Overexpressed epidermal growth factor receptor (EGFR)‐induced progestin insensitivity in human endometrial carcinoma cells by the EGFR/mitogen‐activated protein kinase signaling pathway

Abstract

BACKGROUND: Fertility-sparing management is an important treatment for young women who have endometrial carcinoma (EC). Many patients with EC exhibit insensitivity or resistance to progestin therapy, and the molecular mechanisms of that insensitivity and resistance have been elusive. Epidermal growth factor receptor (EGFR) overexpression has been observed in EC, but the roles of EGFR in progestin resistance have not been investigated. METHODS: EGFR and progesterone receptor isotype B (PR-B) messenger RNA and protein levels were determined in EC tissue samples and cell lines by immunohistochemical, real-time reverse transcriptase-polymerase chain reaction and Western blot analyses. The biologic function of EGFR in the regulation of PR-B expression and induced progestin resistance was investigated by transfecting recombinant plasmids that expressed EGFR into Ishikawa EC cells. In addition, the role of the mitogen-activated protein kinase (MAPK) signal pathway was investigated by Western blot analysis. RESULTS: EGFR was detected in 60% of PR-B-positive samples and in 90.5% of PR-B-negative samples (P ¼.015). EGFR expression was higher in progestin-resistant KLE EC cells than in progestin-sensitive Ishikawa EC cells. In contrast, PR-B expression was higher in Ishikawa cells than KLE cells. Higher EGFR expression reduced sensitivity to progestin and decreased PR-B expression in Ishikawa cells; it also abnormally activated the MAPK signaling pathway and inhibited cell apoptosis. The EGFR tyrosine kinase-specific inhibitor AG1478 effectively inhibited the proliferation of EC cells that overexpressed EGFR. CONCLUSIONS: The current results indicated that EGFR overexpression may play an important role in reducing sensitivity to progestin treatment in EC. An EGFR tyrosine kinasespecific inhibitor may be useful in the treatment of EC. Cancer 2010;116;3603-13.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…The results are in agreement with those of Hipp et al (2009) who showed regulation of SNAIL by activation of EGFR via Akt and ERK1/2 pathways in Ishikawa cells. Activation of EGFR/MAPK pathway via overexpression of EGFR and its contribution to reduced PR-B expression and increased progestin resistance in EC has been reported (Ai et al 2010).…”

Prognostic analysis of patients with locally advanced nasopharyngeal carcinoma following intensity modulated radiation therapy

“…Potential therapeutic targets for HNSCC, including epidermal growth factor receptor (EGFR), have been researched over the past decade. High EGFR expression is associated with poor prognosis in head and neck squamous-cell carcinoma and with resistance to radiotherapy (10,11). A previous study demonstrated that nimotuzumab combined with radiotherapy or chemotherapy was associated with improved locoregional tumor control and survival compared with standard chemoradiotherapy in patients with locally advanced HNSCC (12).…”

Progestin therapy for endometrial cancer: The potential of fourth-generation progestin (Review)

“…When further EGFR expression was stimulated in Ishikawa cells, the susceptibility to progestin decreased, accompanied by reduction in PRB expression. AG1478 (a specific inhibitor for EGFR tyrosine kinase) effectively suppressed the proliferation of EGFR-overexpressed endometrial cancer cells (45). On the basis of these findings, we may say that excessive expression of EGFR in endometrial cancer cells can reduce the susceptibility to progestin therapy.…”