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.
Highlights
Protein tyrosine phosphatases (PTPs) and tyrosine kinases modulate cellular levels of tyrosine phosphorylation and regulate many cellular events such as differentiation, cell growth, motility and proliferation.[1]
We have studied the expression of Protein tyrosine phosphatase 1B (PTP1B) in human breast tissue and human breast epithelial progenitor cells
PTP1B expression is abundant in primary human breast tissue with highest expression in primary basal/myoepithelial cells and fibroblasts
Summary
Protein tyrosine phosphatases (PTPs) and tyrosine kinases modulate cellular levels of tyrosine phosphorylation and regulate many cellular events such as differentiation, cell growth, motility and proliferation.[1]. In addition to insulin regulation, PTP1B has a role in other signaling pathways, such as growth factor and integrin mediated processes, as well as cancer development.[7,8] PTP1B is a major activator of Src by dephosphorylating the inhibitory tyrosine phosphorylation site (Y529) on the COOH terminus of the kinase.[9] PTP1B has been shown to be a positive mediator of the ErbB2-induced signals that trigger breast tumorigenesis[10,11] and to be required for ErbB2 transformation in breast epithelial cells through Src activation.[12] Substrate trapping and biochemical studies have identified various substrates of PTP1B involved in cell adherence and matrix attachment. We show that the transition from an epithelial to a mesenchymal state sensitizes mammary cells to PTP1B inhibition, suggesting the therapeutic potential of PTP1B inhibition in cancer treatment
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