Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients.
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).
Journe
Fabrice
F
Laboratory of Endocrinology & Translational Research Unit, Department of Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. fabrice.journe@bordet.be
Durbecq
Virginie
V
Chaboteaux
Carole
C
Rouas
Ghizlane
G
Laurent
Guy
G
Nonclercq
Denis
D
Sotiriou
Christos
C
Body
Jean-Jacques
JJ
Larsimont
Denis
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D017698:Postmenopause; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D005765:Gastrointestinal Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C506487:ESR1 protein, human