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=.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 kinase-specific inhibitor may be useful in the treatment of EC. © 2010 American Cancer Society.