title: Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition.
abstract: The retinoblastoma tumor suppressor protein (Rb) is mutated or expressed at very low levels in several tumor types, including retinoblastoma and osteosarcoma, as well as small cell lung, colon, prostate, bladder, and breast carcinomas. Loss or reduction of Rb expression is seen most commonly in high-grade breast adenocarcinomas, suggesting that a relationship may exist between loss of Rb function and a less-differentiated state, increased proliferation, and high metastatic potential. In this study, we found that knockdown of Rb by small interfering RNA in MCF7 breast cancer cells disrupts cell-cell adhesion and induces a mesenchymal-like phenotype. The epithelial-to-mesenchymal transition (EMT), a key event in embryonic morphogenesis, is implicated in the metastasis of primary tumors. Additionally, Rb is decreased during growth factor- and cytokine-induced EMT and overexpression of Rb inhibits the EMT in MCF10A human mammary epithelial cells. Ectopic expression and knockdown of Rb resulted in increased or reduced expression of E-cadherin, which is specifically involved in epithelial cell-cell adhesion. Other EMT-related transcriptional factors, including Slug and Zeb-1, are also induced by Rb depletion. Furthermore, we confirmed that Rb binds to an E-cadherin promoter sequence in association with the transcription factor activator protein-2alpha. Finally, in breast cancer specimens, we observed a concurrent down-regulation of Rb and E-cadherin expression in mesenchymal-like invasive cancers. These findings suggest that Rb inactivation contributes to tumor progression due to not only loss of cell proliferation control but also conversion to an invasive phenotype and that the inhibition of EMT is a novel tumor suppressor function of Rb.
authors.affiliation: Radiobiology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Arima
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Hidemi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D047108:Embryonic Development / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034741:RNA, Small Interfering / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D015820:Cadherins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020741:rho GTP-Binding Proteins