Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

J Mol Endocrinol. 2014 Mar 12;52(2):223-34. doi: 10.1530/JME-13-0286. Print 2014 Apr.


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.

Keywords: apoptosis; cell viability; epidermal growth factor receptor (EGFR) inhibition; granulosa cell tumor (GCT); ovary.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Activation / drug effects
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • Granulosa Cell Tumor / drug therapy*
  • Granulosa Cell Tumor / enzymology*
  • Granulosa Cell Tumor / genetics
  • Granulosa Cell Tumor / pathology
  • Humans
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Protein Kinase Inhibitors
  • RNA, Messenger
  • ErbB Receptors
  • Caspase 3
  • Caspase 7

Supplementary concepts

  • Granulosa cell tumor of the ovary