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Gain-of-Function Mutant p53 R273H Interacts with Replicating DNA and PARP1 in Breast Cancer.
- Source :
-
Cancer research [Cancer Res] 2020 Feb 01; Vol. 80 (3), pp. 394-405. Date of Electronic Publication: 2019 Nov 27. - Publication Year :
- 2020
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Abstract
- Over 80% of triple-negative breast cancers (TNBC) express mutant p53 (mtp53) and some contain oncogenic gain-of-function (GOF) p53. We previously reported that GOF mtp53 R273H upregulates the chromatin association of mini chromosome maintenance (MCM) proteins MCM2-7 and PARP and named this the mtp53-PARP-MCM axis. In this study, we dissected the function and association between mtp53 and PARP using a number of different cell lines, patient-derived xenografts (PDX), tissue microarrays (TMA), and The Cancer Genome Atlas (TCGA) database. Endogenous mtp53 R273H and exogenously expressed R273H and R248W bound to nascent 5-ethynyl-2´-deoxyuridine-labeled replicating DNA. Increased mtp53 R273H enhanced the association of mtp53 and PARP on replicating DNA. Blocking poly-ADP-ribose gylcohydrolase also enhanced this association. Moreover, mtp53 R273H expression enhanced overall MCM2 levels, promoted cell proliferation, and improved the synergistic cytotoxicity of treatment with the alkylating agent temozolomide in combination with the PARP inhibitor (PARPi) talazoparib. Staining of p53 and PARP1 in breast cancer TMAs and comparison with the TCGA database indicated a higher double-positive signal in basal-like breast cancer than in luminal A or luminal B subtypes. Higher PARP1 protein levels and PAR proteins were detected in mtp53 R273H than in wild-type p53-expressing PDX samples. These results indicate that mtp53 R273H and PARP1 interact with replicating DNA and should be considered as dual biomarkers for identifying breast cancers that may respond to combination PARPi treatments. SIGNIFICANCE: p53 gain-of-function mutant 273H and PARP1 interact with replication forks and could serve as potential biomarkers for breast cancer sensitivity to PARP inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/394/F1.large.jpg.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Antineoplastic Agents, Alkylating
Cell Proliferation
DNA, Neoplasm genetics
Female
Humans
Minichromosome Maintenance Complex Component 2 genetics
Minichromosome Maintenance Complex Component 2 metabolism
Poly (ADP-Ribose) Polymerase-1 genetics
Temozolomide pharmacology
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms genetics
Triple Negative Breast Neoplasms metabolism
DNA Replication
DNA, Neoplasm metabolism
Gain of Function Mutation
Poly (ADP-Ribose) Polymerase-1 metabolism
Triple Negative Breast Neoplasms pathology
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 80
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31776133
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-19-1036