title: Mitochondrial DNA content in breast cancer: Impact on in vitro and in vivo phenotype and patient prognosis.
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.
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marjolein J A
authors.initials: MJ
authors.lastname: Weerts
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis
chemical_list: D004272:DNA, Mitochondrial
keywords: breast cancer; distant metastasis; epithelial-to-mesenchymal transition; mitochondrial DNA; mtDNA content