title: 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.affiliation: Departement of Gynecology and Obstetrics, Georg-August-University,                     Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Block
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründker
authors.forename: Stefanie
authors.initials: S
authors.lastname: Fister
authors.forename: Julia
authors.initials: J
authors.lastname: Kubin
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.forename: Michael D
authors.initials: MD
authors.lastname: Mueller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmerlein
authors.forename: Günter
authors.initials: G
authors.lastname: Emons
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Günthert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D055028:Comparative Genomic Hybridization; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib; D007987:Gonadotropin-Releasing Hormone; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010767:Phosphorylcholine; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011966:Receptors, LHRH; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; C016601:afimoxifene; C105905:perifosine; C484760:PIK3CA protein, human; C512478:EGFR protein, human