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 presence of single nucleotide polymorphisms in the coding region, some of which 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. We showed that this polymorphism markedly impairs the phosphorylation of p53 on a critical residue, serine 46, and also significantly impairs the apoptotic ability of p53. In order to assess the impact of this polymorphism on cancer risk and therapy, we created a mouse model for the S47 variant, and compared it to wild type human p53. We also analyzed human lymphoblast cell lines that are homozygous for the S47 variant, compared to WT p53. We find in both mouse and human cells that the S47 variant has markedly decreased ability to induce apoptosis in response to genotoxic agents, particularly cisplatin. S47 also has decreased ability to transactivate a small subset of p53 target genes involved in apoptosis and metabolism (NOXA, GLS2 and SCO2). We show that cells with S47 have dramatic resistance to some chemotherapeutic agents, yet intriguingly, show increased sensitivity to at least one other agent. We show that S47 mice are susceptible to a wide variety of spontaneous cancers. Finally, we show that the S47 allele is a significant risk factor for breas cancer in pre-menopausal African American women (OR 1.84, p=0.03). The broad, long term objective of this proposal is to better define the mechanisms for impaired tumor suppression by S47. An added goal is to identify the impact of S47 on the response to therapy in a mouse model of breast cancer. There are three aims.
In Aim 1, we will test the ability of S47 to suppress cancer when it exists as a single allele in mice (S47/ - and S47/WT).
In Aim 2 we will assess the impact of the S47 allele on breast cancer incidence and p53 function in our novel animal model. We will also assess the efficacy of chemotherapeutic agents commonly used for breast cancer.
In Aim 3 we will focus on p53 target genes with impaired transactivation by S47, and test their contribution tumor suppression. We will also elucidate the mechanism for impaired transcription by S47, with focus on iASPP, a protein with increased ability to interact with S47. We believe these studies will probe deeply the mechanism for impaired tumor suppression, and the consequences of S47 on cancer risk and efficacy of therapy. For these studies we include experts in p53 and gene expression (Murphy), mouse models of breast cancer (Huang), metabolism (Raychaudhuri), and biostatistics (Liu). The proposed research marks the first time that the impact of this deleterious polymorphism on breast cancer risk and therapy will be assessed.

Public Health Relevance

Africa is the homeland of all modern human populations within the last 200,000 years. Despite the important role that African populations have played in human history, they remain one of the most understudied groups in human genomics and cancer. Preliminary data from our group indicate that a deleterious variant in a critical tumor suppressor gene in human cancer, p53, exists in individuals of African descent. We will test the impact of this variant on p53 function, and on cancer risk and therapy using novel mouse models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA102184-10A1
Application #
9035881
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
2003-07-01
Project End
2020-11-30
Budget Start
2015-12-11
Budget End
2016-11-30
Support Year
10
Fiscal Year
2016
Total Cost
$384,750
Indirect Cost
$182,250
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kung, Che-Pei; Liu, Qin; Murphy, Maureen E (2017) The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation. Cancer Biol Ther 18:484-491
Murphy, Maureen E; Liu, Song; Yao, Song et al. (2017) A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer 3:5
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285
Murphy, Maureen E (2016) Ironing out how p53 regulates ferroptosis. Proc Natl Acad Sci U S A 113:12350-12352
Kung, Che-Pei; Basu, Subhasree; Murphy, Maureen E (2016) A link between TP53 polymorphisms and metabolism. Mol Cell Oncol 3:e1173769
Kung, Che-Pei; Leu, Julia I-Ju; Basu, Subhasree et al. (2016) The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction. Cell Rep 14:2413-25
Basu, Subhasree; Murphy, Maureen E (2016) p53 family members regulate cancer stem cells. Cell Cycle 15:1403-4
Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree et al. (2016) An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 30:918-30
Tutton, Stephen; Azzam, Greggory A; Stong, Nicholas et al. (2016) Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres. EMBO J 35:193-207
Basu, Subhasree; Murphy, Maureen E (2016) Genetic Modifiers of the p53 Pathway. Cold Spring Harb Perspect Med 6:a026302

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