Role of NAD(P)H:quinone oxidoreductase 1 polymorphism in breast cancer cell sensitivity to quinone-based chemotherapeutic agents

Abstract

Alterations in antioxidant enzymes expression are associated with changes in cancer cell sensitivity to chemotherapeutic drugs. We investigated mechanisms of resistance to pro-oxidant drugs by using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). A genomic gain of the chromosomal band 16q22 was discovered in Resox cells as compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. By using different pharmacological and genetic invalidation strategies we showed that 16q22-associated amplification of NAD(P)H:quinone oxidoreductase 1 (NQO1) gene was critical for Resox oxidative stress-resistance. Considering that NQO1 is frequently modified in tumor, at genomic or transcriptomic levels, we take advantage of this discover to explore NQO1 modulations roles in breast cancer chemosensitivity. Using different cellular models we found that NQO1 overexpression is a main determinant for the classical resistance, such as menadione and doxorubicin. This resistance was associated with an increased -lapachone, and inversely, conditions leading to the decrease of NQO1 activity trigger quinone- based chemotherapies-sensitivity. This places NQO1 modulations as a potential link between redox alterations in cancers and chemoresistance. Furthermore, this study underlines that the copy number alterations of NQO1 could be taken into account to specifically target breast tumors.