Cesar F Ortega-Cava1, Srikumar M Raja2, Zenab Laiq1, Tameka A Bailey1, Haitao Luan3, Bhopal Mohapatra4, Stetson H Williams1, Aaron C Ericsson5, Rasna Goswami6, Manjari Dimri7, Lei Duan8, Vimla Band9, Mayumi Naramura9, Hamid Band10
1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
2 Eppley Institute for Research in Cancer and Allied Diseases; UNMC-Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
3 Eppley Institute for Research in Cancer and Allied Diseases; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, College of Medicine, Omaha, NE, USA.
4 Eppley Institute for Research in Cancer and Allied Diseases; Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
5 Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA.
6 Abbott Laboratories, Abbott Park, IL, USA.
7 Department of Biochemistry, George Washington University School of Medicine, Washington, DC, USA
8 Eppley Institute for Research in Cancer and Allied Diseases; Current address for LD – Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.
9 Eppley Institute for Research in Cancer and Allied Diseases; UNMC-Eppley Cancer Center; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, College of Medicine, Omaha, NE, USA.
10 Eppley Institute for Research in Cancer and Allied Diseases; UNMC-Eppley Cancer Center; Department of Genetics, Cell Biology and Anatomy; Biochemistry and Molecular Biology; Pathology and Microbiology; Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, College of Medicine, Omaha, NE, USA.
DOI: 10.4103/1477-3163.90443
ABSTRACT
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.
Keywords: 3-D Matrigel, EMT, ErbB2/Her2/Neu, lapatinib, mouse models, syngeneic xenografts