Dynamic Role of the Codon 72 P53 Single Nucleotide Polymorphism in Mammary Tumorigenesis in a Humanized Mouse Model
Abstract
Female breast cancer (BrCa) is the most common noncutaneous cancer among
women in the United States. Human epidemiological studies reveal that p53 codon 72 single
nucleotide variants, encoding proline (P72) or arginine (R72), are associated with increased
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. R72 mice had a significantly higher mammary
tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse
mammary tumor models. Our studies revealed that susceptible mammary glands of E-R72
mice developed a senescence-associated secretory phenotype (SASP), with influx of
proinflammatory macrophages, ultimately resulting in chronic, pro-tumorigenic
inflammation. Mammary tumors arising in E-R72 mice also had increased proliferation and
influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor
growth rates. These results demonstrate that the R72 variant increases susceptibility to
aggressive BrCas through chronic inflammation, suggesting potential benefits of antiinflammatory
agents in the prevention or treatment of BrCa in women who are homozygous
for the R72 variant.
Citation
Gunaratna, Ramesh Tharindu (2018). Dynamic Role of the Codon 72 P53 Single Nucleotide Polymorphism in Mammary Tumorigenesis in a Humanized Mouse Model. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /173408.