The main goals of this research are to learn more about the biology of two biomarkers, newly-identified to have prognostic utility when considered together, and how to apply this knowledge for clinical benefit. Specifically, mRNA co-expression of the protein methyltransferase PRMT5 and a newly-discovered target of this enzyme, PDCD4, corresponds to poor prognosis in breast cancer. In an orthotopic xenograft model, cancer cells engineered to express elevated levels of these two proteins displayed significantly accelerated tumor growth. A recently developed antibody that specifically recognizes the methylated form of PDCD4 now provides the opportunity to directly detect activity of this novel pathway in cancer cells, presenting the possibility of a unique bioactive prognostic marker. Further, the reported activity of PDCD4 as a tumor suppressor suggests a novel hypothesis for the contribution of this pathway to tumor progression. The specific prediction is that PDCD4 function can keep aspects of tumorigenesis in check, but when PRMT5 levels become elevated as well, PDCD4 tumor suppressive function is abrogated by methylation and the two proteins cooperate to accelerate tumor growth. Here, clinical samples will be used to test and improve the prognostic power of these biomarkers, as well as to determine how their expression corresponds to tumor progression. The goals of the research proposed are to use tumor microarrays to rigorously assess both PDCD4 and PRMT5 protein levels and the direct detection of methylated PDCD4 as prognostic markers. Clinical samples will also be used to test the model that acquisition of PRMT5 in the presence of PDCD4 corresponds to tumor progression. Concurrently, these biomarkers will be investigated experimentally to elucidate their role in tumorigenesis. This complementary goal will involve identifying 1) protein partners that interact preferentially with methylated PDCD4 and 2) the gene expression changes that lie downstream of PDCD4-PRMT5 co-expression. This experimental analysis will give new and unbiased insight into how the PDCD4-PRMT5 pathway contributes to aggressive tumor growth. Together, the results of these studies will set the stage for the development of a new prognostic cancer biomarker that may be paired rationally with a particular treatment strategy.

Public Health Relevance

A recently discovered pathway that contributes to aggressive tumor growth will be used to develop new biomarkers that hold the potential to be strategic tools for classifying cancer, understanding its stage of progression, and determining how aggressive treatment should be. This research also aims to understand the biology of this pathway in order to tailor treatment to this biomarker signature.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RPRB-O (M1))
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Lively, Tracy (LUGO)
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Fay, Marta M; Clegg, James M; Uchida, Kimberly A et al. (2014) Enhanced arginine methylation of programmed cell death 4 protein during nutrient deprivation promotes tumor cell viability. J Biol Chem 289:17541-52