Abstract
Reduced mitochondrial DNA (mtDNA) content in breast cancer cell lines has been associated with transition towards a mesenchymal phenotype, but its clinical consequences concerning breast cancer dissemination remain unidentified. Here, we aimed to clarify the link between mtDNA content and a mesenchymal phenotype and its relation to prognosis of breast cancer patients. We analyzed mtDNA content in 42 breast cancer cell lines and 207 primary breast tumor specimens using a combination of quantitative PCR and array-based copy number analysis. By associating mtDNA content with expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) and with the intrinsic breast cancer subtypes, we could not identify a relation between low mtDNA content and mesenchymal properties in the breast cancer cell lines or in the primary breast tumors. In addition, we explored the relation between mtDNA content and prognosis in our cohort of primary breast tumor specimens that originated from patients with lymph node-negative disease who did not receive any (neo)adjuvant systemic therapy. When patients were divided based on the tumor quartile levels of mtDNA content, those in the lowest quarter (≤ 350 mtDNA molecules per cell) showed a poorer 10-year distant metastasis-free survival than patients with > 350 mtDNA molecules per cell (HR 0.50 [95% CI 0.29–0.87], P = 0.015). The poor prognosis was independent of established clinicopathological markers (HR 0.54 [95% CI 0.30–0.97], P = 0.038). We conclude that, despite a lack of evidence between mtDNA content and EMT, low mtDNA content might provide meaningful prognostic value for distant metastasis in breast cancer.
Highlights
Mitochondria play a role in many cellular processes including oxidative phosphorylation, redox homeostasis, controlling calcium levels for regulation of signal transduction pathways, and the intrinsic apoptotic pathway [1]
By associating mitochondrial DNA (mtDNA) content with expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) and with the intrinsic breast cancer subtypes, we could not identify a relation between low mtDNA content and mesenchymal properties in the breast cancer cell lines or in the primary breast tumors
When patients were divided based on the tumor quartile levels of mtDNA content, those in the lowest quarter (≤ 350 mtDNA molecules per cell) showed a poorer 10-year distant metastasis-free survival than patients with > 350 mtDNA molecules per cell (HR 0.50 [95% confidence intervals (CI) 0.29–0.87], P = 0.015)
Summary
Mitochondria play a role in many cellular processes including oxidative phosphorylation, redox homeostasis, controlling calcium levels for regulation of signal transduction pathways, and the intrinsic apoptotic pathway [1]. The mitochondria contain their own genome – mtDNA – encoding their own translational machinery and 13 crucial proteins for the oxidative phosphorylation system. Numerous mtDNA molecules may exist in a single cell. This number is dependent on the amount of mitochondria per cell and on the number of mtDNA molecules per mitochondrion. The effects of changes in mtDNA content are illustrated in several mtDNA depletion syndromes [9], which are all characterized by impaired energy production
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