Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells.
Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The alphaIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IR-stimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.
Byron
S A
SA
Department of Pharmacology, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Horwitz
K B
KB
Richer
J K
JK
Lange
C A
CA
Zhang
X
X
Yee
D
D
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection
D000911:Antibodies, Monoclonal; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1