Alovudine Targets mtDNA-dependent Proteins Encoded by Genes Recurrently Amplified in Metastatic Breast Cancer Cohorts.

Abstract

Previously, we demonstrated that high levels of mitochondrial DNA (mtDNA) were functionally associated with "stemness" and aggressive phenotypic behaviors in human breast cancer cells, including spontaneous metastasis. More specifically, we showed that treatment with Alovudine induced mtDNA-depletion in MDA-MB-231 cells and prevented their ability to form colonies in vitro and metastasize in vivo. To better understand the underlying mechanism(s) and identify candidate mtDNA-dependent mitochondrial protein biomarkers relevant to metastatic breast cancer, Alovudine-treated MDA-MB-231 cells were subjected to proteomics analysis. For comparison purposes, mtDNA-depleted cells (MDA-MB-231 and MCF-7) were generated and also subjected to proteomics analysis. Intersection of these three distinct data sets revealed that a small number of proteins were commonly downregulated in mtDNA-depleted cells and Alovudine-treated cells. Remarkably, many of these nuclear-encoded mitochondrial genes (>20) exhibited recurrent genomic amplification across metastatic breast cancer cohorts. Therefore, the action of a single drug, namely Alovudine, was sufficient to effectively suppress the expression of a large number of mitochondrial proteins associated with i) gene amplification and ii) cancer cell metastasis, in human breast cancer patients. These findings may have important clinical implications for the development of new therapeutics targeting advanced breast cancer.