ArticleCancer research2012
CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer.
Article in Cancer research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 70 citations in OpenAlex.
- CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/β-Catenin Signaling to Inhibit EZH2-Driven EMT.Cancer research · 2024Article
- The emerging role and mechanism of HMGA2 in breast cancer.Journal of cancer research and clinical oncology · 2024Review
- Multiomics-based molecular subtyping based on the commensal microbiome predicts molecular characteristics and the therapeutic response in breast cancer.Molecular cancer · 2024Article
- Dual roles of cellular communication network factor 6 (CCN6) in the invasion and metastasis of oral cancer cells to bone via binding to BMP2 and RANKL.Carcinogenesis · 2023Article
- Structural insights into regulation of CCN protein activities and functions.Journal of cell communication and signaling · 2023Review
- The Impact of BMP-4 Tissue Expression on Progression and Survival in Breast Cancer.Medical archives (Sarajevo, Bosnia and Herzegovina) · 2023Article
- The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas.Journal of cell communication and signaling · 2022Article
- CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology.Journal of cell communication and signaling · 2021Review
- Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives.Current oncology (Toronto, Ont.) · 2021Review
- USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1.Cell cycle (Georgetown, Tex.) · 2021Article
- CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment.Frontiers in genetics · 2021Review
- The emerging role of WISP proteins in tumorigenesis and cancer therapy.Journal of translational medicine · 2019Review
- CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast.Breast cancer research and treatment · 2018Article
- The role of K63-linked polyubiquitination in cardiac hypertrophy.Journal of cellular and molecular medicine · 2018Review
- Identifying osteosarcoma metastasis associated genes by weighted gene co-expression network analysis (WGCNA).Medicine · 2018Article
- TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis.Nature communications · 2018Article
- Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas.Journal of cell communication and signaling · 2018Review
- p38 predicts depression and poor outcome in esophageal cancer.Oncology letters · 2017Article
- Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance.Endocrine-related cancer · 2017Review
- Identification of hub genes involved in the development of hepatocellular carcinoma by transcriptome sequencing.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
CCN6 (WISP3) is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition, cell invasion, and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated TAK1/p38 activation and invasive capacity, both by binding BMP4 protein as well as decreasing BMP4 protein levels. Effects on BMP4 and p38 were confirmed in vivo where they correlated with decreased metastasis. In clinical specimens, we found that CCN6 expression was inversely associated with BMP4 and phospho-p38 levels in 69% of invasive breast carcinomas examined, consistent with the functional results. Together our findings identify a novel modifier pathway through which CCN6 acts to limit breast cancer invasion and metastasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.