Elevated Expression of the Tyrosine Phosphatase SHP-1 Defines a Subset of High-Grade Breast Tumors

Abstract

Objectives: Protein tyrosine phosphatases are key regulators of intracellular signaling that contribute to determining cancer cell growth, which thus makes them attractive targets for therapeutic and diagnostic agents. SHP-1 phosphotyrosine phosphatase is rarely expressed in epithelial tumor cells, but expression has been found in several breast cancer cell lines and tumors. To determine the potential significance of SHP-1 as a prognostic marker in the clinical setting, we examined SHP-1 protein expression in breast tumors. Methods: We analyzed SHP-1 expression by immunohistochemistry in a breast tissue microarray composed of 2,081 cores, either alone or in combination with known prognostic markers. Results: Our data showed that SHP-1 expression was confined to a well-defined subset of high-grade tumors characterized by unique biological parameters. SHP-1 expression correlated directly with expression of the tyrosine kinase receptor HER-2 and inversely with expression of the estrogen receptor, while it was weakly associated with Bcl-2 expression. Conclusions: Levels of SHP-1 were correlated with conventional pathologic parameters of tumor aggressiveness and were associated with reduced patient survival, suggesting that elevated expression of SHP-1 is a common molecular abnormality in a defined subset of breast tumors and might be used in routine diagnosis to identify patients with high-risk tumors.

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

“…Insabato et al 27 reported that PTPN6 protein expression correlates with grade III in 7% of breast tumors. 27 This investigation has shown that PTPN6 overexpression was an independent predictor of poor 5, 10, and 15 years' disease-free survival in estrogen receptor-positive tumors with hazard ratios of 2.60 (P ¼ 0.029), 2.07 (P ¼ 0.069), and 2.13 (P ¼ 0.040), respectively.…”

“…Insabato et al 27 reported that PTPN6 protein expression correlates with grade III in 7% of breast tumors. 27 This investigation has shown that PTPN6 overexpression was an independent predictor of poor 5, 10, and 15 years' disease-free survival in estrogen receptor-positive tumors with hazard ratios of 2.60 (P ¼ 0.029), 2.07 (P ¼ 0.069), and 2.13 (P ¼ 0.040), respectively. These findings together with results showing a correlation between high PTPN6 levels and grade III by Pearsons w 2 (correlation ¼ 0.153, P ¼ 0.013) and Spearman's rank (rank ¼ 0.151, P ¼ 0.015) support the findings of Insabato et al 27 This investigation has demonstrated that breast cancer tumors expressing NTRK1-pY674/pY675 together with low or undetectable levels of TP53 and PTPN6 are strongly associated with improved 5, 10, and 15 years' disease-free survival.…”

“…26,27 High levels of cytoplasmic PTPN6 protein was detected in 30 (11%) tumors, moderate in 84 (29%), and weak in 112 (39%) tumors. No PTPN6 was detected in 59 (21%) samples (Supplementary Table S2).…”

“…27 Interestingly, when histological grade was included in the multivariate analysis, the hazard ratios of PTPN6 were perturbed (Supplementary Table S3). The hazard ratio of 5, 10, and 15 years' disease-free survival was reduced from 1.54 to 1.35, 1.19 to 0.97, and 1.25 to 1.01, respectively, which is indicative of a positive correlation between histological grade and PTPN6 expression.…”

“…25 In breast cancer, PTPN6 is upregulated and preferentially located in the cytoplasm of tumor cells, and high expression has been associated with poor patient prognosis. 26,27 A novel mechanism for nerve growth factor-independent NTRK1 activation has been demonstrated. We have shown that in breast cancer wild-type TP53 represses PTPN6 expression via the PTPN6 proximal-P1 promoter and the NF-Y transcription factor.…”