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

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

Title: Inhibition of PTP1B disrupts cell–cell adhesion and induces anoikis in breast epithelial cells
Author: Hilmarsdóttir, Bylgja
Briem, Eiríkur   orcid.org/0000-0001-7383-3570
Halldórsson, Skarphéðinn
Kricker, Jennifer   orcid.org/0000-0002-0757-1936
Ingthorsson, Saevar   orcid.org/0000-0001-8480-9680
Gústafsdóttir, Sigrún
Mælandsmo, Gunhild M
Magnusson, Magnus Karl   orcid.org/0000-0001-8593-4934
Gudjonsson, Thorarinn   orcid.org/0000-0001-9645-9665
Date: 2017-05-11
Language: English
Scope: e2769
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Rannsóknarsetur í kerfislíffræði (HÍ)
Center for Systems Biology (UI)
Series: Cell Death and Disease;8(5)
ISSN: 2041-4889
DOI: 10.1038/cddis.2017.177
Subject: Stofnfrumurannsóknir; Lyfjafræði; Offita; Brjóstakrabbamein
URI: https://hdl.handle.net/20.500.11815/307

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Bylgja Hilmarsdottir, Eirikur Briem, Skarphedinn Halldorsson, Jennifer Kricker, Sævar Ingthorsson, Sigrun Gustafsdottir, Gunhild M Mælandsmo, Magnus K Magnusson and Thorarinn Gudjonsson. Cell Death and Disease (2017) 8, e2769; doi:10.1038/cddis.2017.177


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.


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