title: Nucleolin-binding by ErbB2 enhances tumorigenicity of ErbB2-positive breast cancer.
abstract: ErbB2 is an important member of the ErbB family, which activates growth and proliferation signaling pathways. ErbB2 is often overexpressed in various malignancies, especially in breast cancer, and is a common target for anti-cancer drugs. Breast cancer is currently one of the leading mortality causes in women, and acquired resistance to ErbB2-targeted therapies is a major obstacle in its treatment. Thus, understanding ErbB2-mediated signaling is crucial for further development of anti-cancer therapeutics and disease treatment. Previously, we have reported that the ErbB receptors interact with the major nucleolar protein nucleolin. In addition to its function in the nucleoli of cells, nucleolin participates in various cellular processes at the cytoplasm and cell-surface. Deregulated nucleolin is frequently overexpressed on the membrane of cancer cells. Here, we show that nucleolin increases colony formation and anchorage-independent growth of ErbB2-overexpressing cells. Importantly, this enhanced tumorigenicity also occurs in human ErbB2-positive breast cancer patients; namely, nucleolin overexpression in these patients is associated with reduced patient survival rates and increased disease-risk. ErbB2-nucleolin complexes are formed endogenously in both normal and cancer cells, and their effect on tumorigenicity is mediated through activation of ErbB2 signaling. Accordingly, nucleolin inhibition reduces cell viability and ErbB2 activation in ErbB2-positive cancer cells.
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Eya
authors.initials: E
authors.lastname: Wolfson
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Goldenberg
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Solomon
authors.affiliation: Department of Cell Research and Immunology, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Frishberg
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D063646:Carcinogenesis; D002448:Cell Adhesion; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D000097796:Nucleolin
chemical_list: D000970:Antineoplastic Agents; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000097796:Nucleolin; C508053:ERBB2 protein, human
keywords: ErbB/HER family; TCGA; breast cancer; nucleolin; tyrosine kinase