DNMT1: A key drug target in triple-negative breast cancer

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
• Epigenetic dysregulation, particularly DNA hypermethylation by DNA methyltransferase 1 (DNMT1), contributes to TNBC development.
• DNMT1 overexpression is linked to poor prognosis in breast cancer patients.

Purpose of the Study:

• To review the oncogenic functions of DNMT1 in TNBC.
• To discuss DNMT1 inhibitors as potential therapeutic agents for TNBC.

Main Methods:

• Literature review of studies investigating DNMT1 in TNBC.
• Analysis of DNMT1's molecular mechanisms in TNBC tumorigenesis.
• Evaluation of DNMT1 inhibitors' efficacy against TNBC cells.

Main Results:

• DNMT1 is overexpressed in TNBC and associated with poor survival.
• DNMT1 promotes TNBC by repressing estrogen receptor (ER) expression, driving epithelial-mesenchymal transition (EMT), inducing autophagy, and supporting cancer stem cell growth.
• DNMT1 achieves these effects through hypermethylation of key genes, microRNAs, and EMT-suppressing markers.
• DNMT1 inhibitors, including hypomethylating agents like azacitidine, decitabine, and guadecitabine, show anti-tumorigenic effects and may sensitize TNBC to immunotherapy.

Conclusions:

• DNMT1 plays critical oncogenic roles in TNBC, driving its aggressive and metastatic phenotypes.
• Targeting DNMT1 epigenetically presents a viable strategy for TNBC treatment, potentially overcoming therapeutic resistance and enhancing immunotherapy efficacy.