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.