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Article

The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells

  • Authors:
    • Antonia Bellizzi
    • Maria Raffaella Greco
    • Rosa Rubino
    • Angelo Paradiso
    • Stefania Forciniti
    • Katrine Zeeberg
    • Rosa Angela Cardone
    • Stephan Joel Reshkin
  • View Affiliations / Copyright

    Affiliations: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, I-70125 Bari, Italy, Clinical Experimental Oncology Laboratory, National Cancer Research Centre ‘Giovanni Paolo II’, I-70124 Bari, Italy
  • Pages: 1214-1224
    |
    Published online on: December 19, 2014
       https://doi.org/10.3892/ijo.2014.2805
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Abstract

Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress the epidermal growth factor receptor (EGFR), but are resistant to tyrosine kinase inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the downregulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB‑231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1‑EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs.
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Copy and paste a formatted citation
Spandidos Publications style
Bellizzi A, Greco MR, Rubino R, Paradiso A, Forciniti S, Zeeberg K, Cardone RA and Reshkin SJ: The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. Int J Oncol 46: 1214-1224, 2015.
APA
Bellizzi, A., Greco, M.R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K. ... Reshkin, S.J. (2015). The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. International Journal of Oncology, 46, 1214-1224. https://doi.org/10.3892/ijo.2014.2805
MLA
Bellizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., Reshkin, S. J."The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells". International Journal of Oncology 46.3 (2015): 1214-1224.
Chicago
Bellizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., Reshkin, S. J."The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells". International Journal of Oncology 46, no. 3 (2015): 1214-1224. https://doi.org/10.3892/ijo.2014.2805
Copy and paste a formatted citation
x
Spandidos Publications style
Bellizzi A, Greco MR, Rubino R, Paradiso A, Forciniti S, Zeeberg K, Cardone RA and Reshkin SJ: The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. Int J Oncol 46: 1214-1224, 2015.
APA
Bellizzi, A., Greco, M.R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K. ... Reshkin, S.J. (2015). The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. International Journal of Oncology, 46, 1214-1224. https://doi.org/10.3892/ijo.2014.2805
MLA
Bellizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., Reshkin, S. J."The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells". International Journal of Oncology 46.3 (2015): 1214-1224.
Chicago
Bellizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., Reshkin, S. J."The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells". International Journal of Oncology 46, no. 3 (2015): 1214-1224. https://doi.org/10.3892/ijo.2014.2805
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