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  • Original Paper
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Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2

Oncogene volume 22, pages 8178–8186 (2003)Cite this article

Abstract

Ligands of the ErbB family of receptors and estrogens control the proliferation of breast cancer cells. Overexpression of human EGF receptor HER-2 (erbB2) leads to amplified heregulin (HRG) signaling, promoting more aggressive breast cancer that is nonresponsive to estrogen and the antiestrogenic drug tamoxifen. Herstatin (Hst), a secreted HER-2 gene product, binds to the HER-2 receptor ectodomain blocking receptor activation. The aim of this study was to investigate the impact of this HER-2 inhibitor on HRG-induced signaling, proliferation, and sensitivity to tamoxifen in breast cancer cells with and without HER-2 overexpression. The expression of Hst in MCF7 cells eliminated HRG signaling through both mitogen-activated protein kinase and Akt pathways and prevented HRG-mediated proliferation. The loss in signaling corresponded to downregulation of the HRG receptors, HER-3 and HER-4, whereas HER-2 overexpression strongly stimulated the levels of both HRG receptors. Although Hst blocked HRG signaling in both parental and HER-2 transfected cells, it enhanced sensitivity to tamoxifen only in the MCF7 cells that overexpressed HER-2. To evaluate further the efficacy of Hst as an anticancer agent, His-tagged Hst was expressed in transfected insect cells, purified, and added to the breast cancer cells. As in the transfected cells, purified Hst inhibited HER-3 levels and suppressed HRG-induced proliferation of MCF7 and BT474 breast cancer cells. In contrast, the HER-2 monoclonal antibody, herceptin, downregulated HER-2, but not HER-3. These results suggest the potential use of Hst against HRG-mediated growth of breast cancers with high and low levels of HER-2 and against tamoxifen resistance in HER-2 overexpressing breast cancer.

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Abbreviations

RTK:

receptor tyrosine kinase

EGF:

epidermal growth factor

HER:

Human EGF receptors 1–4

EGFR:

EGF receptor

HRG:

heregulin

RT–PCR:

reverse transcriptase–polymerase chain reaction

MAPK:

mitogen-activated protein kinase

PI3K:

phosphatidylinositol 3-kinase

SDS–PAGE:

sodium dodecyl polyacrilamide-gel electrophoresis

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Acknowledgements

We thank Jennifer Rhodes for Herstatin purification and Tina Purnat for excellent administrative assistance. This study was supported by an NIH grant from the National Cancer Institute to GMC.

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  1. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, 97239-3098, OR, USA

    Farida Jhabvala-Romero, Adam Evans, Shuhua Guo, Michael Denton & Gail Mary Clinton

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Correspondence to Gail Mary Clinton.

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Jhabvala-Romero, F., Evans, A., Guo, S. et al. Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2. Oncogene 22, 8178–8186 (2003). https://doi.org/10.1038/sj.onc.1206912

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