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 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<0.05). A similar result was observed in tumors expressing wild-type TP53, NTRK1-pY674/pY675, and low or undetectable levels of PTPN6. Given that estrogen receptor-positive breast cancers encode wild-type TP53, we analyzed this expression pattern in these tumors. Multivariate analysis showed that it was significantly and independently predictive of prolonged survival by 66%, 70%, and 84%, respectively, (P<0.05). The Kaplan-Meir method demonstrated that NTRK1-pY674/pY675 together with undetectable or low levels of PTPN6 correlated with 59% probability of disease-free survival (median survival 15 years), compared with 7% probability of disease-free survival (median survival 4.5 years) when absent. In luminal A tumors, the presence of this pattern was estimated to have a 61% probability of disease-free survival (median survival 15 years), compared with 6% probability of disease-free survival (median survival 3 years) when it was absent. These results strongly suggest that expression of NTRK1-pY674/pY675 together with wild-type TP53 and low levels of PTPN6 expression are predictors of improved disease-free survival and that they could be useful biomarkers to predict clinical outcome.
1] Immunobiology Unit, UCL, Institute of Child Health, London, UK [2] Molecular Hematology and Cancer Biology Unit, UCL, Institute of Child Health, London, UK.
Gehad
G
Youssef
Breast Tissue & Data Bank, Division of Cancer Studies, King's College London, Guys Hospital, London, UK.
Cheryl
C
Gillett
Cancer Epidemiology Group, Division of Cancer Studies, King's College London, Guys Hospital, London, UK.
Orunsola
O
Agbaje
Immunobiology Unit, UCL, Institute of Child Health, London, UK.
Tessa
T
Crompton
1] Immunobiology Unit, UCL, Institute of Child Health, London, UK [2] Molecular Hematology and Cancer Biology Unit, UCL, Institute of Child Health, London, UK [3] School of Health and Social Work, Department of Allied Health Professions and Midwifery University of Hertfordshire, Hatfield, UK.
Ximena
X
Montano
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020917:Receptor, trkA; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6