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Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines

Oncogene volume 20, pages 7318–7325 (2001)Cite this article

Abstract

Insulin-like growth factors (IGFs) regulate breast cancer cell proliferation, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was selected for growth as an ascites tumor in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac injection of the MDA-MB-231 cell line in athymic mice. Compared to the parental cell lines, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-1 in the metastatic variants. IGF-I stimulated cell migration in the variant cells, but not in the parental cells. To determine the role for IRS-2 in IGF-mediated motility, we transfected MDA-231BO cells with an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2 with diminished IGF-mediated motility and anchorage independent growth when compared to control cells. However, adherence to fibronectin was enhanced in the transfected cells compared to MDA-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activation and signaling. In these cells, IGF-I enhances cell adhesion and motility suggesting that IRS-2 may mediate these aspects of the malignant phenotype.

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Acknowledgements

This was supported by Public Health Service (PHS) grant R01CA74285, and PHS Cancer Center Support grant P30CA54174. Drs Robert Clark and Nils Brünner kindly provided the MDA-MB-435 parental and LCC6 variant cells. The authors wish to thank Adrian V Lee and Carol Lange for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

    Xihong Zhang & Douglas Yee

  2. Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Texas, USA

    James G Jackson

  3. Department of Medicine, Division of Endocrinology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Texas, USA

    Toshiyuki Yoneda

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  1. James G Jackson
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  2. Xihong Zhang
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Correspondence to Douglas Yee.

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Jackson, J., Zhang, X., Yoneda, T. et al. Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene 20, 7318–7325 (2001). https://doi.org/10.1038/sj.onc.1204920

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