Translational Significance of p53 Loss of Heterozygosity in Breast Cancer
Abstract
Mutations in the p53 tumor suppressor gene are the most prevalent genetic events in human Her2-positive breast cancer and are associated with poor prognosis. Frequently in early stages of cancer, a p53 mutation in one allele is followed by loss of heterozygosity (LOH) in the second allele, during tumor progression. Despite a strong notion that p53 mutations with subsequent LOH are driving events in breast cancer, the translational significance of p53 mutational and LOH status, and their role in breast cancer development and progression have not been evaluated. Previously we found that the irradiation of pre-malignant lesions of p53 heterozygous mice (R172H p53 mutant or null) aggravates tumorigenesis in an MMTV/ErbB2 mouse breast cancer model. This study aims to test whether spontaneous or genotoxic stress-induced LOH promotes progression in mutp53 heterozygous tumors and whether different hot-spot p53 mutations are equal in this respect. The major innovative findings for reporting period: we generated and analyzed novel R248Q/+;ErbB2 mouse model. We found that in initially heterozygous mouse tumors carrying the R248Q (p53Q/+) allele, the loss of the remaining wild-type p53 allele is necessary prerequisite for mutant p53 stabilization and gain-of-function (GOF) in vivo. In mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (94%) and tumor onset is significantly accelerated compared with p53+/ tumors. In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (80%) and GOF is not observed. Thus, p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2017
- Accession Number
- AD1050431
Entities
People
- Natalia Marchenko
Organizations
- Research Foundation for the State University of New York