title: Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma.
abstract: OBJECTIVE
  Progestin 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.
  
  
  METHODS
  Ishikawa 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.
  
  
  RESULTS
  The MPA-resistant subline showed growth stimulation rather than inhibition after MPA treatment. Immunocytochemical analysis showed reduced ER alpha and PR-B expression and increased ER beta expression in this subline compared with parental Ishikawa cells. Progestin-resistant Ishikawa cells also showed increased expression of transforming growth factor alpha (TGFalpha), the epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK); MPA treatment further stimulated the expression of TGFalpha in these cells. Additionally, progestin-resistant Ishikawa cells were highly sensitive to growth stimulation by TGFalpha and to growth inhibition by the EGFR-TK-specific inhibitor AG1478, and they showed increased dependence on TGFalpha-EGFR signaling.
  
  
  CONCLUSIONS
  Our 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 ER alpha and PR-B, the upregulation of ER beta, 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.
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai 200011, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Zhao
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D011372:Progestins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D019938:Cyclin D1; D017258:Medroxyprogesterone Acetate; D066246:ErbB Receptors