title: Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer.
abstract: We previously showed that depletion of the retinoblastoma protein (RB) induces down-regulation of the adhesion molecule E-cadherin and thereby triggers the epithelial-mesenchymal transition. To further characterize the effect of RB inactivation on the phenotype of cancer cells, we have now examined RB expression in human breast cancer cell lines and clinical specimens. We found that RB-inactive cells exhibit a mesenchymal-like morphology and are highly invasive. We also found that ZEB proteins, transcriptional repressors of the E-cadherin gene, are markedly up-regulated in these cells in a manner sensitive to the miR-200 family of microRNAs. Moreover, depletion of ZEB in RB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial marker expression. These results implicate ZEB in induction of the epithelial-mesenchymal transition, as well as in maintenance of the mesenchymal phenotype in RB-inactive cells. We also developed a screening program for inhibitors of ZEB1 expression and thereby identified several cyclin-dependent kinase inhibitors that blocked both ZEB1 expression and RB phosphorylation. Together, our findings suggest that RB inactivation contributes to tumor progression not only through loss of cell cycle control but also through up-regulation of ZEB expression and induction of an invasive phenotype.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Arima
authors.forename: Hidemi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Mikako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Mari
authors.initials: M
authors.lastname: Hosonaga
authors.forename: Takaaki M
authors.initials: TM
authors.lastname: Goto
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Chiyoda
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D012334:RNA, Neoplasm; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1