Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma.
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.
Zhao
Shujun
S
Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai 200011, China.
Chen
Xiaojun
X
Lu
Xin
X
Yu
Yinhua
Y
Feng
Youji
Y
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
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