Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma

ObjectiveProgestin is an effective endocrine treatment for patients with atypical hyperplasia or with endometrial carcinoma that is estrogen receptor (ER) positive and progesterone receptor (PR) positive. However, long-term progestin treatment may lead to resistance. We have studied the progestin resistance phenotype that frequently develops in endometrial carcinoma.MethodsIshikawa endometrial carcinoma cells were cultured for a long period (10 months) in the presence of the synthetic progestin medroxyprogesterone acetate (MPA), thereby generating a subline refractory to the growth-suppressive effects of MPA.ResultsThe MPA-resistant subline showed growth stimulation rather than inhibition after MPA treatment. Immunocytochemical analysis showed reduced ERα and PR-B expression and increased ERβ expression in this subline compared with parental Ishikawa cells. Progestin-resistant Ishikawa cells also showed increased expression of transforming growth factor α (TGFα), the epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK); MPA treatment further stimulated the expression of TGFα in these cells. Additionally, progestin-resistant Ishikawa cells were highly sensitive to growth stimulation by TGFα and to growth inhibition by the EGFR-TK-specific inhibitor AG1478, and they showed increased dependence on TGFα-EGFR signaling.ConclusionsOur results suggest that prolonged treatment of endometrial carcinoma cells with MPA induces resistance to the growth-suppressive effects of MPA and enhances cancer cell proliferation. The downregulation of ERα and PR-B, the upregulation of ERβ, and highly activated TGF-EGFR signaling are thus likely to contribute to progestin resistance in endometrial carcinoma. Therefore, an EGFR-TK-specific inhibitor might be useful in the treatment of progestin-resistant endometrial carcinoma.