Treatment resistance remains one of the main obstacles in the management of breast cancer, particularly in the most aggressive forms, such as triple-negative breast cancers. Although chemotherapies such as paclitaxel and doxorubicin are standard treatments, their effectiveness is often compromised by the gradual emergence of tumour resistance mechanisms.
In this study, the authors developed several breast cancer cell models resistant to paclitaxel or doxorubicin, representing different tumour subtypes. They then combined genomic, transcriptomic and epigenomic analyses to identify the molecular mechanisms associated with the acquisition of this resistance.
The results reveal that resistant cells undergo extensive remodelling of their DNA methylation profile, accompanied by major changes in gene expression. The researchers showed in particular that resistance to paclitaxel is associated with especially pronounced epigenetic reprogramming, reflecting a profound adaptation of tumour cells under treatment pressure.
The study also evaluated the effect of decitabine, a DNA methyltransferase inhibitor already used in certain haematological malignancies. In experimental models of resistant breast cancer, this compound was able to modify methylation profiles and partially restore tumour sensitivity to chemotherapy. These findings suggest that targeting epigenetic alterations could be a promising approach to overcoming certain resistance mechanisms.
Finally, the epigenetic signatures identified in the experimental models also made it possible to distinguish patients according to their response to treatment in an independent clinical cohort. This observation highlights the potential of DNA methylation as a predictive biomarker of therapeutic efficacy.
This work reinforces the idea that the epigenome is both a valuable source of information on tumour evolution and a potential therapeutic target for improving the management of treatment-resistant breast cancers.
Contact : Jorg Tost