The Tumorigenicity Potential of LRH1 in Pancreatic Cancer (2012 – Present)

Investigator:  Xiaoqun Dong, University of Rhode Island
Mentor:  Jack Wands, Brown University

Abstract:  Pancreatic Cancer (PC) ranks as the 4th-leading cause of cancer deaths in the United States, with a mortality approaching its incidence.  Pancreatic cancer has the lowest 5-year survival rate (<5%) in all malignancies due to its aggressive progression and refractoriness to therapy.  Novel therapies targeting these pathways are potential candidates for more effective therapeutic strategies.  Notably, liver receptor homolog 1 (LRH1) is a major driver of pancreas development and differentiation.  LRH1 also regulates bile acid/cholesterol metabolism and maintains glucose homeostasis.  Accumulating evidence supports a critical role for involvement of LRH1 in the tumorigenesis of various cancers including breast, gastric and intestinal tumors.  Previous studies reported that individuals carrying LRH1 genetic variants are at increased risk for PC.  Interestingly, overexpression of LRH1 has also been shown to promote PC cell proliferation.  In the preliminary study, we observed LRH1 overexpression in the nucleus correlated with reduced overall survival and a more aggressive tumor type in PC patients, suggesting that LRH1 may be involved in PC development.  We will generate several stable pancreatic cell lines expressing LRH1 to test whether LRH1 overexpression promotes tumor cell invasion, migration, and tumor formation using an animal model.  In the intestine LRH1 overexpression spurs cell proliferation and self-renewal by activating the β-catenin-Tcf4-cyclin D1/E1 pathway.  Structural analysis indicated that PIP3 [Phosphatidylinositol (3,4,5)-triphosphate], a substrate of PI3K, is a potential ligand of LRH1.  PI3K regulates cell proliferation, differentiation, motility, survival and intracellular trafficking.  The hypothesis to be tested is whether LRH1 contributes to PC by activating the β-catenin-Tcf4-cyclin D1/E1 pathway.  We will determine whether 1) LRH1 is activated by PIP3 binding; 2) LRH1 overexpression causes tumor formation in the animal model; 3) LRH1 overexpression activates β-catenin signaling in PC; 4) the process depends on β-catenin (e.g., using β-catenin inhibitors in PC cells and measuring β-catenin signaling levels in response to LRH1 stimulation); and 5) LRH1 knockdown/inhibitor can reverse PC tumorigenesis in vitro and in the animal model.