SHP-1 acts as a tumor suppressor by interacting with EGFR and predicts the prognosis of human breast cancer

Abstract

Objective:The aims of this study were to examine the prognostic value of SHP-1 in breast cancer, its roles in the regulation of breast cancer cell growth and metastasis, and the underlying mechanisms. Methods: Tumor specimens from 160 patients with breast cancer and 160 noncancerous tissues were used to examine the expression of SHP-1 and to analyze its association with overall survival through Kaplan-Meier and multivariate Cox regression analyses. RNA sequencing data and the expression and clinical importance of SHP-1 in breast cancer were evaluated with data from The Cancer Genome Atlas. In vitro and in vivo assays were performed to elucidate the effects of SHP-1 on breast cancer cell proliferation and invasion. Confocal immunofluorescence and GST pulldown assays were used to demonstrate the interaction between SHP-1 and epidermal growth factor receptor, as well as its downstream pathways. Immunohistochemistry and The Cancer Genome Atlas database were used to investigate the clinical association between SHP-1 and EGFR in human breast cancer. Results: SHP-1 expression was associated with better survival in patients with breast cancer, whereas SHP-1 expression was negatively correlated with EGFR in human breast cancer. Ectopic SHP-1 expression significantly suppressed breast cancer cell proliferation, migration, and invasion. SHP-1 knockdown induced a more invasive phenotype and accelerated cell growth. Mechanistically, EGFR, a protein directly interacting with SHP-1, mediates the SHP-1-induced inactivation of Ras/Erk/GSK3β signaling and its downstream effectors. Conclusions: SHP-1 is an important prognostic biomarker in patients with breast cancer, and the SHP-1-EGFR axis is a promising target for treatment.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection

“…This suggests that the role of SHP1 in non‐hematopoietic cells requires further validation. Exogenous expression of SHP1 in these cells shows anti‐proliferative, anti‐migratory, and anti‐invasive effects, implying that SHP1 also functions as a tumor suppressor in non‐hematopoietic cancers 49,50 . Recent studies have shown that SHP1 silencing is prevalent in gastric adenocarcinoma tissues 51 and that its full activation prevents H. pylori ‐infected cells from forming the “hummingbird” phenotype, indicating its negative roles in the development of H. pylori‐ associated gastric cancer.…”

“…Exogenous expression of SHP1 in these cells shows anti-proliferative, anti-migratory, and anti-invasive effects, implying that SHP1 also functions as a tumor suppressor in non-hematopoietic cancers. 49,50 Recent studies have shown that SHP1 silencing is prevalent in gastric adenocarcinoma tissues 51 and that its full activation prevents H. pylori-infected cells from forming the "hummingbird" phenotype, indicating its negative roles in the development of H. pylori-associated gastric cancer. Although the cancer-promoting effect of SHP2, the homolog of SHP1, on H. pylori-associated carcinogenesis has been extensively studied, the specific roles of SHP1 in this process remain obscure.…”

Consideration of SHP-1 as a Molecular Target for Tumor Therapy

“…The association between SHP-1 expression and patient survival differs based on tumor type ( Table 1 ). High levels of SHP-1 expression are related to high survival rates in patients with tumors, including breast cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, and prostate cancer [ 20 , 33 , 34 , 35 , 36 , 37 ]. Additionally, there is a report on the antitumor function of SHP-1 in gastric cancer, although it is not associated with SHP-1 expression [ 38 ].…”

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

“…More importantly, loss of PTPN2 is coupled with activation of oncogenic signaling pathways, such as protein kinase B (AKT), Src family kinase (SFK) and STAT3 signaling pathways, and also with resistance to tamoxifen ( 29 , 30 ). PTPN6 dampens the oncogenic characteristics of breast cancer by dephosphorylating STAT3 and inactivating the Ras/extracellular signal-regulated kinase (Erk)/glycogen synthase kinase-3beta (GSK-3β) signaling pathway ( 31 , 32 ). PTPN9 suppresses the growth and invasion of breast cancer cells by negatively regulating HER2 and epidermal growth factor receptor (EGFR) and suppressing STAT3 activation ( 33 , 34 ).…”