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

Abstract

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 (Po0.05). 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, (Po0.05). 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. Breast cancer is a leading cause of early mortality among women. 1 The incidence varies worldwide, with developed countries having higher rates than developing countries. 1,2 Although the rate of breast cancer has continued to increase, 3 mortality rates have decreased, partly due to the enhanced use of diagnostic and screening techniques. 4,5

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

“…High levels of Lpd mRNA correlated with reduced metastasis-free and disease-free survival of breast cancer patients in three separate cohorts ( Figures 1b and c ; Supplementary Figures 1B and C ). 22 , 23 , 24 In addition, we explored whether Lpd protein expression levels correlate with clinical outcome for breast cancer patients by staining a tumor microarray (TMA) 25 generated from 312 patients with invasive breast cancer with anti-Lpd antibodies. Moderately, but not highly, increased abundance of Lpd in the cytoplasm (Histoscore 2; Hazard ratio (HR) (95% confidence interval (CI)): 1.765 (1.026–3.036); Supplementary Figures 1D and 2A,B ) and at the plasma membrane (Histoscore 2: HR, (95% CI): 2.231 (1.26–3.949); Figures 1d and e ; compared with respective histoscore 1) was significantly associated with increased risk for breast cancer-associated mortality.…”

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

“…TrkA (NTRK1) gene overexpression has also been shown to occur preferentially in invasive tumours [23]. In breast cancer patients, increased TrkA phosphorylation has been described in malignant pleural effusions [24] while phosphorylation of Tyr674/675 and activation of tyrosine kinase activity in the cytoplasmic domain of TrkA has been shown as a potential prognostic biomarker [25]. However, TrkA protein expression in a large clinically relevant cohort of breast tumours, as well as its overall clinical significance remain unclear [26].…”

Cancer Stem Cell Transcriptome Landscape Reveals Biomarkers Driving Breast Cancer Heterogeneity

“…For example, we previously reported the suppressive role of FOXA1 on breast cancer stemness [17]; SOX9 is as a stem cell factor [18] that drives the epithelial mesenchymal transition (EMT) in non-small cell lung cancer through Wnt pathway [19] and maintains human breast luminal progenitor and breast cancer stem cells through SOX9 mediated signaling [20], and both the SOX9/FXYD3/SRC [21] and the SOX9/SOX2 [20] axes are critical for breast cancer stem cell functionalities; PLA2G7 is associated with ER negativity in clinical breast cancer samples and regulates EMT in vitro [22]. The prognostic values of several markers have been reported, including PTPN6 and KRT19 in breast cancers [23][24][25], EPPK1 in non-small cell lung cancers [26], SERPINB5 in colorectal cancers [27], and NCCRP1 in squamous cell carcinoma [28]. Besides, the roles of S100A7 and SLC37A1 was implicated in breast cancers [29,30], that of SERPINB4 was reported in squamous cell carcinoma [31], and that of MYH14 was lately identi ed in pancreatic cancers [32].…”