Altered epigenetic events in docetaxel-resistant human breast cancer cells

Lena Kastl, Iain Brown, Elizabeth Lamers, Andrew Craig Schofield

Research output: Contribution to journalArticlepeer-review


Docetaxel is an effective chemotherapy drug for breast cancer treatment. The mechanisms of resistance to docetaxel are poorly understood, however, epigenetic modifications, DNA methylation and histone modification, may be important. DNA methyltransferase (DNMT) 1, 3a and 3b are involved in DNA methylation whereas histone deacetylases control histone deacetylation. Epigenetic changes can be reversed using DNA methylation and histone deacetylation inhibitors. We hypothesise that inhibiting epigenetic events can reverse docetaxel resistance.
Methods: Docetaxel-sensitive and docetaxel-resistant MCF-7 breast cancer cells were treated with and without decitabine (DNA methylation inhibitor) or trichostatin A (histone deacetylation inhibitor). RT-PCR was performed to study DNMT gene expression and enzyme activity was also measured. Cell viability was measured by MTT assay.
Results: In docetaxel-resistant cells, DNMT3a and DNMT3b gene expression was decreased (8-fold; 13-fold) and so too was enzyme activity (20%). Decitabine treatment increased DNMT3a and DNMT3b gene expression (3-fold and 2-fold, respectively) as well as enzyme activity (30%) in docetaxel-resistant cells. In contrast, docetaxel-sensitive cells showed decreased DNMT3a and DNMT3b gene expression after decitabine treatment (both 3-fold). Response to docetaxel in resistant cells was not altered upon decitabine treatment. Addition of trichostatin A, however, led to an increased response to docetaxel (IC50: 42.5 µM vs. 22 µM; p = 0.14).
Conclusions: Histone deacetylation, leading to epigenetic silencing, may be a mechanism of docetaxel resistance in breast cancer cells. DNA methylation, however, does not appear to be involved in resistance.
Original languageEnglish
Pages (from-to)1193-1194
Number of pages2
JournalEuropean Journal of Surgical Oncology
Issue number10
Early online date7 Sept 2008
Publication statusPublished - Oct 2008


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