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Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

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Abstract

The farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is normally produced in the liver and the gastrointestinal tract, where it acts as a bile acid sensor. It has been recently detected in breast cancer cell lines and tissue specimens. The expression of FXR was scored (0–8) by immunohistochemistry on 204 breast cancer samples and correlated with established cancer biomarkers. Moreover, the effect of the FXR activator chenodeoxycholic acid (CDCA) was determined on cell proliferation and estrogen receptor regulation/activation in breast cancer cell lines. FXR was detected in 82.4% of samples with a high median expression score of 5. FXR expression significantly correlated with estrogen receptor (ER) expression (P = 0.009) and luminal-like markers. In ER-positive tumors, FXR expression was significantly correlated with the proliferation marker Ki-67 (P < 0.001) and the nodal status (P = 0.028), but only so in postmenopausal women, suggesting that lack of estrogens may disclose the association between FXR and cell proliferation. In vitro experiments confirmed clinical data since CDCA stimulated the proliferation of ER-positive cells only in steroid-free medium, a stimulation inhibited upon siRNA-silencing of FXR expression as well as ER blockade by antiestrogens. Moreover, co-immunoprecipitation experiments revealed that CDCA activated-FXR interacted with ER. These results suggest that ER-positive breast tumors could be stimulated to proliferate via a crosstalk between FXR and ER, particularly in a state of estrogen deprivation (menopause, aromatase inhibitors).

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Acknowledgements

This study received financial support from the “Fondation Medic”, from the “Fondation contre le Cancer”, from the Belgian Fund for Medical Scientific Research (grants no. 3.4512.03 and 3.4501.08), from the “Fondation Lambeau-Marteaux”, and from “Les Amis de l’Institut Bordet”. Virginie Durbecq, Christos Sotiriou and Guy Laurent are respectively Scientific Research Worker, Research Associate and Senior Research Associate of the National Fund for Scientific Research (Belgium).

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Authors and Affiliations

  1. Laboratory of Endocrinology & Translational Research Unit, Department of Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

    Fabrice Journe, Virginie Durbecq, Carole Chaboteaux, Ghizlane Rouas, Christos Sotiriou, Jean-Jacques Body & Denis Larsimont

  2. Laboratory of Endocrinology and Bone Diseases, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1 rue Héger-Bordet, 1000, Brussels, Belgium

    Fabrice Journe

  3. Laboratory of Histology, Faculty of Medicine and Pharmacy, Université de Mons-Hainaut (UMH), Mons, Belgium

    Guy Laurent & Denis Nonclercq

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  1. Fabrice Journe
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Correspondence to Fabrice Journe.

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Fabrice Journe and Virginie Durbecq had contributed equally to this work and should be considered as joint first authors.

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Journe, F., Durbecq, V., Chaboteaux, C. et al. Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients. Breast Cancer Res Treat 115, 523–535 (2009). https://doi.org/10.1007/s10549-008-0094-2

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  • DOI: https://doi.org/10.1007/s10549-008-0094-2

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