Inhibition of PTP1B disrupts cell–cell adhesion and induces anoikis in breast epithelial cells

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a well-known inhibitor of insulin signaling pathways and inhibitors against PTP1B are being developed as promising drug candidates for treatment of obesity. PTP1B has also been linked to breast cancer both as a tumor suppressor and as an oncogene. Furthermore, PTP1B has been shown to be a regulator of cell adhesion and migration in normal and cancer cells. In this study, we analyzed the PTP1B expression in normal breast tissue, primary breast cells and the breast epithelial cell line D492. In normal breast tissue and primary breast cells, PTP1B is widely expressed in both epithelial and stromal cells, with highest expression in myoepithelial cells and fibroblasts. PTP1B is widely expressed in branching structures generated by D492 when cultured in 3D reconstituted basement membrane (3D rBM). Inhibition of PTP1B in D492 and another mammary epithelial cell line HMLE resulted in reduced cell proliferation and induction of anoikis. These changes were seen when cells were cultured both in monolayer and in 3D rBM. PTP1B inhibition affected cell attachment, expression of cell adhesion proteins and actin polymerization. Moreover, epithelial to mesenchymal transition (EMT) sensitized cells to PTP1B inhibition. A mesenchymal sublines of D492 and HMLE (D492M and HMLEmes) were more sensitive to PTP1B inhibition than D492 and HMLE. Reversion of D492M to an epithelial state using miR-200c-141 restored resistance to detachment induced by PTP1B inhibition. In conclusion, we have shown that PTP1B is widely expressed in the human breast gland with highest expression in myoepithelial cells and fibroblasts. Inhibition of PTP1B in D492 and HMLE affects cell–cell adhesion and induces anoikis-like effects. Finally, cells with an EMT phenotype are more sensitive to PTP1B inhibitors making PTP1B a potential candidate for further studies as a target for drug development in cancer involving the EMT phenotype.

The Landscape of Somatic Copy Number Alterations in Head and Neck Squamous Cell Carcinoma

“…We applied GISTIC algorithm (36) to perform focal CNA analysis and identified a number of candidate genes, including driver genes from other tumor types, as well as genes not previously reported to be associated with any cancer. Over-expression of PTPN1 has been linked to colon cancer and breast cancer development and progression (54,55). The phosphatase activity of PTPN1 is responsible for the regulation of cell motility and invasion, and may enhance the expression of EGFR.…”

“…It directly dephosphorylates insulin receptor and insulin receptor substrates, which results in down regulation of insulin signaling. In recent studies, the overexpression of PTPN1 was detected in several cancer types such as colon cancer and breast cancer (54,55). It has also been reported as an indicator of poor prognosis in gastric cancer (56).…”

Protection against gamma-radiation injury by protein tyrosine phosphatase 1B

“…Work form several groups has demonstrated that protein tyrosine phosphatases play a relevant role in the process of macrophage polarization acting, not only as negative regulators of pro-inflammatory signaling, but also as attenuators of anti-inflammatory pathways [21] , [33] , [34] , [35] , [36] , [37] . Moreover, in addition to immune regulation, an essential role for PTP1B in obesity-induced chronic low-grade inflammation and in other pathologies including diabetes, cancer, neuroinflammation, liver diseases or Rett syndrome, has been described as evidenced by the use of selective PTP1B inhibitors or animal models targeted for PTP1B [12] , [18] , [20] , [22] , [38] , [39] , [40] , [41] .…”

Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?

“…Inhibition of PTP1B in breast cancer cells leads to cell death and loss of extracellular matrix fixation, leading to negative regulation of cell adhesion proteins and interrupted actin polymerization. They saw that with the inhibition of PTP1B the activity of Src is consequently decreased by the adhesion pathway and motility is impaired [78].…”