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Endocrine resistance in breast cancer remains a major clinical problem andis caused by crosstalk mechanisms of growth factor receptor cascades, such asthe erbB and PI3K/AKT pathways. The possibilities a single breast cancer cellhas to achieve resistance are manifold. We developed a model of 4-hydroxy-tamoxifen(OHT)‑resistant human breast cancer cell lines and compared their different expressionpatterns, activation of growth factor receptor pathways and compared cells bygenomic hybridization (CGH). We also tested a panel of selective inhibitors ofthe erbB and AKT/mTOR pathways to overcome OHT resistance. OHT‑resistant MCF-7-TRand T47D-TR cells showed increased expression of HER2 and activation of AKT. T47D-TRcells showed EGFR expression and activated MAPK (ERK-1/2), whereas in resistantMCF-7-TR cells activated AKT was due to loss of CTMP expression. CGH analysesrevealed remarkable aberrations in resistant sublines, which were predominantlydepletions. Gefitinib inhibited erbB signalling and restored OHT sensitivity inT47D-TR cells. The AKT inhibitor perifosine restored OHT sensitivity in MCF-7-TRcells. All cell lines showed expression of receptors for gonadotropin-releasinghormone (GnRH) I and II, and analogs of GnRH-I/II restored OHT sensitivity inboth resistant cell lines by inhibition of erbB and AKT signalling. In conclusion,mechanisms to escape endocrine treatment in breast cancer share similarities inexpression profiling but are based on substantially different genetic aberrations.Evaluation of activated mediators of growth factor receptor cascades is helpfulto predict response to specific inhibitors. Expression of GnRH-I/II receptorsprovides multi-targeting treatment strategies.

international journal of oncology

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