Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation

Abstract

Farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver and traditionally considered as a bile acid sensor. Yet, FXR has been recently demonstrated in other tissues and cells, such as the kidneys, the adrenals, and arterial smooth muscle cells. Immunohistochemical data reported in this study point to the expression of FXR in human breast cancer. In addition, FXR expression was also found by Western blotting and immunofluorescence microscopy in breast-cancer-derived cell lines MCF-7 (estrogen receptor [ER]-positive) and MDA-MB-231 (ER-negative). The FXR activator farnesol, a mevalonate pathway intermediate, exerts a mitogenic effect on MCF-7 cells. The growth stimulation is completely suppressed by antiestrogens. In contrast, MDA-MB-231 cells appear farnesol-insensitive, suggesting an involvement of ER in farnesol mitogenicity. In accordance with this interpretation, farnesol induces in MCF-7 cells a decrease of ER level, consistent with a phenomenon of receptor downregulation. Farnesol also increases progesterone receptor (PgR) expression in MCF-7 cells and stimulates ER-mediated gene transactivation in MVLN cells (MCF-7 cells stably transfected with an ER reporter gene). Of note, both effects of farnesol on ER expression and activity are completely suppressed by antiestrogens. In addition, farnesol-induced PgR is markedly reduced by FXR gene silencing (siRNA), demonstrating the involvement of FXR in the estrogenic effects of farnesol. Finally, coimmunoprecipitation experiments (FXR immunoprecipitation followed by Western blot analysis of ER in the immunoprecipitate) produced definite evidence that FXR interacts with ER. Altogether, these observations reveal the hitherto unreported presence of FXR in breast cancer and show that the latter receptor functionally interacts with ER. The occurrence of such a crosstalk calls for some caution regarding the pharmacological use of FXR agonists.