TY - JOUR
T1 - Nucleolin-binding by ErbB2 enhances tumorigenicity of ErbB2-positive breast cancer
AU - Wolfson, Eya
AU - Goldenberg, Maria
AU - Solomon, Shira
AU - Frishberg, Amit
AU - Pinkas-Kramarski, Ronit
N1 - Funding Information:
This work was supported by the Israel Science Foundation (Grant no. 848/12), by the Israel Cancer Association and by the Kauffman Prostate Cancer Research Fund. We thank Yuri Rozhansky for his help in data sorting and analysis.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Breast cancer
KW - ErbB/HER family
KW - Nucleolin
KW - TCGA
KW - Tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=84994099880&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11323
DO - 10.18632/oncotarget.11323
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C2 - 27542246
AN - SCOPUS:84994099880
SN - 1949-2553
VL - 7
SP - 65320
EP - 65334
JO - Oncotarget
JF - Oncotarget
IS - 40
ER -