| 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 | Shujun Zhao, Xiaojun Chen, Xin Lu, Yinhua Yu, Youji Feng
(Affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai 200011, China.)
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| Journal | Gynecologic oncology
(Gynecol Oncol)
Vol. 105
Issue 1
Pg. 45-54
(Apr 2007)
ISSN: 0090-8258 United States |
| PMID | 17240435
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Antineoplastic Agents, Hormonal
- Estrogen Receptor alpha
- Progestins
- RNA, Messenger
- Receptors, Progesterone
- Cyclin D1
- Medroxyprogesterone 17-Acetate
- Receptor, Epidermal Growth Factor
|
| Topics |
- Antineoplastic Agents, Hormonal
(pharmacology)
- Cell Cycle
(drug effects)
- Cyclin D1
(biosynthesis)
- Drug Resistance, Neoplasm
- Endometrial Neoplasms
(drug therapy, enzymology)
- Estrogen Receptor alpha
(biosynthesis)
- Female
- Humans
- Immunohistochemistry
- Medroxyprogesterone 17-Acetate
(pharmacology)
- Progestins
(pharmacology)
- RNA, Messenger
(biosynthesis, genetics)
- Receptor, Epidermal Growth Factor
(metabolism)
- Receptors, Progesterone
(biosynthesis)
- Signal Transduction
(drug effects)
|
