title: MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis.
abstract: Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Chao
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Chang
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Wu
authors.forename: How-Wen
authors.initials: HW
authors.lastname: Ko
authors.forename: Da
authors.initials: D
authors.lastname: Wang
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D016764:Cell Polarity; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000378:metabolism; D059016:Tumor Microenvironment; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C489734:Hes1 protein, mouse; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C534425:MIR205, human; C576666:MIRN205 microRNA, mouse; C497764:NOTCH2 protein, human; C497765:Notch2 protein, mouse; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; C078493:HES1 protein, human