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.