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Article

Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells

  • Authors:
    • Martin Block
    • Carsten Gründker
    • Stefanie Fister
    • Julia Kubin
    • Ludwig Wilkens
    • Michael D. Mueller
    • Bernhard Hemmerlein
    • Günter Emons
    • Andreas R. Günthert
  • View Affiliations / Copyright

    Affiliations: Departement of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany, Institute of Pathology, University of Bern, Bern, Switzerland, Department of Gynecology and Obstetrics, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland, Institute of Pathology, Georg-August-University, Göttingen, Germany
  • Pages: 1845-1854
    |
    Published online on: August 21, 2012
       https://doi.org/10.3892/ijo.2012.1591
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Abstract

Endocrine resistance in breast cancer remains a major clinical problem and is caused by crosstalk mechanisms of growth factor receptor cascades, such as the erbB and PI3K/AKT pathways. The possibilities a single breast cancer cell has to achieve resistance are manifold. We developed a model of 4-hydroxy-tamoxifen (OHT)‑resistant human breast cancer cell lines and compared their different expression patterns, activation of growth factor receptor pathways and compared cells by genomic hybridization (CGH). We also tested a panel of selective inhibitors of the erbB and AKT/mTOR pathways to overcome OHT resistance. OHT‑resistant MCF-7-TR and T47D-TR cells showed increased expression of HER2 and activation of AKT. T47D-TR cells showed EGFR expression and activated MAPK (ERK-1/2), whereas in resistant MCF-7-TR cells activated AKT was due to loss of CTMP expression. CGH analyses revealed remarkable aberrations in resistant sublines, which were predominantly depletions. Gefitinib inhibited erbB signalling and restored OHT sensitivity in T47D-TR cells. The AKT inhibitor perifosine restored OHT sensitivity in MCF-7-TR cells. All cell lines showed expression of receptors for gonadotropin-releasing hormone (GnRH) I and II, and analogs of GnRH-I/II restored OHT sensitivity in both resistant cell lines by inhibition of erbB and AKT signalling. In conclusion, mechanisms to escape endocrine treatment in breast cancer share similarities in expression profiling but are based on substantially different genetic aberrations. Evaluation of activated mediators of growth factor receptor cascades is helpful to predict response to specific inhibitors. Expression of GnRH-I/II receptors provides multi-targeting treatment strategies.
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Copy and paste a formatted citation
Spandidos Publications style
Block M, Gründker C, Fister S, Kubin J, Wilkens L, Mueller MD, Hemmerlein B, Emons G and Günthert AR: Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. Int J Oncol 41: 1845-1854, 2012.
APA
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M.D. ... Günthert, A.R. (2012). Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. International Journal of Oncology, 41, 1845-1854. https://doi.org/10.3892/ijo.2012.1591
MLA
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M. D., Hemmerlein, B., Emons, G., Günthert, A. R."Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells". International Journal of Oncology 41.5 (2012): 1845-1854.
Chicago
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M. D., Hemmerlein, B., Emons, G., Günthert, A. R."Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells". International Journal of Oncology 41, no. 5 (2012): 1845-1854. https://doi.org/10.3892/ijo.2012.1591
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x
Spandidos Publications style
Block M, Gründker C, Fister S, Kubin J, Wilkens L, Mueller MD, Hemmerlein B, Emons G and Günthert AR: Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. Int J Oncol 41: 1845-1854, 2012.
APA
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M.D. ... Günthert, A.R. (2012). Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. International Journal of Oncology, 41, 1845-1854. https://doi.org/10.3892/ijo.2012.1591
MLA
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M. D., Hemmerlein, B., Emons, G., Günthert, A. R."Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells". International Journal of Oncology 41.5 (2012): 1845-1854.
Chicago
Block, M., Gründker, C., Fister, S., Kubin, J., Wilkens, L., Mueller, M. D., Hemmerlein, B., Emons, G., Günthert, A. R."Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells". International Journal of Oncology 41, no. 5 (2012): 1845-1854. https://doi.org/10.3892/ijo.2012.1591
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