期刊
BRITISH JOURNAL OF CANCER
卷 95, 期 9, 页码 1220-1228出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6603354
关键词
insulin-like growth factor-I; type I insulin-like growth factor receptor; insulin receptor substrate; proliferation; motility
类别
资金
- NCI NIH HHS [R01 CA077398, P30 CA77398, R01 CA074285, CA74285] Funding Source: Medline
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-1-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-1-stimulated motility, but did not stimulate proliferation. The alpha IR-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.
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