Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition.
Epidermal growth factor receptor (EGFR) is implicated in the progression of many human cancers, but its significance in ovarian granulosa cell tumor (GCT) pathobiology remains poorly understood. We assessed the EGFR gene copy number, surveyed the mRNA and protein expression patterns of EGFR in 90 adult GCTs, and assessed the in vitro sensitivity of GCT cells to EGFR inhibition. Low-level amplification of EGFR gene was observed in five GCTs and high-level amplification in one sample. EGFR mRNA was robustly expressed in GCTs. Most tumors expressed both unphosphorylated and phosphorylated EGFR protein, but the protein expression did not correlate with clinical parameters, including the risk of recurrence. Small-molecule EGFR inhibitors reduced the EGF-induced activation of EGFR and its downstream signaling molecules at nanomolar doses, but cell viability was reduced, and caspase-3/7 was activated in GCT cells only at micromolar doses. Based on the present results, EGFR is active and abundantly expressed in the majority of GCTs, but probably has only minor contribution to GCT cell growth. Given the high doses of EGFR inhibitors required to reduce GCT cell viability in vitro, they are not likely to be effective for GCT treatment as single agents; they should rather be tested as part of combination therapies for these malignancies.
Children's Hospital, University of Helsinki and Helsinki University Central Hospital, PO Box 20, 00014 University of Helsinki, Finland Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, PO Box 140, 00290 Helsinki, Finland Department of Pathology, Helsinki University Central Hospital, University of Helsinki and HUSlab, Haartmaninkatu 3, 00290 Helsinki, Finland Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Missouri 63110, USA.
Noora
N
Andersson
Mikko
M
Anttonen
Anniina
A
Färkkilä
Marjut
M
Pihlajoki
Ralf
R
Bützow
Leila
L
Unkila-Kallio
Markku
M
Heikinheimo
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D066246:ErbB Receptors; D053148:Caspase 3; D053179:Caspase 7
apoptosis; cell viability; epidermal growth factor receptor (EGFR) inhibition; granulosa cell tumor (GCT); ovary