title: Glypican-3 induces a mesenchymal to epithelial transition in human breast cancer cells.
abstract: Breast cancer is the disease with the highest impact on global health, being metastasis the main cause of death. To metastasize, carcinoma cells must reactivate a latent program called epithelial-mesenchymal transition (EMT), through which epithelial cancer cells acquire mesenchymal-like traits.Glypican-3 (GPC3), a proteoglycan involved in the regulation of proliferation and survival, has been associated with cancer. In this study we observed that the expression of GPC3 is opposite to the invasive/metastatic ability of Hs578T, MDA-MB231, ZR-75-1 and MCF-7 human breast cancer cell lines. GPC3 silencing activated growth, cell death resistance, migration, and invasive/metastatic capacity of MCF-7 cancer cells, while GPC3 overexpression inhibited these properties in MDA-MB231 tumor cell line. Moreover, silencing of GPC3 deepened the MCF-7 breast cancer cells mesenchymal characteristics, decreasing the expression of the epithelial marker E-Cadherin. On the other side, GPC3 overexpression induced the mesenchymal-epithelial transition (MET) of MDA-MB231 breast cancer cells, which re-expressed E-Cadherin and reduced the expression of vimentin and N-Cadherin. While GPC3 inhibited the canonical Wnt/β-Catenin pathway in the breast cancer cells, this inhibition did not have effect on E-Cadherin expression. We demonstrated that the transcriptional repressor of E-Cadherin - ZEB1 - is upregulated in GPC3 silenced MCF-7 cells, while it is downregulated when GPC3 was overexpressed in MDA-MB231 cells. We presented experimental evidences showing that GPC3 induces the E-Cadherin re-expression in MDA-MB231 cells through the downregulation of ZEB1.Our data indicate that GPC3 is an important regulator of EMT in breast cancer, and a potential target for procedures against breast cancer metastasis.
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: Lilian Fedra
authors: LF
authors: Castillo
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: Rocío
authors: R
authors: Tascón
authors: Universidad de Buenos Aires, CONICET, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
authors: María Amparo
authors: MR
authors: Lago Huvelle
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: Gisela
authors: G
authors: Novack
authors: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba and Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina.
authors: María Candelaria
authors: MC
authors: Llorens
authors: Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, Brazil.
authors: Ancely Ferreira
authors: AF
authors: Dos Santos
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: Jorge
authors: J
authors: Shortrede
authors: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba and Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina.
authors: Ana María
authors: AM
authors: Cabanillas
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: Elisa
authors: E
authors: Bal de Kier Joffé
authors: Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, Brazil.
authors: Leticia
authors: L
authors: Labriola
authors: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Area Investigación, Buenos Aires, Argentina.
authors: María Giselle
authors: MG
authors: Peters
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053673:Glypicans / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D034622:RNA Interference; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C105937:GPC3 protein, human; D053673:Glypicans; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: breast cancer; epithelial-mesenchymal transition; glypican-3; invasion; metastasis