Cortactin potentiates bone metastasis of breast cancer cells.
Gene amplification of the chromosome 11q13 in breast cancer and squamous carcinomas in the head and neck results in frequent overexpression of cortactin, a prominent substrate of Src-related tyrosine kinases in the cell cortical areas. To investigate the role of cortactin in tumor progression, we analyzed MDA-MB-231 breast cancer cells overexpressing green fluorescent protein-tagged murine cortactin (GFP-cortactin) and a cortactin mutant deficient in tyrosine phosphorylation under the control of a retroviral vector. Injection of MDA-MB-231 cells overexpressing GFP-cortactin into nude mice through cardiac ventricles caused bone osteolysis at a frequency approximately 85% higher than that of cells expressing the vector alone, whereas injection of cells overexpressing the mutant deficient in tyrosine phosphorylation induced 74% fewer osteolytic metastases as compared with the control group. Interestingly, the cells expressing either GFP-cortactin or the mutant did not show significant differences in growth in vitro or when injected m.f.p. in vivo. On the other hand, the cells overexpressing GFP-cortactin but not the mutant acquired a >60% enhanced capability for transendothelial invasion and endothelial cell adhesion. These data suggest that cortactin contributes to tumor metastasis by enhancing the interaction of tumor cells with endothelial cells and the invasion of tumor cells into bone tissues.
Li
Y
Y
Department of Experimental Pathology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Tondravi
M
M
Liu
J
J
Smith
E
E
Haudenschild
C C
CC
Kaczmarek
M
M
Zhan
X
X
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D051356:Cortactin; D004727:Endothelium / Q000166:cytology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014183:Transplantation, Heterologous
C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; D008164:Luminescent Proteins; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins