Phosphorylation of NTRK1 at Y674/Y675 induced by TP53-dependent repression of PTPN6 expression: A potential novel prognostic marker for breast cancer

We have identified a ligand-independent mechanism whereby the tumor suppressor, TP53, induces nerve growth factor receptor, NTRK1, phosphorylation at Y674/Y675 (NTRK1-pY674/pY675), via the repression of the NTRK1-phosphatase, PTPN6. This results in suppression of breast cancer cell proliferation. In...

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Bibliographic Details
Published in:Modern pathology 2014-03, Vol.27 (3), p.361-374
Main Authors: Youssef, Gehad, Gillett, Cheryl, Agbaje, Orunsola, Crompton, Tessa, Montano, Ximena
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Apoptosis
Biomarkers
Biomarkers, Tumor - analysis
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - mortality
Cell cycle
Cell division
Cell growth
Childrens health
Disease-Free Survival
Estrogens
Female
Gene Expression Regulation, Neoplastic - physiology
Growth factors
Hematology
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Kinases
Localization
Medical prognosis
Middle Aged
Mortality
Multivariate analysis
NTRK1
Phosphatase
Phosphorylation
Prognosis
Protein expression
Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism
Proteins
PTPN6
Receptor, trkA - metabolism
Signal transduction
TP53
Transcription factors
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary:We have identified a ligand-independent mechanism whereby the tumor suppressor, TP53, induces nerve growth factor receptor, NTRK1, phosphorylation at Y674/Y675 (NTRK1-pY674/pY675), via the repression of the NTRK1-phosphatase, PTPN6. This results in suppression of breast cancer cell proliferation. In this investigation, we aimed to establish whether perturbation of the wild-type TP53-NTRK1-pY674/pY675-PTPN6 pathway has an impact on disease-free survival of breast cancer patients without neo-adjuvant treatment. A total of 308 tumor samples were stained for NTRK1, NTRK1-pY674/pY675, PTPN6, and TP53 expression. Association between expression levels and disease-free survival was determined by the univariate/multivariate and Kaplan–Meir methods of analysis. DNA from tumors was sequenced to identify mutant or wild-type TP53. Tumors expressing NTRK1-pY674/pY675 but with undetectable or low levels of PTPN6 and TP53 were associated with prolonged 5, 10, and 15 years' disease-free survival by 48%, 36%, and 37%, respectively, in the multivariate analysis (P
ISSN:0893-3952
1530-0285
DOI:10.1038/modpathol.2013.129