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Multiple Signaling Pathways are Activated During Insulin-like Growth Factor-I (IGF-I) Stimulated Breast Cancer Cell Migration

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Abstract

In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.

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Authors and Affiliations

  1. Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN, 55455, USA

    Xihong Zhang & Douglas Yee

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Min Lin & Kenneth L. van Golen

  3. Laboratory of Tumor Biology, Osaka Medical Center for Cancer, Osaka, Japan

    Kiyoko Yoshioka & Kazuyuki Itoh

Authors
  1. Xihong Zhang
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  2. Min Lin
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  3. Kenneth L. van Golen
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  4. Kiyoko Yoshioka
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  5. Kazuyuki Itoh
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  6. Douglas Yee
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Correspondence to Douglas Yee.

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Zhang, X., Lin, M., van Golen, K.L. et al. Multiple Signaling Pathways are Activated During Insulin-like Growth Factor-I (IGF-I) Stimulated Breast Cancer Cell Migration. Breast Cancer Res Treat 93, 159–168 (2005). https://doi.org/10.1007/s10549-005-4626-8

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