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.
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.
  
  
  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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Cesar F
authors.initials: CF
authors.lastname: Ortega-Cava
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Zenab
authors.initials: Z
authors.lastname: Laiq
authors.forename: Tameka A
authors.initials: TA
authors.lastname: Bailey
authors.forename: Haitao
authors.initials: H
authors.lastname: Luan
authors.forename: Bhopal
authors.initials: B
authors.lastname: Mohapatra
authors.forename: Stetson H
authors.initials: SH
authors.lastname: Williams
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Ericsson
authors.forename: Rasna
authors.initials: R
authors.lastname: Goswami
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Hamid
authors.initials: H
authors.lastname: Band