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

Abstract

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 GCTcells to EGFR inhibition. Low-level amplification of EGFR gene was observed in five GCTs and highlevel 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. Smallmolecule 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 GCTcells 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.

FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development

“…Moreover, altered activation of the insulin-like growth factor 1 receptor and epidermal growth factor receptor pathways have been implicated in promoting adult human GCT progression (49,50), and this might be related to elevated gonadotropins in women during the perimenopausal period when adult type GCT occur most frequently (6). Specific targets of AKT include members of FOXO family of transcription factors that are highly conserved from Caenorhabditis elegans to man (51)(52)(53)(54).…”

Obovatol inhibits the growth and aggressiveness of tongue squamous cell carcinoma through regulation of the EGF‑mediated JAK‑STAT signaling pathway

“…Studies have demonstrated that the inhibition of EGF expression contributes to the inhibition of tumor growth and further inhibits tumor metastasis (25,26). Al-Hazzaa et al (27) reported that EGF receptor tyrosine kinase inhibitor ZD1839 promoted cisplatin-induced apoptosis in SCC-15 cells.…”