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International Journal of Oncology
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Print ISSN: 1019-6439 Online ISSN: 1791-2423
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International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

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International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

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Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

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Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

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International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

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Article

The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines

  • Authors:
    • Tove Kirkegaard
    • Christina W. Yde
    • Marie Kveiborg
    • Anne E. Lykkesfeldt
  • View Affiliations / Copyright

    Affiliations: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark, Department of Biomedical Sciences and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
  • Pages: 393-400
    |
    Published online on: May 9, 2014
       https://doi.org/10.3892/ijo.2014.2434
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Abstract

Breast cancer cells can switch from estrogen receptor α (ER)- to human epidermal growth factor receptor (HER)-driven cell growth upon acquiring antiestrogen resistance. HER ligands are cleaved by metalloproteinases leading to release of active HER ligands, activation of HER receptors and consequently increased cell growth. In this study, we investigated the importance of HER receptors, in particular HER3, and HER ligand shedding for growth and signaling in human MCF-7 breast cancer cells and MCF-7-derived sublines resistant to the antiestrogen fulvestrant. The HER3/HER4 ligand heregulin 1β induced phosphorylation of HER3, Akt and Erk, and partly rescued fulvestrant-inhibited growth of MCF-7 cells. HER3 ligands were found to be produced and shed from the fulvestrant-resistant cells as conditioned medium from fulvestrant-resistant MCF-7 cells induced phosphorylation of HER3 and Akt in MCF-7 cells. This was prevented by treatment of resistant cells with the metalloproteinase inhibitor TAPI-2. Only the broad-spectrum metalloproteinase inhibitor BB-94, and not the more selective inhibitors GM6001 or TAPI-2, which inhibited shedding of the HER ligands produced by the fulvestrant-resistant cells, was able to inhibit growth and activation of HER3 and Erk in resistant cells. Compared to MCF-7, fulvestrant-resistant cells have increased HER3 phosphorylation, but knockdown of HER3 had no inhibitory effect on resistant cell growth. The EGFR inhibitor gefitinib exhibited only a minor growth inhibition, whereas the pan-HER inhibitor CI-1033 exerted growth arrest. Thus, neither HER3 nor EGFR alone are the main driver of fulvestrant-resistant cell growth and treatment should target both receptors. Ligand shedding is not a treatment target, as receptor activation occurred, independent of release of ligands. Only the broad-spectrum metalloproteinase inhibitor BB-94 could abrogate HER3 and Erk activation in the resistant cells, which stresses the complexity of the resistance mechanisms and the requirement of targeting signaling from HER receptors by multiple strategies.
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Copy and paste a formatted citation
Spandidos Publications style
Kirkegaard T, Yde CW, Kveiborg M and Lykkesfeldt AE: The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines. Int J Oncol 45: 393-400, 2014.
APA
Kirkegaard, T., Yde, C.W., Kveiborg, M., & Lykkesfeldt, A.E. (2014). The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines. International Journal of Oncology, 45, 393-400. https://doi.org/10.3892/ijo.2014.2434
MLA
Kirkegaard, T., Yde, C. W., Kveiborg, M., Lykkesfeldt, A. E."The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines". International Journal of Oncology 45.1 (2014): 393-400.
Chicago
Kirkegaard, T., Yde, C. W., Kveiborg, M., Lykkesfeldt, A. E."The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines". International Journal of Oncology 45, no. 1 (2014): 393-400. https://doi.org/10.3892/ijo.2014.2434
Copy and paste a formatted citation
x
Spandidos Publications style
Kirkegaard T, Yde CW, Kveiborg M and Lykkesfeldt AE: The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines. Int J Oncol 45: 393-400, 2014.
APA
Kirkegaard, T., Yde, C.W., Kveiborg, M., & Lykkesfeldt, A.E. (2014). The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines. International Journal of Oncology, 45, 393-400. https://doi.org/10.3892/ijo.2014.2434
MLA
Kirkegaard, T., Yde, C. W., Kveiborg, M., Lykkesfeldt, A. E."The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines". International Journal of Oncology 45.1 (2014): 393-400.
Chicago
Kirkegaard, T., Yde, C. W., Kveiborg, M., Lykkesfeldt, A. E."The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines". International Journal of Oncology 45, no. 1 (2014): 393-400. https://doi.org/10.3892/ijo.2014.2434
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