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Originally published In Press as doi:10.1074/jbc.M305403200 on November 13, 2003

J. Biol. Chem., Vol. 279, Issue 6, 5017-5024, February 6, 2004
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A Dominant Negative Type I Insulin-like Growth Factor Receptor Inhibits Metastasis of Human Cancer Cells*

Deepali Sachdev, Julie S. Hartell, Adrian V. Lee{ddagger}, Xihong Zhang, and Douglas Yee§

From the Department of Medicine and Cancer Center, University of Minnesota, Minnesota 55455 and {ddagger}Breast Center, Baylor College of Medicine, Houston, Texas 77030

We have previously shown that LCC6 wild-type (WT) cells, a metastatic variant of MDA-MB-435 cancer cells originally derived from a breast cancer patient, exhibit enhanced motility in response to IGF-I compared with the parent MDA-MB-435 cells. To further understand the role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in cancer metastasis we inhibited signaling via IGF1R using a C-terminal-truncated IGF1R. The truncated receptor retains the ligand binding domain but lacks the autophosphorylated tyrosine residues in the carboxyl terminus. Cells stably transfected with this truncated receptor (LCC6-DN cells) overexpressed the truncated IGF1R messenger RNA nearly 50-fold over endogenous receptor. The truncated receptor in the LCC6-DN cells behaved in a dominant negative manner to inhibit endogenous IGF1R activation by IGF-I. Compared with the LCC6-WT cells, LCC6-DN cells failed to phosphorylate the adaptor proteins insulin receptor substrate-1 and -2 in response to IGF-I and did not activate Akt after exposure to IGF-I. Unlike LCC6-WT cells, LCC6-DN cells did not show enhanced motility in response to IGF-I. To assay for metastasis, LCC6-WT and LCC6-DN cells were injected into the mammary fat pads of mice, and the primary xenograft tumors were removed after 21 days. Mice sacrificed 5 weeks later showed multiple lung metastases derived from LCC-WT xenografts, whereas mice harboring LCC6-DN xenografts showed no lung metastases. Our data show that IGF1R can regulate several aspects of the malignant phenotype. In these cells, metastasis but not proliferation requires IGF1R function.


Received for publication, May 22, 2003 , and in revised form, November 10, 2003.

* This work was supported by U. S. Army Medical Research and Material Command Grant DAMD17-00-1-0347 (to D. S.), National Institutes of Health Grant R01 CA74285, and Public Health Service Cancer Center Support Grant P30 CA77398. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: University of Minnesota Cancer Center, MMC 806, 420 Delaware St. SE, Minneapolis, MN 55455. Tel.: 612-626-8487; Fax: 612-626-4842; E-mail: yeexx006{at}umn.edu.


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