Decitabine Response in Breast Cancer Requires Efficient Drug Processing and Is Not Limited by Multidrug Resistance

Area of Science:

• Oncology
• Cancer Therapeutics
• Epigenetics

Background:

• DNA methylation dysregulation is common in breast cancers.
• Decitabine, a DNA demethylating agent, is a potential treatment for triple-negative breast cancers (TNBC).
• Identifying response indicators for decitabine therapy in TNBC is crucial.

Purpose of the Study:

• To investigate decitabine's effects on breast cancer cell lines.
• To identify key factors influencing decitabine response.
• To evaluate decitabine's potential as a second-line treatment for chemoresistant breast cancer.

Main Methods:

• Screening decitabine sensitivity across 10 breast cancer cell lines.
• Investigating the role of deoxycytidine kinase (DCK) via knockdown experiments.
• Analyzing methylome and transcriptome data to understand decitabine's molecular mechanisms.
• Assessing decitabine response in taxol-resistant cell lines with high ABCB1 expression.

Main Results:

• Decitabine sensitivity varied across cell lines, not correlating with specific subtypes.
• Deoxycytidine kinase (DCK) is essential for decitabine response in breast cancer cells.
• Higher DCK levels were observed in TNBCs and were maintained post-chemotherapy.
• Methylome changes and viral mimicry pathways did not predict decitabine response.
• Decitabine induced apoptosis, cell cycle, stress, and immune-related gene expression.
• Taxol-resistant cells remained sensitive to decitabine.

Conclusions:

• Deoxycytidine kinase (DCK) is a key determinant of decitabine response in breast cancer.
• Sufficient DCK levels are likely present in TNBC patients for decitabine treatment.
• Decitabine's efficacy is independent of viral mimicry response.
• Decitabine shows potential as a second-line therapy for chemoresistant breast cancer, including TNBC.