Prostate cancer (PCA) incidence and mortality rates vary widely among races in the United States. Among all men, PCA is the most commonly diagnosed form of cancer, but Native American men suffer a nearly two-fold higher rate of PCA mortality than whites following diagnosis. The extent of this disparity is not mirrored by other common cancer types, suggesting a unique burden of PCA-associated mortality in Native American men. Among the Navajo, PCA is more often diagnosed at a stage when the cancer has extended beyond the margins of the prostate (17.9% of PCA diagnoses among the Navajo, 3.3% among non-Hispanic Whites in New Mexico).These data underscore the need to understand the molecular mechanisms underlying clinically aggressive prostate cancer in all men, and Native Americans in particular. Among all races, PCA is highly heterogeneous and can vary from latent localized disease that does not require active treatment to aggressive disease associated with a high risk of mortality. Our goal is to better understand the genetic and molecular correlates of aggressive PCA. Our experimental approach will allow us to characterize genetic risk factors of particular importance to Native American populations. Previous studies have identified numerous somatic and germline genetic variants that increase risk for aggressive PCA. Of particular importance are mutations that affect the dosage of the tumor suppressor gene PTEN. Deletion of one PTEN allele occurs in 20-40% of localized PCA cancers and ~60% of metastases. Recent evidence also shows that PTEN protein loss occurs in 45% of primary tumors in the absence of deletion mutations, suggesting alternative mechanisms by which PTEN silencing is affected. Our proposed study will focus on the role of microRNA-mediated (miRNA) regulation of PTEN, which is a critical regulatory mechanism for this tumor suppressor gene. Specifically, we will identify and analyze variants in miRNA response elements of PTEN and its expressed pseudogene, PTENP1. These two genes engage in regulatory crosstalk mediated by competition for miRNAs, such that allelic variations in PTENP1 can affect indirectly the expression of PTEN. This research extends the findings of our Pilot Project which found PTEN to be affected by allelic variation in miRNA interaction networks, and identified specific genetic variants in the miRNA response elements of PTEN that are unique to Native Americans. We propose a general model whereby germline genetic variants in the miRNA response elements of PTEN/PTENP1 3'UTR perturb competing endogenous RNA networks and function as modifiers of aggressive features of PCA. To test this hypothesis, and to identify variants with potential for effects in Native Americans, we propose the following specific aims:
Specific Aim 1. To identify miRNAs that target functional single nucleotide polymorphisms in PTEN and PTENPI miRNA response elements and determine miRNA expression in prostate cancer. We hypothesize that a variant alleles affecting miRNA-targeting of the PTEN/PTENP1 gene/pseudogene pair will be associated with recurrent prostate cancer Specific Aim 2.To evaluate the function of candidate allelic variant targeting miRNAs in relevant signaling pathways in prostate cancer progression. We hypothesize that there are polymorphisms in PTENP1 that will alter the PTEN network of miRNA: mRNA Interactions. Thus, alteration of candidate miRNAs in key pathways will be correlated with mechanisms of carcinoma differentiation that underlie aggressive PCA.
Specific Aim 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. We hypothesize that there Is abundant genetic variation in Native American and Native American-admixed populations (i.e. Hispanics) that is not shared with other world populations, and that variation may be associated with prostate cancer risk. We examine here 3'UTR variants that may affect regulatory crosstalk between gene/pseudogene pairings and play a role in cancer susceptibility and progression.
|Gilbert, Jack A; Blaser, Martin J; Caporaso, J Gregory et al. (2018) Current understanding of the human microbiome. Nat Med 24:392-400|
|Bokulich, Nicholas A; Dillon, Matthew R; Zhang, Yilong et al. (2018) q2-longitudinal: Longitudinal and Paired-Sample Analyses of Microbiome Data. mSystems 3:|
|Varadaraj, Archana; Magdaleno, Carina; Mythreye, Karthikeyan (2018) Deoxycholate Fractionation of Fibronectin (FN) and Biotinylation Assay to Measure Recycled FN Fibrils in Epithelial Cells. Bio Protoc 8:|
|Bea, Jennifer W; de Heer, Hendrik Dirk; Valdez, Luis et al. (2018) Physical Activity among Navajo Cancer Survivors: A Qualitative Study. Am Indian Alsk Native Ment Health Res 25:54-73|
|Bokulich, Nicholas A; Kaehler, Benjamin D; Rideout, Jai Ram et al. (2018) Optimizing taxonomic classification of marker-gene amplicon sequences with QIIME 2's q2-feature-classifier plugin. Microbiome 6:90|
|Huenneke, Laura F; Stearns, Diane M; Martinez, Jesse D et al. (2017) Key Strategies for Building Research Capacity of University Faculty Members. Innov High Educ 42:421-435|
|Jim, Venessa; LaViolette, Corinne; Briehl, Margaret M et al. (2017) Spatial distribution of uranium in mice kidneys detected by laser ablation inductively coupled plasma mass spectrometry. J Appl Bioanal 3:43-48|
|Schwartz, Anna L; de Heer, Hendrik Dirk; Bea, Jennifer W (2017) Initiating Exercise Interventions to Promote Wellness in Cancer Patients and Survivors. Oncology (Williston Park) 31:711-7|
|Bokulich, Nicholas A; Rideout, Jai Ram; Mercurio, William G et al. (2016) mockrobiota: a Public Resource for Microbiome Bioinformatics Benchmarking. mSystems 1:|
|Corlin, Laura; Rock, Tommy; Cordova, Jamie et al. (2016) Health Effects and Environmental Justice Concerns of Exposure to Uranium in Drinking Water. Curr Environ Health Rep 3:434-442|
Showing the most recent 10 out of 20 publications