Tamoxifen-mediated growth inhibition of human cholangiocarcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 57; no. 9; pp. 1743 - 1749
• Main Authors: SAMPSON, L. K, VICKERS, S. M, YING, W, PHILLIPS, J. O
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-05-1997
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Northern; Cell Division - drug effects; Chemotherapy; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - pathology; Female; Gene Expression Regulation, Neoplastic; Growth Inhibitors - pharmacology; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Pharmacology. Drug treatments; Precipitin Tests; Receptors, Estrogen - genetics; Tamoxifen - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Human; Prognosis; Liver; Antiestrogen; Estrogen; Hepatic disease; Malignant tumor; Biliary tract disease; In vitro; Tamoxifene; In vivo; Chemotherapy; Experimental disease; Treatment; Malignant cholangioma; Established cell line; Digestive diseases; Non steroid compound; Hormonal receptor
• ISSN: 0008-5472; 1538-7445

Cholangiocarcinoma represents a challenging primary malignancy of the liver with no effective medical therapy and a poor prognosis. We have investigated the role of tamoxifen and estrogen receptors (ERs) in the regulation of growth of human cholangiocarcinoma. Two human cholangiocarcinoma cell lines, OZ and SK-ChA-1, were grown in the presence of graded concentrations of tamoxifen; the effects on cell growth were determined by cell counting or 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium proliferation assay. The presence of ER protein was tested by indirect immunofluorescence and immunoprecipitation. In addition, cells were grown in estrogen-depleted media supplemented with exogenous 17beta-estradiol. ER mRNA was evaluated by reverse transcription-PCR and Northern blotting. Finally, one cholangiocarcinoma cell line was grown as a xenograft in athymic nude mice; tamoxifen effects on in vivo tumor growth were determined with biweekly caliper measurements. Tamoxifen (5-10 microM) caused dose-dependent in vitro growth inhibition of two human cholangiocarcinoma cell lines. In addition, growth inhibition of one cell line (SK-ChA-1) grown as a xenograft in nude mice by tamoxifen was observed. The presence of ER protein was suggested by 17beta-estradiol stimulation of tumor cell growth in vitro and confirmed by immunoprecipitation. Immunofluorescence microscopy was ineffective at detection of ER protein. Reverse transcription-PCR demonstrated the presence of ER mRNA in both cell lines. Northern blot analysis confirmed the presence of full-length 6.5-kb ER mRNA. No ER deletion mutants were detected. Tamoxifen inhibited the growth of human cholangiocarcinoma in vitro and in vivo. ER protein and mRNA were detected in both cell lines. The mechanism(s) of tamoxifen-mediated growth inhibition is unclear but may occur via ER protein or additional pathways. The ability of tamoxifen to inhibit tumor growth may offer an alternative adjunctive treatment for cholangiocarcinoma.