocopied the anti-metastatic effects elicited by NRG4, providing further proof of concept for targeting this axis therapeutically.
Validation of these findings extended to the use of recombinant NRG4 (rNRG4) and patient-derived breast cancer organoids. Treatment with rNRG4 not only suppressed tumor cell migration but also significantly inhibited lung metastasis and tumor-associated angiogenesis in vivo. These experimental outcomes highlight the translational potential of modulating NRG4 signaling pathways to mitigate obesity-associated breast cancer progression.
Despite these compelling advances, the authors underscore the necessity for further research into the precise molecular interactions and post-translational modifications underpinning the ERBB4–YAP1 axis. Detailed characterization of these mechanisms will deepen our understanding and aid in the development of targeted therapies. In addition, larger clinical cohorts and robust preclinical models are warranted to substantiate the prognostic and therapeutic value of NRG4 in metastatic breast cancer.
The study’s insights elucidate how metabolic dysfunction in adipose tissue exacerbates breast cancer dissemination by depleting protective adipokines such as NRG4. This establishes a previously underappreciated link between systemic metabolic state and local tumor microenvironment dynamics, advancing the frontier of cancer metabolism research. By inhibiting the oncogenic YAP1-mediated transcriptional program, NRG4 reinstates control over metastatic gene expression, underscoring the therapeutic promise of activating the ERBB4 receptor.
In conclusion, the identification of NRG4 as a key suppressor of breast cancer metastasis via the ERBB4–YAP1–MMP signaling axis represents a paradigm shift in understanding the molecular interplay between obesity and cancer progression. Therapeutic strategies aimed at restoring or mimicking NRG4 activity have the potential to significantly ameliorate metastatic outcomes, especially in obese patients. This discovery opens innovative paths for molecular targeted therapies in breast cancer that address the metabolic components of tumor biology.
As scientists continue to decode the complex signaling networks that govern cancer metastasis, this study adds a crucial piece to the puzzle, illuminating how adipose-derived factors influence tumor invasiveness at multiple molecular levels. It is an exemplar of how integrative approaches combining proteomics, single-cell transcriptomics, and clinical data can yield transformative insights with direct applicability to patient care.
The research not only enhances the mechanistic understanding of breast cancer metastasis but also offers hope that reprogramming the tumor microenvironment through manipulation of adipokines like NRG4 may improve clinical outcomes. In an era of personalized medicine, targeting obesity-associated molecular vulnerabilities stands as a compelling frontier in oncologic therapeutics.
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Subject of Research: Breast cancer metastasis, adipokine signaling, obesity-related cancer progression, ERBB4–YAP1 pathway
Article Title: NRG4 suppresses breast cancer metastasis via ERBB4-YAP1-mediated down-regulation of MMPs
References: DOI 10.1016/j.gendis.2025.101691
Image Credits: Saijun Wang, Mingwei Guo, Lingyun Xu, Jiaming Xue, Shuai Chen, Ke Xu, Yan Zhou, Aihua Gu, Wei Gao, Jianwei Zhou, Yi Zhang, Liming Tang, Dongmei Wang
Keywords: Breast cancer, metastasis, obesity, neuregulin 4, NRG4, ERBB4, YAP1, matrix metalloproteinases, MMP9, MMP12, epithelial–mesenchymal transition, EMT, adipokine, tumor microenvironment
