title: MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling.
abstract: Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Song
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Laura
authors.initials: L
authors.lastname: Poliseno
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Webster
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Systems Biology, Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: Gary
authors.initials: G
authors.lastname: Beringer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Brikbak
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Systems Biology, Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D042002:Chromatin Assembly and Disassembly; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: C533896:MIRN200 microRNA, human; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine