title: Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression.
abstract: Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Chu-An
authors.initials: CA
authors.lastname: Wang
authors.affiliation: Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: David
authors.initials: D
authors.lastname: Drasin
authors.affiliation: Program in Cancer Biology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pham
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Vadym
authors.initials: V
authors.lastname: Zaberezhnyy
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Michelle
authors.initials: M
authors.lastname: Guney
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Howard
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Raphael
authors.initials: R
authors.lastname: Nemenoff
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado. Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado. Program in Cancer Biology, University of Colorado School of Medicine, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado. Heide.Ford@ucdenver.edu.
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C497420:Six2 protein, mouse; D014157:Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2