ArticleOncogenesis2017
MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells.
Article in Oncogenesis, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 60 citations in OpenAlex.
- Regulation of E-cadherin by mixed lineage kinase 3 (MLK3) mediates cell adhesion in ovarian cancer spheroids.Biochimica et biophysica acta. Molecular cell research · 2026Article
- Effect of combined blue light and 5-ALA on mitochondrial functions and cellular responses in B16F1 melanoma and HaCaT cells.Cytotechnology · 2024Article
- Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC.Journal of medicinal chemistry · 2024Article
- FOSL1's Oncogene Roles in Glioma/Glioma Stem Cells and Tumorigenesis: A Comprehensive Review.International journal of molecular sciences · 2024Review
- Fra-1 affects chemotherapy sensitivity by inhibiting ferroptosis in gastric cancer cells.Cancer drug resistance (Alhambra, Calif.) · 2024Article
- The Expression Profiles and Clinical Significance of Mixed Lineage Kinases in Glioma.Mediators of inflammation · 2024Article
- Overexpression of FRA1 (Cells · 2023Article
- FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer.International journal of molecular sciences · 2023Review
- TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer.Oncogene · 2023Article
- Elevated ITGA2 expression promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma.Scientific reports · 2022Article
- Article
- Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins.International journal of molecular sciences · 2022Article
- New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer.Genes · 2021Review
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- Will CRISPR-Cas9 Have Cards to Play Against Cancer? An Update on its Applications.Molecular biotechnology · 2021Review
- Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8Journal for immunotherapy of cancer · 2020Article
- The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications' door.Oncogene · 2020Review
- Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase.Cancers · 2020Article
- MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration.PloS one · 2020Article
- Expression and function of FRA1 protein in tumors.Molecular biology reports · 2020Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mixed-lineage kinase 3 (MLK3), a mitogen-activated protein kinase kinase kinase (MAP3K), has critical roles in metastasis of triple-negative breast cancer (TNBC), in part by regulating paxillin phosphorylation and focal adhesion turnover. However the mechanisms and the distinct step(s) of the metastatic processes through which MLK3 exerts its influence are not fully understood. Here we report that in non-metastatic, estrogen receptor-positive breast cancer (ER+ BC) cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), which is accompanied by elevation of matrix metalloproteinases (MMPs), MMP-1 and MMP-9. MLK3-induced ER+ BC cell invasion is abrogated by FRA-1 silencing, demonstrating that MLK3 drives invasion through FRA-1. Conversely, in metastatic TNBC models, high FRA-1 levels are significantly reduced upon depletion of MLK3 by either gene silencing or by the CRISPR/Cas9n editing approach. Furthermore, ablation of MLK3 or MLK inhibitor treatment decreases expression of both MMP-1 and MMP-9. Consistent with the role of tumor cell-derived MMP-1 in endothelial permeability and transendothelial migration, both of these are reduced in MLK3-depleted TNBC cells. In addition, MLK inhibitor treatment or MLK3 depletion, which downregulates MMP-9 expression, renders TNBC cells defective in Matrigel invasion. Furthermore, circulating tumor cells derived from TNBC-bearing mice display increased levels of FRA-1 and MMP-1 compared with parental cells, supporting a role for the MLK3-FRA-1-MMP-1 signaling axis in vascular intravasation. Our results demonstrating the requirement for MLK3 in controlling the FRA-1/MMPs axis suggest that MLK3 is a promising therapeutic target for treatment of TNBC.
Identifiers
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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.