DNA Methyltransferase 3B-Mediated Intratumoral Heterogeneity and Therapeutic Targeting in Breast Cancer Recurrence and Metastasis

The mechanisms of how cancer cells are selected and evolve to establish distant metastatic colonies remain unclear. Tumor het-erogeneity 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 mul-tiple 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 chemo-therapy 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 hetero-geneity and chemoresistance, and therapeutic targeting of DNMT3B in combination with chemotherapy offer additional treatment options for metastatic disease especially for patients with TNBC.

Automated summary

This study finds that high expression of DNA methyltransferase 3B (DNMT3B) is associated with poor clinical outcomes in breast cancer patients. Clonal cells with high DNMT3B expression display enhanced epithelial-to-mesenchymal transition capacity, and perioperative targeting of DNMT3B in combination with chemotherapy can significantly suppress tumor recurrence and metastasis.