The insulin-like growth factor-I receptor (IGF-IR) mediates the growth and differentiation effects of the IGFs. Cancer cells overexpress IGF-IRs and this may impart to the cancer cells a growth potential particularly by inhibiting apoptosis as well as enhancing proliferation. A. Using MCF-7 cells, we have reduced the endogenous levels of IGF-I receptors and evaluated the effect on these cells. Fewer IGF-I receptors esulted in a more metastatic phenotype as demonstrated by increased migration, reduced attachment and reduced aggregation. There was an effect on cadherins and intracellular signaling pathways that explained these effects. In particular, there was a reduction in the E-cadherin-catenin-p120 complex and an increase in active rac1 and Cdc42. Thus the IGF-I receptor maybe important in preventing a more malignant phenotype in these cells. B. The MCF-7 cells were also used to study the interaction of the estrogen receptor and the IGF-I receptor. Estradiol and IGF-I stimulation of MCF-7 cells showed an early synergistic effect on proliferation suggesting a non-genomic effect on the estrogen receptor. The synergistic effects were seen at both early and late signaling events of the IGF-I receptor signaling cascade and also in cell cycle events. C. The IGF-I receptor apparently plays a role in DNA repair. Follwoing UV irradiation, DNA repair was enhanced by IGF-I receptor activation in fibroblasts via the p38 MAPkinase pathway and involved the reduction in p53 protein levels in these cells. Nuclear expulsion of p53 was enhanced by IGF-I-stimulated mdm2 binding of p53 and degradation of p53 in the cytoplasm via the proteosome pathway. D. Using DNA chip microarray in fibroblasts, Twist was discovered to be induced by IGF-I. This transcription factor was also found to play a role in IGF-I receptor signaling. When levels of twist were reduced in these cells by antisense strategy, IGF-I inhibition of apoptosis was inhibited. Thus the IGF-I receptor is essential for cellular proliferation and anti-apoptosis, as well as other important cellular functions.