Reduced expression of insulin-like growth factor I receptors in MCF-7 breast cancer cells leads to a more metastatic phenotype.
Several lines of evidence support an important role for the insulin-like growth factor system in breast cancer. Alterations in insulin-like growth factor I receptor (IGF-IR) have been associated with breast cancer metastasis; however, the specific role played by the IGF-IR in this process remains unclear. To address this issue, we evaluated MCF-7 breast cancer cells stably transfected either with an antisense construct to the IGF-IR, which reduced the expression of the IGF-IRs by approximately 50% (SX13 cells), or with the empty vector as control (NEO cells). Using functional assays for motility, attachment, and aggregation, we found a 3-fold increase in migration using both the wounding assay and the Boyden chamber migration assay. In addition, the SX13 cells attached less, and there was a reduction in cellular aggregation. These functional changes were accompanied by approximately 50% decrease in expression of E-cadherin and approximately 80% increase in p120 protein levels. Moreover, there was a significant reduction in p120 present in the E-cadherin-catenin-p120 complex. There was a 2-fold increase in active Rac1 and Cdc42 and a 35% decrease in active Rho in the SX13 cells. Our findings strongly suggest that the IGF-IR plays a role in the stabilization of the E-cadherin-catenin complex, thereby providing one possible explanation for the association between low levels of IGF-IR and a higher risk of mammary tumor metastasis.
Pennisi
Patricia A
PA
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1758, USA.
Barr
Valarie
V
Nunez
Nomeli P
NP
Stannard
Bethel
B
Le Roith
Derek
D
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002449:Cell Aggregation / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D016373:DNA, Antisense; D017526:Receptor, IGF Type 1; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein