Type

Journal Article

Authors

M J Duffy
J Crown
W M Gallagher
D P O'Connor
N O'Donovan
P A Kiely
M Kiely
P M McGowan
A Murray
N C Synnott

Subjects

Biochemistry

Topics
mutant triple negative breast cancer anti cancer cell proliferation novel the cancer treatment breast cancer patients cancer cell lines

Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer? (2016)

Abstract The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1(MET) (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1(MET) was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1(MET) than p53 WT cells (p = 0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p = 0.0089, r=-0.57, n = 19). In addition to inhibiting cell proliferation, PRIMA-1(MET) induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1(MET) is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

M J Duffy, J Crown, W M Gallagher, D P O'Connor, N O'Donovan, P A Kiely, M Kiely, P M McGowan, A Murray, N C Synnott

Experts in our system

1
Michael J Duffy
University College Dublin
 
2
John Crown
Dublin City University
Total Publications: 104
 
3
William M Gallagher
University College Dublin
Total Publications: 148
 
4
Darran P O'Connor
Royal College of Surgeons in Ireland
Total Publications: 43
 
5
Norma O'Donovan
Dublin City University
Total Publications: 59
 
6
Patricia M McGowan
Dublin City University
Total Publications: 8
 
7
Alyson Murray
Dublin City University
Total Publications: 6
 
8
Naoise C Synnott
Dublin City University