title: Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.
abstract: Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell-like features.
authors.affiliation: Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: McCoy
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Iwanaga
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Nee-Shamo
authors.initials: NS
authors.lastname: Abbey
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Karen A
authors.initials: KA
authors.lastname: Heichman
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004848:Epithelium / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; C099236:SIX1 protein, human; D016212:Transforming Growth Factor beta