title: Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway.
abstract: In the MCF-7 breast cancer cell line, insulin-like growth factors (IGFs) are known to elicit antiproliferative actions via the insulin receptor substrate-1 (IRS-1)/PI 3-kinase/AKT pathway. All-trans retinoic acid (RA) is a potent inhibitor of MCF-7 cell proliferation, but the mechanism by which growth regulation is achieved remains unclear. We investigated the effects of RA on the regulation of the IGF-IR and its key signaling elements: IRS-1, IRS-2, and SHC. Treatment of MCF-7 cells with RA caused a significant reduction in IRS-1 protein and tyrosine phosphorylation levels at a concentration and time consistent with RA-mediated growth inhibition. IRS-1 regulation is selective, as RA did not influence IRS-2 or SHC levels. Downstream signaling events were also selectively reduced, as RA abrogated IGF-I-stimulated AKT activation but did not alter erk1/2 activation. To confirm the importance of IRS-1 regulation by RA, we examined the response to RA in MCF-7 cells overexpressing IGF-IR and IRS-1. RA resistance was observed in MCF-7 cells overexpressing IRS-1 but not IGF-IR. This suggests that RA-mediated growth inhibition requires the selective downregulation of IRS-1 and AKT. Therapeutic agents targeting the IRS-1/PI 3-kinase/AKT pathway may enhance the cytostatic effects of RA in breast cancer, since overexpression of IRS-1 and AKT have been reported in primary breast tumors.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Department of Oncology, Montreal, Quebec, Canada.
authors.forename: Sonia V
authors.initials: SV
authors.lastname: del Rincón
authors.forename: Caroline
authors.initials: C
authors.lastname: Rousseau
authors.forename: Ratna
authors.initials: R
authors.lastname: Samanta
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D055504:Insulin Receptor Substrate Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D055504:Insulin Receptor Substrate Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D014212:Tretinoin; C526292:IRS1 protein, human; C494918:AKT1 protein, human