Abstract

The orphan nuclear receptor Liver Receptor Homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of ER positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid DLPC activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic non-phospholipid small molecule repressor of LRH-1, SR1848. In co-transfection studies SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1, dose-dependently reduced the expression of CyclinD1 and E1 resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated following transfection of cells with siRNAs targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 impacting expression of genes involved in proliferation in LRH-1-expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.