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Murine c-erbB2: an oncogene that could be a target for vaccination therapy? : and the effect of HER2/c-erbB2/NeuT expression on cell signaling and milk protein formation in mouse mammary epithelial cells

Noyer, Mathieu. Murine c-erbB2: an oncogene that could be a target for vaccination therapy? : and the effect of HER2/c-erbB2/NeuT expression on cell signaling and milk protein formation in mouse mammary epithelial cells. 2006, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7927

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Abstract

ErbB2 is an orphan receptor tyrosine kinase which can dimerize with other ligand-activated
members of the EGF receptor family to signal in pathways inducing cell proliferation.
Frequently overexpressed in breast cancer and other human cancers, homologs of ErbB2 are
oncogenes in different animal species which have been studied for their contribution to the
development of carcinomas.
The first part of this project was aimed at developing a method for vaccination of
mouse, so that a transplanted tumor expressing the endogenous mouse c-erbB2 would be
rejected. Initially, it was necessary to prepare a functional expression clone of mouse cerbB2.
Then the question of how to break the natural tolerance against an immune response
against the self-antigen, mouse c-erbB2, had to be approached. Several protocols were
attempted as described below, but I was unsuccessful in obtaining the intended protective
effect against transplanted tumor.
In the second part of this work, we have examined phenotypes induced by several
ErbB2 homologs in Line 31E mouse mammary epithelial cells which are capable of
differentiation in vitro to undergo dome formation and to produce milk protein in response to
lactogenic hormones. Included in this comparative study are the functional clone of the mouse
proto-oncogene c-erbB2, a human homolog overexpressed in breast cancer, HER2, and the
mutated rat homolog, NeuT, which is known to be oncogenic.
Line 31E mammary epithelial cells were infected with retroviral pBabepuro constructs
of the different ErbB2 homologs. Typical features of epithelial intercellular organization,
such as density of tight junctions and dome formation, were disturbed by ErbB2 expression.
While a dominant negative mutant of HER2 had no effect on the epithelial cells, both
transepithelial monolayer resistance and dome formation were reduced by all three of the
functional ErbB2 homologs, most dramatically by NeuT. While expression of both the mouse
proto-oncogene c-erbB2 and HER2 resulted in significant inhibition of β-casein mRNA and
protein levels after lactogenic hormone treatment, NeuT completely abrogated β-casein
production and caused oncogenic transformation as evidenced by large colonies in soft agar
and Matrigel suspension culture. While the cells expressing the homologs remain acutely
responsive to EGF ligand in terms of Akt/PKB, ERK 1/2 and PKCα phosphorylation, an
elevated basal phosphorylation in the absence of ligand was not apparent for PKCα.
Advisors:Krähenbühl, Stephan
Committee Members:Friis, Robert R. and Hynes, Nancy
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7927
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:71
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 16:06

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