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Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models

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Abstract

The relationship between estrogen and prolactinoma is well documented. But the anti-tumor effects of a pure estrogen receptor antagonist fulvestrant on prolactinomas, especially in vivo, and the possible mechanisms are still unclear. Therefore, the aim of this study was to evaluate the effects of fulvestrant and the involvement of the Wnt signaling pathway on rat prolactinoma models. Forty female F344 rat prolactinoma models were established by subcutaneous administration of 10 mg 17β-estradiol for 6 weeks. Rats were intramuscularly injected with fulvestrant (0, 0.5, 3, 20, 40 mg/kg), and tumor size, weight and serum prolactin (PRL) levels were evaluated before and after fulvestrant treatment at 3, 7 and 14 days. Expression of estrogen receptor α (ERα), β-catenin and Wnt inhibitory factor-1 (WIF-1) in prolactinomas was measured using quantitative PCR and western blotting, and methylation of the WIF-1 promoter was investigated using pyrosequencing. Tumor size, weight and serum PRL levels were inhibited in dose-dependent and time-dependent manners after fulvestrant treatments. β-catenin expression was downregulated but WIF-1 expression was upregulated following fulvestrant treatment. The methylation of the CpG site of the WIF-1 promoter was negatively correlated to the expression of WIF-1. In addition, the anti-cell proliferation of fulvestrant on GH3 cells was partly disrupted by Wnt signaling pathway agonist SB 216763. In conclusion, fulvestrant inhibited tumor proliferation and PRL secretion of prolactinomas via ERα, and the Wnt signaling pathway was involved in this anti-tumor effect. Therefore, fulvestrant may be a potential new drug for prolactinomas.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81271627, 30971005, 31000498, 81272522 and 81072075), the Key Program of the Natural Science Foundation of Beijing (7121004), and the Ladder Program of the Key Lab in Beijing (Z121107002812031).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Beijing Neurosurgical Institute, Capital Medical University, 6 Tiantan Xili, Beijing, 100050, People’s Republic of China

    Lei Cao, Hua Gao, Songbai Gui, Giwei Bai, Runchun Lu, Fei Wang & Yazhuo Zhang

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  1. Lei Cao
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  2. Hua Gao
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  3. Songbai Gui
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  4. Giwei Bai
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  7. Yazhuo Zhang
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Correspondence to Yazhuo Zhang.

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Lei Cao and Hua Gao contributed equally to this work.

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Supplemental Fig. 1

The cell proliferation and β-catenin expressions of GH3 cells after FVT and SB 216763 treatments. The cell proliferation of GH3 cells was inhibited by fulvestrant (FVT) and promoted by SB 216763(SB). But the anti-cell proliferation effect of FVT on GH3 cells was partly disrupted by SB treatment (a). Also, the mRNA and protein levels of β-catenin were down-regulated by FVT and up-regulated by SB. The downregualtion of β-catenin by fulvestrant could be reversed by SB treatment (b) (**, P < 0.01)

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Cao, L., Gao, H., Gui, S. et al. Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models. J Neurooncol 116, 523–531 (2014). https://doi.org/10.1007/s11060-013-1351-8

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  • DOI: https://doi.org/10.1007/s11060-013-1351-8

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