The Nuclear Receptor FXR Links Metabolism with Breast Cancer.
Authors: Kounalakis N. , Lau S. , Darling D. , Smith D. , Palomares M. , Lai L. 
Published: December 2010

Background:Abnormal metabolism, as measured by obesity, has been associated with an increase risk in both the development of breast cancer as well as breast cancer recurrence and death. To date, identification of a molecular link between obesity and breast cancer remains elusive. Farnesoid X receptor (FXR) is a ligand dependent transcriptional factor and plays a critical role in bile acid, cholesterol and carbohydrate metabolism. Little is known of the function of FXR in cancer although several recent studies have shown that FXR may contribute to breast, colorectal and hepatocellular cancer. Given the role of FXR in metabolism and emerging data suggesting a role for FXR in cancer, we hypothesize that expression of FXR in breast tissue may be related to metabolism. In addition, changes in FXR expression may also be associated with breast cancer development and progression.Methods:Clinical data on estrogen/progesterone receptor positive, Stage I and II breast cancer patients were extracted from an institutionally approved prospective database established in 2006. Paired formaldehyde fixed, paraffin embedded normal, in situ, and invasive tissues from these patients were identified from the COH tissue repository. Immunohistochemical staining of FXR using a validated polyclonal antibody was completed with appropriate positive and negative controls. The slides were graded independently by two investigators using an agreed upon scale to detect the percentage of positively stained cells to the nearest 10th percentile. Clinical data were correlated with expression analysis. Statistical analyses were performed with ANOVA tests followed by Fisher's t-tests for pair-wise comparisons. In determination of factors accounting for FXR expression, a multivariate analysis was completed. A p-value of 0.05 was considered significant in all analyses.Results:Paired normal tissue and invasive cancer was identified in all 43 patient specimens. In 40% (17/43) of these specimens, in situ disease was also identified. FXR expression in normal breast tissue was significantly less when compared to both invasive and noninvasive cancer (p≤ 0.001). The mean percentage of cells staining positive for FXR in normal breast tissue was 60%, non-invasive 77% and invasive 83% (p &lt; 0.0001). FXR expression did not correlate with grade, histology, nodal status, Her 2 neu status, HTN, DM or hyperlipidemia in normal, in situ and invasive tissue on multivariate analysis. BMI strongly correlated with FXR expression in normal tissues (p = 0.02) and may correlate in in situ tissues (p = 0.07). However, there was no correlation of BMI with FXR expression in invasive cancer (p = 0.55).Conclusions:FXR expression is upregulated in invasive cancer and increases progressively along the continuum from normal breast tissue to malignancy. Expression of FXR correlates with BMI in normal breast tissue, suggesting that FXR may be a molecular link between obesity and the development and progression of breast cancer. Our results warrant further investigation into the relationship of FXR, obesity and breast cancer. These findings may provide support for the development of targeted FXR agents in prevention and treatment of obesity related cancers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5153.