The Role of Mutant p53 Protein in Breast Cancer

1998 ◽  
Author(s):  
Carol L. Prives
Keyword(s):  
Breast Cancer ◽  
P53 Protein ◽  
Mutant P53

Mutant p53 protein associated with chemosensitivity in breast cancer specimens

The Lancet ◽  
1994 ◽  
Vol 344 (8937) ◽  
pp. 1647-1648 ◽  
Author(s):  
OssiR. Koechli ◽  
GabrielN. Schaer ◽  
Burkhart Seifert ◽  
René Hornung ◽  
Urs Haller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
P53 Protein ◽  
Mutant P53

Targeting mutant p53 with PK11007: A new approach for the treatment of patients with triple-negative breast cancer?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14099-e14099 ◽  
Author(s):  
Naoise C Synnott ◽  
Matthias R Bauer ◽  
Stephen F. Madden ◽  
Alyson M. Murray ◽  
Rut Klinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
P53 Protein ◽  
Mutant P53 ◽  
Inhibition Of Proliferation ◽  
Tnbc Cell ◽  
Induced Apoptosis

e14099 Background:The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. Since the p53 gene is mutated in approximately 80% of TNBC patients, it is a potential therapeutic target for this form of breast cancer. PK11007 is a 2-sulfonypyrimidine that stabilizes and reactivates mutant p53 (Bauer et al, PNAS 2016). The compound recently was reported to preferentially decrease viability in p53-compromised cancer cells. The aim of this investigation was to evaluate PK11007 as a potential new treatment for TNBC. Methods: Cell viability was determined using the MTT assay. Apoptosis was detected using Annexin V Apoptosis Detection Kit. Migration was determined by Transwell migration assay. Knockdowns of p53 protein were carried out using predesigned Flexitube sequences (Qiagen). Results: IC50 values for inhibition of proliferation by PK11007 in the panel of 17 breast cell lines ranged from 2.3 to 42.2 μM. There were significantly lower IC50values for TNBC than for non-TNBC cell lines (p = 0.03) and for p53-mutated cell lines compared with p53 WT cells (p = 0.003). Response to PK11007 however, was independent of ER or HER2 status of the cells. In addition, PK11007 induced apoptosis and inhibited migration in p53 mutant cell lines. Using RNAseq and gene ontogeny analysis, we found that PK11007 altered the expression of genes enriched in pathways involved in regulated cell death, regulation of apoptosis, signal transduction, protein refolding and locomotion. To establish if PK11007 acts by targeting mutant p53, we used siRNA to knockdown p53 in 3 p53-mutated TNBC cell lines. Reduction in p53 protein levels resulted in a significant decrease in the growth inhibitory effects of PK11007, in all 3 cell lines investigated, suggesting that PK11007 mediates growth inhibition via p53. The observations that PK11007 inhibited cell growth, induced apoptosis, blocked cell migration and altered genes involved in cell death, are all consistent with the ability of PK11007 to activate mutant p53. Conclusions: Based on our data, we conclude that targeting mutant p53 with PK11007 is a potential approach for treating p53-mutated TNBC.

scholarly journals Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells

2015 ◽  
Vol 150 (3) ◽  
pp. 487-499 ◽  
Author(s):  
Samaya R. Krishnan ◽  
Binoj C. Nair ◽  
Gangadhara R. Sareddy ◽  
Sudipa Saha Roy ◽  
Mohan Natarajan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Chemotherapy Response ◽  
Mutant P53

Abstract 1392: Role of mutant p53 for anti-TGF-β therapy in isogenic basal-like breast cancer models.

2013 ◽  
Author(s):  
Fernando P. Lugo ◽  
Shu Lin ◽  
Abhik Bandyopadhyay ◽  
Junhua Yang ◽  
Lu-Zhe Sun
Keyword(s):  
Breast Cancer ◽  
Mutant P53 ◽  
Cancer Models ◽  
Basal Like Breast Cancer

scholarly journals Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53

2003 ◽  
Vol 23 (1) ◽  
pp. 322-334 ◽  
Author(s):  
Yoichi Ohiro ◽  
Anny Usheva ◽  
Shinichiro Kobayashi ◽  
Shannon L. Duffy ◽  
Regan Nantz ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Protein ◽  
Gene Mutations ◽  
P53 Gene ◽  
Mutant P53 ◽  
Inhibition Of Proliferation ◽  
Dependent Inhibition ◽  
Tumor Types ◽  
Precise Role

ABSTRACT More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH2-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

Sign in / Sign up

Export Citation Format

Share Document