Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells.

The insulin-like growth factor I receptor (IGF-IR) paracrine or autocrine loop plays an important role in the maintenance of breast cancer growth. Cancer cells contain several-fold higher levels of the IGF-IR than normal breast tissue; however, it is still not clear whether abnormally high activation of IGF-IR signaling may induce progression of the disease. To address this question, we have established several MCF-7-derived clones (MCF-7/IGF-IR cells) overexpressing the IGF-IR. We report here that overexpression of the IGF-IR did not modify sensitivity of cells to IGF-I; however, responsiveness to the ligand was moderately enhanced in most of the MCF-7/IGF-IR clones (measured by [3H]thymidine incorporation into DNA). All MCF-7/IGF-IR clones responded to the synergistic action of 1 nM estradiol (E2) and small amounts of IGF-I (up to 0.8 ng/ml). Exposure of cells to higher concentrations of IGF-I abolished estrogen requirements for stimulation of DNA synthesis in all MCF-7/IGF-IR clones, but not in the parental cells. The most important finding of this work was that the amplification of the IGF-IR induced cell-cell adhesion in MCF-7 cells. High levels of the IGF-IR promoted cell aggregation on Matrigel, allowed proliferation of cells within the aggregates, and protected clustered cells from death. In both MCF-7 and MCF-7/IGF-IR cells, IGF-I stimulated aggregation, whereas an anti-E cadherin antibody blocked cell-cell adhesion. Furthermore, immunofluorescence staining with specific antibodies revealed co-localization of the IGF-IR and E-cadherin at the points of cell-cell contacts. Moreover, the IGF-IR and its two substrates, insulin receptor substrate 1 and SHC, were contained within the E-cadherin complexes. Our results suggest that overexpressed IGF-IRs, by promoting the aggregation, growth, and survival of breast cancer cells, may accelerate the increase of tumor mass and may also prevent cell scattering.