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Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer
BACKGROUND: Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alt...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Medknow Publications & Media Pvt Ltd
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243085/ https://www.ncbi.nlm.nih.gov/pubmed/22190871 http://dx.doi.org/10.4103/1477-3163.90443 |
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author | Ortega-Cava, Cesar F. Raja, Srikumar M. Laiq, Zenab Bailey, Tameka A. Luan, Haitao Mohapatra, Bhopal Williams, Stetson H. Ericsson, Aaron C. Goswami, Rasna Dimri, Manjari Duan, Lei Band, Vimla Naramura, Mayumi Band, Hamid |
author_facet | Ortega-Cava, Cesar F. Raja, Srikumar M. Laiq, Zenab Bailey, Tameka A. Luan, Haitao Mohapatra, Bhopal Williams, Stetson H. Ericsson, Aaron C. Goswami, Rasna Dimri, Manjari Duan, Lei Band, Vimla Naramura, Mayumi Band, Hamid |
author_sort | Ortega-Cava, Cesar F. |
collection | PubMed |
description | BACKGROUND: Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alterations that culminate in aggressive breast cancers. Cellular models that exhibit ErbB2 kinase dependency and can induce metastatic breast cancer in immune competent hosts are likely to help bridge this gap. MATERIALS AND METHODS: Here, we derived and characterized a cell line model obtained from a transgenic ErbB2/Neu-driven mouse mammary adenocarcinoma. RESULTS: The MPPS1 cell line produces metastatic breast cancers when implanted in the mammary fat pads of immune-compromised as well as syngeneic immune-competent hosts. MPPS1 cells maintain high ErbB2 overexpression when propagated in DFCI-1 or related media, and their growth is ErbB2-dependent, as demonstrated by concentration-dependent inhibition of proliferation with the ErbB kinase inhibitor Lapatinib. When grown in 3-dimensional (3-D) culture on Matrigel, MPPS1 cells predominantly form large irregular cystic and solid structures. Remarkably, low concentrations of Lapatinib led to a switch to regular acinar growth on Matrigel. Immunofluorescence staining of control vs. Lapatinib-treated acini for markers of epithelial polarity revealed that inhibition of ErbB2 signaling led to rapid resumption of normal mammary epithelium-like cell polarity. CONCLUSIONS: The strict dependence of the MPPS1 cell system on ErbB2 signals for proliferation and alterations in cell polarity should allow its use to dissect ErbB2 kinase-dependent signaling pathways that promote loss of cell polarity, a key component of the epithelial mesenchymal transition and aggressiveness of ErbB2-driven breast cancers. |
format | Online Article Text |
id | pubmed-3243085 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Medknow Publications & Media Pvt Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-32430852011-12-21 Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer Ortega-Cava, Cesar F. Raja, Srikumar M. Laiq, Zenab Bailey, Tameka A. Luan, Haitao Mohapatra, Bhopal Williams, Stetson H. Ericsson, Aaron C. Goswami, Rasna Dimri, Manjari Duan, Lei Band, Vimla Naramura, Mayumi Band, Hamid J Carcinog Original Article BACKGROUND: Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alterations that culminate in aggressive breast cancers. Cellular models that exhibit ErbB2 kinase dependency and can induce metastatic breast cancer in immune competent hosts are likely to help bridge this gap. MATERIALS AND METHODS: Here, we derived and characterized a cell line model obtained from a transgenic ErbB2/Neu-driven mouse mammary adenocarcinoma. RESULTS: The MPPS1 cell line produces metastatic breast cancers when implanted in the mammary fat pads of immune-compromised as well as syngeneic immune-competent hosts. MPPS1 cells maintain high ErbB2 overexpression when propagated in DFCI-1 or related media, and their growth is ErbB2-dependent, as demonstrated by concentration-dependent inhibition of proliferation with the ErbB kinase inhibitor Lapatinib. When grown in 3-dimensional (3-D) culture on Matrigel, MPPS1 cells predominantly form large irregular cystic and solid structures. Remarkably, low concentrations of Lapatinib led to a switch to regular acinar growth on Matrigel. Immunofluorescence staining of control vs. Lapatinib-treated acini for markers of epithelial polarity revealed that inhibition of ErbB2 signaling led to rapid resumption of normal mammary epithelium-like cell polarity. CONCLUSIONS: The strict dependence of the MPPS1 cell system on ErbB2 signals for proliferation and alterations in cell polarity should allow its use to dissect ErbB2 kinase-dependent signaling pathways that promote loss of cell polarity, a key component of the epithelial mesenchymal transition and aggressiveness of ErbB2-driven breast cancers. Medknow Publications & Media Pvt Ltd 2011-11-30 /pmc/articles/PMC3243085/ /pubmed/22190871 http://dx.doi.org/10.4103/1477-3163.90443 Text en © 2011 Cava http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Ortega-Cava, Cesar F. Raja, Srikumar M. Laiq, Zenab Bailey, Tameka A. Luan, Haitao Mohapatra, Bhopal Williams, Stetson H. Ericsson, Aaron C. Goswami, Rasna Dimri, Manjari Duan, Lei Band, Vimla Naramura, Mayumi Band, Hamid Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title | Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title_full | Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title_fullStr | Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title_full_unstemmed | Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title_short | Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer |
title_sort | continuous requirement of erbb2 kinase activity for loss of cell polarity and lumen formation in a novel erbb2/neu-driven murine cell line model of metastatic breast cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243085/ https://www.ncbi.nlm.nih.gov/pubmed/22190871 http://dx.doi.org/10.4103/1477-3163.90443 |
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