Dynamic role of the codon 72 p53 single-nucleotide polymorphism in mammary tumorigenesis in a humanized mouse model.

Autor: Gunaratna RT; Interdisciplinary Program in Genetics, Texas A&M University, College Station, TX, USA.; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA.; Department of Molecular Biology, Princeton University, Princeton, NJ, USA., Santos A; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA.; Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, USA., Luo L; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA., Nagi C; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA., Lambertz I; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA., Spier M; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA., Conti CJ; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA.; Departamento de Bioingeniería, Universidad Carlos III de Madrid, Madrid, Spain.; Fundación Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), Madrid, Spain., Fuchs-Young RS; Interdisciplinary Program in Genetics, Texas A&M University, College Station, TX, USA. fuchs-young@medicine.tamhsc.edu.; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA. fuchs-young@medicine.tamhsc.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2019 May; Vol. 38 (18), pp. 3535-3550. Date of Electronic Publication: 2019 Jan 16.
DOI: 10.1038/s41388-018-0630-4
Abstrakt: Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV-Erbb2/Neu) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the p53 R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.
Databáze: MEDLINE
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