Farnesoid X receptor (FXR): A new marker for the prediction of bone metastases in breast cancer.
Journe F and Durbecq V
and Chaboteaux C and Rouas G and Haibe-Kains B
and IdBoufker H and Laurent G and Sotiriou C
and Larsimont D and Body J
FXR is a nuclear receptor for
bile acids which is normally expressed in liver tissue and the GI
tract. We recently detected FXR in breast cancer and reported a
significant correlation between FXR and estrogen receptor (ER)
expression. Moreover, we observed that FXR is associated with
proliferation markers in ER+ breast cancer, and that chenodeoxycholic
acid (CDCA) stimulates the proliferation of MCF-7 (ER+) cells through a
physical interaction between FXR and ER, resulting in ER activation. In
the current study, we first assessed the prognostic value of FXR
expression in breast cancer by retrospectively analyzing microarray
data in 2473 patients in relation with overall survival and distant
metastasis-free survival. FXR had a good prognostic value in ER+/node+
subgroup (p = 0.02; HR = 2.16; 95% CI [1.32–3.54]), discriminating high
versus low proliferative tumors, and was significantly associated with
late metastatic relapses (>1000 days) (p = 0.002; HR = 3.21; 95% CI
[1.55–6.65]), which generally occurred in the skeleton, in the
ER-/age<=50 subpopulation. In this context, we found that CDCA
increased the expression of metalloproteinase MMP-2 in MDA-MB-231 (ER-)
cells, indicating that bile acids/FXR might be involved in the
invasiveness of tumor cells. Lastly, we studied the expression of FXR
by immunohistochemistry (IHC score 0–8) in primary breast cancer in
relation with the sites of metastatic relapse. We evaluated FXR
expression in primary tumor tissue of patients who developed bone (n =
30) or visceral (lung or liver, n = 30) metastases. FXR was expressed
in 97% of breast cancer tissue samples (IHC mean score = 5) of patients
who developed bone metastases, while it was detected in only 50% of
primitive tumor samples (IHC mean score = 3) of patients who developed
visceral but no bone metastases. In conclusion, FXR expression in
primary breast tumors appears to be a prognostic factor for the
occurrence of bone metastases, especially in ER-negative tumors.