Doxorubicin Increases Mitochondrial DNA Copy Number in Human Breast Cancer Cells

Abstract

Mitochondria are dynamic organelles with important functions in energy production, biosynthesis, and regulation of cell death. Mitochondrial DNA (mtDNA) copy number is the ratio of mtDNA relative to nuclear DNA [1] and is a measure of mitochondrial capacity. Using mtDNA copy number measurements, we can measure an increase or decrease in mitochondrial capacity as a response to different drug treatments. Doxorubicin is a chemotherapy drug that works by disrupting DNA’s structure [2]. It is widely used in the treatment of breast cancer, however recurrence of disease after doxorubicin treatment is a major clinical problem. A greater understanding of doxorubicin’s effects could identify biomarkers that would predict drug resistance or new therapeutic interventions that would decrease the likelihood of resistance. In previous studies, we showed that doxorubicin resistant breast cancer cells have increased mtDNA copy number [3]. We recently showed that mtDNA copy number expansion mediates the ‘survivability’ of doxorubicin exposure in yeast [4]. In the current study, we show breast cancer cells exposed to a dose of doxorubicin that is not acutely cytotoxic respond by increasing their mtDNA copy number. This response is shared by cell lines that represent the four major clinical subtypes of breast cancer. The expansion of mtDNA could represent a remodeling of metabolism to facilitate cell cycle arrest that allows cells to evade cytotoxicity. Alternatively, it could represent a compensation to mitochondrial injury. Future experiments will explore these possibilities.