Interplay between Epigenetic and Transcription Factors Mediating Drug Resistance via Stem Cells in Breast Cancer

Globally, breast cancer (BC) is the most prevalent cancer in women, and drug resistance is a foremost challenge in BC management that contributes to 90% of BC-related deaths. Drug resistance arises as cellular adaptation during treatment, but the underlying mechanisms remain complex and are not yet fully understood. Research studies have shown that most anticancer drugs are effective against the mass of tumor cells rather than Cancer Stem Cells (CSCs). They have the ability to become dormant upon exposure to anticancer drugs and acquire drug resistance over a period of time after silently modifying themselves to resist the drug environment. The maintenance of the stem cell phenotype is mostly driven by stem cell transcription factors (e.g., KLFs, Myc, ZEB2, RUNX1, TWIST1, OCT4, NANOG, FOXO3, SOX2, E2Fs, etc.), which are mediated by epigenetic changes in tumor cells at many levels. These recognized factors/pathways have been demonstrated to be promising therapeutic targets. Therefore, knowledge of epigenetics in regulating cancer stem cells via stem cell transcription factors may be a promising solution for the reversal of therapy-resistant BC. In this review, we emphasize stem cell transcription factors, cancer stem cells, and epigenetic regulation as critical drivers of drug resistance in BC.