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.

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.

• Authors: Martin Block, Carsten Gründker, Stefanie Fister, Julia Kubin, Ludwig Wilkens, Michael D Mueller, Bernhard Hemmerlein, Günter Emons, Andreas R Günthert
• Journal: International journal of oncology (Int J Oncol) Vol. 41 Issue 5 Pg. 1845-54 (Nov 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22922893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolines
• Receptors, LHRH
• Tamoxifen
• Phosphorylcholine
• afimoxifene
• perifosine
• Gonadotropin-Releasing Hormone
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• Gefitinib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Class I Phosphatidylinositol 3-Kinases
• Comparative Genomic Hybridization
• Drug Resistance, Neoplasm
• Enzyme Activation
• ErbB Receptors (metabolism)
• Female
• Gefitinib
• Gene Expression Regulation, Neoplastic
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacology)
• Humans
• MCF-7 Cells
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Quinazolines (pharmacology)
• Receptors, LHRH (genetics, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Tamoxifen (analogs & derivatives, pharmacology)