Abstract 4672: Overexpression of NR5A2/LRH1 in pancreatic cancer and possible association with clinical outcome

Abstract

Abstract Pancreatic cancer is the 4th leading cause of cancer deaths in the United States and it has the lowest 5-year survival rate in all tumors. Genome-wide association study (GWAS) has identified a significant association between NR5A2/LRH1 gene variants and risk for pancreatic cancer. LRH1, a direct target of PDX1, governs liver and pancreas differentiation in early embryonic development and controls cholesterol/bile-acid homeostasis and steroidogenesis in adulthood. LRH1 promotes cell proliferation by interacting with β-catenin/Tcf4 signaling and upregulating estrogen metabolic genes. We hypothesize that LRH1 acts as an oncogene in pancreatic cancer. We measured LRH1 protein expression by immunohistochemistry (IHC) in 129 resected pancreatic tumors and LRH1 mRNA expression by RT-PCR in 15 frozen paired tumor and adjacent normal tissues. We examined the differences in expression levels between tumor and normal tissues using paired t-test. We evaluated the correlation of protein or mRNA expression levels with overall survival (OS) or tumor characteristics by Cox regression or χ2 test, respectively. IHC showed both nuclear and cytoplasm staining for LRH1. Tumors had a higher level of LRH1 expression than normal tissue did (Mean ± SD of staining score: 5.46 ± 1.64 vs. 3.73 ± 1.77, respectively, p<0.001). Patients with a higher level of nuclear LRH1 expression had worse survival (HR = 2.41, 95% CI=0.97-6.00, p=0.059) but patients with a higher level of cytoplasmic LRH1 expression had better survival (HR = 0.36, 95% CI = 0.09-1.46, p=0.15). Eight out of 8 tumors (100%) with lower nuclear LRH1 expression (staining score <3) were well or moderately differentiated, while 44 out of 121 (36.4%) of tumors with higher nuclear LRH1 expression (staining score ≥ 3) were poorly differentiated (p=0.03). The LRH1 mRNA expression level was 8-fold higher in tumors than in normal tissues (p<0.001). The observed association between LRH1 overexpression and worse clinical outcome and more aggressive tumor type supports the hypothesis that LRH1 acts as an oncogene in pancreatic cancer. Whether LRH1 can be a putative therapeutic target for the treatment of pancreatic cancer needs further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4672. doi:10.1158/1538-7445.AM2011-4672