p53 Variants in Cancer Risk and Therapy

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 DESCRIPTION (provided by applicant): The p53 tumor suppressor gene is one of the most important genes in human cancer. Unlike the overwhelming majority of oncogenes and tumor suppressor genes, the TP53 gene is distinguished by the existence of single nucleotide polymorphisms in the coding region that alter p53 function. Several years ago we reported that a polymorphism at amino acid 47 (Pro47Ser, rs1800371) of TP53 occurs in 1:40 African Americans and up to 1:10 of Africans; this polymorphism markedly impairs the phosphorylation of p53 on a critical residue, serine 46, and also significantly impairs the apoptotic ability of p5. In order to assess the impact of this polymorphism on cancer risk and therapy, we created a mouse model for the S47 variant, compared to wild type p53. We also analyzed human lymphoblastoid cell lines that are homozygous for the S47 variant, compared to WT p53. We show in both our mice and in human cells that the S47 variant has markedly decreased ability to induce apoptosis in response to stress, along with decreased ability to transactivate a subset of p53 target genes (Noxa, GLS2 and Sco2), accompanied by a failure to be phosphorylated on serine 46. We show that cells with S47 have dramatic resistance to many chemotherapeutic agents, yet increased sensitivity to others. Surprisingly, we find that S47 mice are cancer- prone, and further that S47 male mice develop spontaneous prostate hyperplasia. In preliminary human studies we show data indicating that the S47 allele may be a significant risk factor for prostate cancer in African American men. The broad, long term objective of this proposal is to test the hypothesis that the impaired function of S47 leads to reduced ability to suppress prostate cancer initiation and progression. We also seek to test the hypothesis that chemotherapy in S47 individuals can be personalized. There are two aims. In Aim 1, our mouse models for WT and S47 will be used to test the function of S47 in the initiation, progression, and chemotherapy of prostate cancer. In Aim 2, we will analyze human prostate cancer samples from African American men, and test the hypothesis that the S47 variant is associated with increased prostate cancer risk and/or aggressiveness. Importantly, information from each aim will be used to inform the other. For these goals, we have combined the expertise of four laboratories, three of which are located on the same campus (Murphy, Altieri and Rebbeck), and two of which have long-standing expertise in the epidemiology of human prostate cancer (Rebbeck and Isaacs). Each group has unique and complementary expertise in mouse models of cancer, p53 function, and epidemiology of prostate cancer in men of African descent. The proposed research marks the first time that the impact of this deleterious polymorphism on cancer risk and therapy in individuals of African descent will be assessed.