Prostate Cancer Risk: Role of Genetic Variation in the microRNA Stress Response to Arsenic Exposure

Project Co-Leaders

NAU

Jason A. Wilder, Ph.D. Assoc. Professor, Dept. of Biological Sciences , College of Engineering, Forestry & Natural Sciences

UACC

Ronald L. Heimark, Ph.D. Professor, Dept. of Surgery, Vice Chair Surgical Research, College of Medicine

Abstract

Prostate cancer is highly heterogeneous varying from latent localized disease to aggressive disease associated with a high risk of mortality. Studies have indicated that this cancer is highly heritable, suggesting a strong genetic component to risk. Prostate cancer mortality in Native Americans is similar to Hispanic and European Americans even though the incidence in Native American men is significantly lower. For Navajo and Northern Plains Indian men, prostate cancer mortality exceeds the US rate and at diagnosis was found occurs at a higher grade and stage than in European Americans. While there are some well-documented social and economic causes for this elevated cancer mortality in Native Americans, there are also differences in tumor biology and/or genetic aspects between groups that could contribute to more aggressive disease and poor outcomes. We are investigating genetic variation in non-coding regions of tumor suppressor genes and their pseudogenes that alter microRNA (miRNA) target sites. miRNAs are critical regulators of cellular functions and we are investigating a novel class of functional genetic variation (miRNA-response element genetic variation – MRE-SNPs)in the PTEN/PTENP1 RNA network for new determinants of cancer recurrence and survival. Based on our preliminary data that identifies unique Native American variation, we test the hypothesis that MRE-SNPs in PTEN/PTENP1 3’UTRs perturb competing endogenous RNA networks and function as modifiers of aggressive feature of prostate cancer. In Aim 1, we will identify miRNAs that target functional MRE-SNPs in PTEN and PTENP1 and determine miRNA expression in prostate cancer. In Aim 2, we will evaluate the function of miRNAs whose targeting is affected by MRE-SNPs in relevant signaling pathways in prostate cancer progression. Studies in Aim 3 will discover uniquely Native American SNPs affecting tumor suppressor gene function and to test for an association of these SNPs with prostate cancer in a Hispanic population characterized by a high degree of Native American admixture. The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new biomarkers that identify aggressive features of the disease.

Specific Aims

1. To identify miRNAs that target functional single nucleotide polymorphisms in PTEN and PTENP1 miRNA response elements and determine miRNA expression in prostate cancer.
2. To evaluate the function of candidate allelic variant targeting miRNAs in relevant signaling pathways in prostate cancer progression.
3. To discover uniquely Native American single nucleotide polymorphisms affecting tumor suppressor gene function and to test for an association of these SNPs with prostate cancer.