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Updated: Sep 4, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA Methyltransferase 3B-Mediated Intratumoral Heterogeneity and Therapeutic Targeting in Breast Cancer Recurrence
Abstract:
The mechanisms of how cancer cells are selected and evolve to establish distant metastatic colonies remain unclear. Tumor heterogeneity and lack of biomarkers are some of the most difficult challenges in cancer biology and treatment. Here using mouse models for triple-negative breast cancer (TNBC) metastasis, we report heterogeneous expression of DNA methyltransferase 3B (DNMT3B) in both mouse and human primary tumors. High levels of DNMT3B were correlated with poor clinical outcomes in multiple human breast cancer datasets. Mechanistically, clonal cells with high DNMT3B (DNMT3BH) showed higher vimentin (VIM) expression and displayed enhanced epithelial-to-mesenchymal transition capacity. Deletion of VIM diminished the metastatic phenotype of DNMT3BH cells. Importantly, in preclinical mouse models in which the primary tumors were surgically removed, perioperative targeting of DNMT3B in combination with chemotherapy markedly suppressed tumor recurrence and metastasis. Our studies identify DNMT3B-mediated transcription regulation as an important mediator of tumor heterogeneity and show that DNMT3B is critical for tumor invasion and metastasis, reinforcing its potential as a target for treating metastatic disease.
Implications:
Our findings of transcriptome changes mediated by DNMT3B provide new mechanistic insight for intratumor heterogeneity and chemoresistance, and therapeutic targeting of DNMT3B in combination with chemotherapy offer additional treatment options for metastatic disease especially for patients with TNBC.
Insights
DNA methyltransferase 3B (DNMT3B) drives triple-negative breast cancer (TNBC) metastasis by enhancing epithelial-to-mesenchymal transition. Targeting DNMT3B with chemotherapy can suppress tumor recurrence and metastasis.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Epigenetics
Background:
- Tumor heterogeneity and metastasis mechanisms are poorly understood challenges in cancer treatment.
- Triple-negative breast cancer (TNBC) presents significant therapeutic difficulties due to its aggressive nature and metastatic potential.
Purpose of the Study:
- To investigate the role of DNA methyltransferase 3B (DNMT3B) in TNBC metastasis.
- To identify biomarkers for predicting clinical outcomes in breast cancer patients.
- To explore therapeutic strategies targeting DNMT3B for metastatic disease.
Main Methods:
- Utilized mouse models of TNBC metastasis.
- Analyzed heterogeneous DNMT3B expression in primary tumors (mouse and human).
- Assessed correlation between DNMT3B levels and clinical outcomes using human breast cancer datasets.
- Investigated the mechanistic link between DNMT3B, vimentin (VIM) expression, and epithelial-to-mesenchymal transition (EMT).
- Evaluated the efficacy of perioperative DNMT3B targeting combined with chemotherapy in preclinical models.
Main Results:
- Heterogeneous DNMT3B expression was observed in both mouse and human primary TNBC tumors.
- High DNMT3B levels correlated with poor clinical outcomes in breast cancer.
- DNMT3B overexpression enhanced VIM expression and promoted EMT.
- VIM deletion attenuated the metastatic phenotype of DNMT3BH cells.
- Perioperative DNMT3B inhibition combined with chemotherapy significantly reduced tumor recurrence and metastasis in mouse models.
Conclusions:
- DNMT3B-mediated transcriptional regulation is a key driver of tumor heterogeneity and metastasis in TNBC.
- DNMT3B is critical for tumor invasion and progression, highlighting its potential as a therapeutic target.
- Targeting DNMT3B in combination with chemotherapy offers a promising strategy for treating metastatic TNBC and overcoming chemoresistance.
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