title: Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells.
abstract: 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.
authors.affiliation: Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Guvakova
authors.forename: E
authors.initials: E
authors.lastname: Surmacz
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000032:analysis / Q000502:physiology*; D002448:Cell Adhesion; D002449:Cell Aggregation / Q000187:drug effects; D002455:Cell Division; D002470:Cell Survival; D003094:Collagen; D004338:Drug Combinations; D004958:Estradiol / Q000494:pharmacology*; D005109:Extracellular Matrix; D005455:Fluorescent Antibody Technique; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007797:Laminin; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D011509:Proteoglycans; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D004338:Drug Combinations; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D007797:Laminin; D010750:Phosphoproteins; D011506:Proteins; D011509:Proteoglycans; C059485:matrigel; D019000:Phosphotyrosine; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D017526:Receptor, IGF Type 1