Aim: The aim of these investigations was to study the role of gefitinib (a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor) on reversing progestin-resistance in a human endometrial carcinoma xenograft model.
Material and methods: To study the effect of gefitinib and epidermal growth factor receptor (EGFR) overexpression on tumor progestin resistance, the Ishikawa endometrial carcinoma cell line was transfected to stably express a high level of EGFR, which resulted in the progestin-resistant Ishikawa-pLWERNL subcell line. BALB/c nude mice were injected subcutaneously with the parental Ishikawa cell line and the Ishikawa-pLWERNL cell line. Therapy experiments with gefitinib alone or in combination with medroxyprogesterone acetate (MPA) were done and samples were analyzed for EGFR and progesterone receptor isoform B (PR-B) expression by Western blot and immumohistochemistry analyses. Role in blocking EGFR autophosphorylation and its downstream signaling pathway and antagonizing progestin resistance by gefitinib was investigated by Western blot analysis.
Results: EGFR expression was higher in progestin-resistant Ishikawa-pLWERNL endometrial cancer (EC) xenografts than in progestin-sensitive Ishikawa EC xenografts; in contrast, PR-B was higher in Ishikawa xenografts than in Ishikawa-pLWERNL xenografts. Higher EGFR expression reduced sensitivity to progestin and decreased PR-B expression in Ishikawa xenografts; it also abnormally activated EGFR autophosphorylation and its downstream signaling pathway. Gefitinib effectively inhibited the proliferation of EC xenografts that overexpressed EGFR, and reversed hormone resistance in progestin-resistant EC xenografts.
Discussion: The present study describes an in vivo model that can provide a valuable tool in studying the interaction of overexpressed EGFR and progestin resistance in EC. Gefitinib may be useful in the treatment of progestin-resistant EC.
© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.