A reduction in mitochondrial DNA (mtDNA) content leads to more aggressive forms of breast cancer, according to research published in Oncogene.
Researchers from the University of Pennsylvania were able to show the connection between the amount of mtDNA in a cell and why some forms of breast cancer metastasize faster and have poorer prognosis.
"Most patients who had low copy numbers of mitochondrial DNA have a poor disease prognosis," said Manti Guha, a senior research investigator at the Penn School of Veterinary Medicine and one of the study’s authors, in a news release. "We've shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease.”
Use of mtDNA as a biomarker could help distinguish patients with aggressive forms of the disease so treatment approaches could be personalized for potentially better outcomes, the authors suggested.
For the study, the researchers purposefully reduced the amount of mtDNA in a cell using two methods: chemical and genetic. Then, they compared normal, non–cancer-forming human breast tissue cells with cancerous breast cells for both methods to compare the altered cells with unmanipulated mtDNA.
The differences were striking, the researchers reported.
"Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells," said Narayan Avadhani, Harriet Ellison Woodward Professor of Biochemistry in the Department of Animal Biology, in a news release. "These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body."
When mtDNA was reduced, the cells appeared disorganized and more like that of metastatic cancer cell. Even non–tumor-forming breast cells started to more closely resemble cancer cells. Plus, the reduced-mtDNA cells became self-renewing and had characteristics of breast cancer stem cells.
The changes could be reversed by either restoring the mtDNA content or through the knockdown of the α isoform of the catalytic subunit of calcineurin (CnAα) mRNA, a key factor in the authors establishing the causal role.
- A reduction in mitochondrial DNA, or mtDNA, content leads to more aggressive forms of breast cancer.
- The authors propose that mtDNA may serve as a biomarker for how to identify, and better treat, cancers that more quickly metastasize.
Guha M, Srinivasan S, Ruthel G, et al. Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells. Oncogene. 4 November 2013;doi:10.1038/onc.2013.467.