Mechanisms of acquired chemotherapy resistance in breast cancer cells

The UDP-glycosyltransferase (UGT) drug metabolising enzymes conjugate sugars to small molecules, including therapeutic drugs. This inactivates the target molecule and aids in its elimination. Epirubicin (EPI) is a cytotoxic drug often used in breast cancer (BC) chemotherapeutic regimes, particularly for triple-negative BC which has few therapeutic options. UGT2B7 (2B7) is thought to be the only UGT responsible for EPI inactivation, however, the role of 2B7 in intratumoural clearance and drug resistance is unknown. This study tested the hypothesis that 2B7 expression is induced by EPI in BC cells, and that subsequent metabolism of EPI by the enzyme could lead to drug resistance. qRTPCR quantification and promoter studies were performed in BC cell lines to characterise 2B7 gene expression following EPI treatment. Stable 2B7-overexpressing cell lines were generated and characterized for response/resistance to EPI, while 2B7 CRISPR knockout lines are under development. Treatment with EPI significantly induced expression of 2B7, other UGTs and drug efflux transporters. The p53 responsive element in the 2B7 promoter was induced by EPI specifically in p53 wildtype cells. Overexpression of 2B7 in BC cells led to increased EPI resistance (IC50=1.74-fold increase). These data support the hypothesis of EPI-mediated transcriptional induction of 2B7 in BC lead to the acquisition of EPI resistance. This regulation may involve both p53-dependent and independent pathways. Current work is examining induction of 2B7 and other drug resistance pathways by targeted therapies (e.g. Tyrosine Kinase Inhibitors) to understand whether combination therapies may synergistically promote drug resistance. Understanding mechanisms of acquired drug resistance may enable enhanced BC treatment efficacy.