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Oncogene. 2014 Nov 6;33(45):5238-50. doi: 10.1038/onc.2013.467. Epub 2013 Nov 4.

Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells.

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Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.
Penn Vet Imaging Core, School of Veterinary Medicine, Philadelphia, PA, USA.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Tumor and Metastasis Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Department of Pathobiology, School of Veterinary Medicine, Philadelphia, PA, USA.


Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells (hMECs) activates Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway, which induces EMT-like reprogramming to fibroblastic morphology, loss of cell polarity, contact inhibition and acquired migratory and invasive phenotype. Notably, mtDNA reduction generates breast cancer stem cells. In addition to retrograde signaling markers, there is an induction of mesenchymal genes but loss of epithelial markers in these cells. The changes are reversed by either restoring the mtDNA content or knockdown of CnAα mRNA, indicating the causal role of retrograde signaling in EMT. Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells, which evade conventional therapies. We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs.

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