Antiproliferative effects of antiestrogens and inhibitors of growth factor receptor signaling on endometrial cancer cells.
OBJECTIVE
In patients with advanced estrogen-dependent type I endometrial cancer (EC), pharmacological treatment with progestins or antiestrogens is recommended, but primary and secondary resistance are common. The aim of our study was to investigate single-agent and dual-agent therapeutic strategies in estrogen receptor-positive human EC cells.


METHODS
Human EC cells Ishikawa and HEC1A were cultivated under estrogen-reduced conditions and exposed to 4-hydroxytamoxifen (OHT), fulvestrant, gefitinib, everolimus, and the AKT inhibitor perifosine. Effects of drugs were analyzed by proliferation and apoptosis assays. Additionally, we analyzed expression of aromatase, phosphatase and tensin homolog (PTEN), AKT and pAKT and G protein-coupled receptor 30 (GPR30).


RESULTS
Neither OHT nor fulvestrant inhibited cell growth, nor did they induce apoptosis. Gefitinib, everolimus and perifosine inhibited proliferation in all cell lines. Only perifosine induced apoptosis. In PTEN-positive HEC1A cells, combined treatment of gefitinib plus OHT showed increased antiproliferative effects. In Ishikawa cells, combined treatment of everolimus plus gefitinib had synergistic antiproliferative effects. The most effective single-agent treatment and the only drug that induced apoptosis was perifosine. Activation of AKT had no predictive value for the effects perifosine. Due to mutation of PTEN, activated AKT was highly expressed in Ishikawa cells and scarcely detectable in HEC1A cells.


CONCLUSIONS
Under estrogen-reduced conditions, growth of ER-positive EC cells can be reduced by inhibitors of AKT, mTOR and the erbB pathway, whereas antiestrogens have no effects. In PTEN-positive HEC1A cells, the absence of estradiol probably restores OHT-induced ER-mediated repression of nuclear co-activators and increases susceptibility to inhibitors of the erbB pathway. In PTEN-negative Ishikawa cells, OHT in combination with any drug had no effects, but inhibition of the PI3K/AKT/mTOR pathway by everolimus in combination with gefitinib showed synergistic effects.
Block
Martin
M
Department of Gynaecology and Obstetrics, Georg-August University, Göttingen, Germany.
Fister
Stefanie
S
Emons
Günter
G
Seeber
Sandrine
S
Gründker
Carsten
C
Günthert
Andreas R
AR
D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000032:analysis; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000032:analysis; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D004965:Estrogen Antagonists; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D017978:Receptors, Growth Factor; D013629:Tamoxifen; D010767:Phosphorylcholine; C016601:afimoxifene; C105905:perifosine; D001141:Aromatase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human