title: MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways.
abstract: The microRNA-200 (miR-200) family has a critical role in regulating epithelial-mesenchymal transition and cancer cell invasion through inhibition of the E-cadherin transcriptional repressors ZEB1 and ZEB2. Recent studies have indicated that the miR-200 family may exert their effects at distinct stages in the metastatic process, with an overall effect of enhancing metastasis in a syngeneic mouse breast cancer model. We find in a xenograft orthotopic model of breast cancer metastasis that ectopic expression of members of the miR-200b/200c/429, but not the miR-141/200a, functional groups limits tumour cell invasion and metastasis. Despite modulation of the ZEB1-E-cadherin axis, restoration of ZEB1 in miR-200b-expressing cells was not able to alter metastatic potential suggesting that other targets contribute to this process. Instead, we found that miR-200b repressed several actin-associated genes, with the knockdown of the ezrin-radixin-moesin family member moesin alone phenocopying the repression of cell invasion by miR-200b. Moesin was verified to be directly targeted by miR-200b, and restoration of moesin in miR-200b-expressing cells was sufficient to alleviate metastatic repression. In breast cancer cell lines and patient samples, the expression of moesin significantly inversely correlated with miR-200 expression, and high levels of moesin were associated with poor relapse-free survival. These findings highlight the context-dependent effects of miR-200 in breast cancer metastasis and demonstrate the existence of a moesin-dependent pathway, distinct from the ZEB1-E-cadherin axis, through which miR-200 can regulate tumour cell plasticity and metastasis.
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Roslan
authors.affiliation: 1] Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia [3] Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia [4] Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: C N
authors.initials: CN
authors.lastname: Johnstone
authors.affiliation: 1] Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia [2] Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Wright
authors.affiliation: 1] Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia [2] Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: C P
authors.initials: CP
authors.lastname: Bracken
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: A G
authors.initials: AG
authors.lastname: Bert
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Selth
authors.affiliation: 1] Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia [3] Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Anderson
authors.affiliation: 1] Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia [2] Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, Australia [3] School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: 1] Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia [2] Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Gregory
authors.affiliation: 1] Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia [2] School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Khew-Goodall
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C071058:moesin