title: Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells.
abstract: 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.
authors.affiliation: Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Guha
authors.affiliation: Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Penn Vet Imaging Core, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ruthel
authors.affiliation: Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Kashina
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Carstens
authors.affiliation: Tumor and Metastasis Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Tumor and Metastasis Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Khanna
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Van Winkle
authors.affiliation: Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Avadhani
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D061986:MCF-7 Cells; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; D019703:Calcineurin; C525673:PPP3CA protein, human