Epigenetic Regulation of ABCB1 Expression in Triple Negative Breast Cancer and its Impact on Taxane Resistance

• Sunil Kumar Yadav

  Kalinga University, Naya Raipur, Chhattisgarh, India

• Brijmohan Singh

  Kalinga University, Naya Raipur, Chhattisgarh, India

Objective: This research was conducted to examine the part played by epigenetic regulation in up-regulating the expression of ABCB1 (P-glycoprotein) and the role it contributes to the development of taxane resistance in triple-negative breast cancer (TNBC).

Methods: Taxane-sensitive and taxane-resistant TNBC cell lines (e.g., MDA-MB-231) were subjected to the evaluation of the ABCB1 expression with the help of the quantitative PCR (qPCR) and the Western blotting procedures. Bisulfite sequencing, chromatin immunoprecipitation (ChIP), and miRNA profiling were used to study epigenetic alterations such as DNA methylation, changes in histone activity (acetylation), and miRNAs, respectively. To test the reversal of resistance, epigenetic inhibitors were utilized and included 5-aza-2'-deoxycytidine and trichostatin A. Patient-derived TNBC samples were used to make clinical correlations that established the connection between the status of ABCB1 methylation and the response to chemotherapy.

Findings: The expression of ABCB1 in taxane-resistant cells was found to be much higher in comparison to that of sensitive cells, as determined by both mRNA and protein. The DNA analysis of the methylation of the promoter of the ABCB1 showed that it is hypomethylated in the resistant cells, and the histone acetylation of ABCB1 was also significantly elevated in the resistant cells. miR-451 and miR-335, which regulate ABCB1, were suppressed in the resistant cells. ABCB1 overexpression was reversed by treatment with epigenetic inhibitors, and sensitivity to taxanes was restored. It was found that low levels of methylation of the promoter of ABCB1 were linked to ineffective taxane chemotherapy response in patients with TNBC.

Conclusion: Taxane resistance in TNBC occurs with the help of epigenetic regulation of ABCB1. The significant contributors to the overexpression of ABCB1 are DNA hypomethylation, histone acetylation, and miRNA dysregulation. Epigenetic therapies, as an adjunct to the taxane chemotherapy, are one such promising approach that could be used to overcome drug resistance in TNBC, and they should be further explored in clinical trials.

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