Summary
The effect of mammary gland-specific expression of the polyomavirus middle T antigen was
examined by establishing lines of transgenic mice that carry the middle T oncogene under
the transcriptional control of the mouse mammary tumor virus (MMTV) promoter/enhancer. By
contrast to most transgenic strains carrying activated oncogenes, expression of
polyomavirus middle T antogen resulted in the rapid induction of multifocal mammary
tumors. Interestingly, the majority of the tumor-bearing transgenic mice developed
secondary metastatic tumors in the lung. Taken together, these results suggest that PyV
middle T antigen acts as a potent oncogene in the mammary epithelium and that cells
express it possess an enhanced metastatic potential.
Citation
Guy, C. T., Cardiff, R.D., and Muller, W.J. 1992. Mol. Cell. Biol. 12, 954-961
Gut, C.T., Muthuswamy, S.K., Cardiff, R.D., Soriano, P., and Muller, W.J. 1994. Genes and Dev. 8, 23-32
Trimble, M.S., Xin, J.H., Guy, C.T., Muller, W.J., and Hassell, J.A. 1993 Oncogene 8, 3037-3042
Background
PyV is a small DNA tumor virus that is capable of inducing a wide spectrum of tumors in
new born mice. Indeed, infection of newborn or nu/nu mice with PyV results in the
formation of a number of epithelial and mesenchymal tumor types of which mammary tumors
represent a significant majority. Genetic analyses of PyV middle T mediated tumorigenesis
has shown that a functional middle T antigen is required for tumor induction. The potent
transforming activity of PyV middle T antigen is due to its ability to associate with a
number of cellular proteins. For example, PyV middle T is able to associate with the src
family kinases, the p85-KDa subunit of the phosphatidylinositol-3' kinase, the SHC adaptor
protein and protein phosphatase 2A. Given the ability of PyV middle T oncogen to affect
cell proliferation through multiple signaling pathways, the MMTV/PyV middle T transgenic
model is an excellent model to assess the relative contribution of these signaling
proteins to the the metastatic mammary tumor phenotype.
Transgene
A MMTV driven PyV middle T cDNA.
mouse strain
FVB/N
Female mice from two independent lines (MT#634 and MT#668) fail to lactate and display evidence of in situ carcinoma as early as 3 weeks of age. All female and male transgene carriers eventually develop mammary tumors. In addition to the high penetrance of mammary tumors, most tumor bearing animals eventually develop metastatic tumors in the lung.
Histology
The mammary tumors were generally highly fibrotic, with dense connective tissue
seperating individual nests of tumor cells. Histological analyses revealed that the tumors
resmbled sclerosing mammary adenocarcinomas. The metastatic foci were found intra-aveolar
rather than intravascular, indicating growth outside the vessel.
Mammary development
Whole mount analyses revealed that even at early stages of mammary gland development (3
weeks virgin animals) the glands were grossly abnormal with irregular formation of side
branches, enlarged terminal buds, and large multilobular tumor massess. The female animals
of these strains fail to lactate.
Gene expression
Transgene expression is detected both at the RNA and protein level in the mammary glands
of both male and female animals. nterstingly significant levels of PyV middle T transgene
can also be detected in the salivary glands and male reproductive tract without apparent
phenotypic consequences.
Mechanistic implications
These observations suggest that expression of PyV middle T antigen can result in the rapid
induction of metastatic tumors. Recent interbreeding experiments with the Src and Yes KO
mice have revealed that activation of the c-Src pathway by PyV middle T antigen plays a
critical role in the induction of mammary tumors by PyV middle T antigen (see Guy et al.,
1994). Given the recent observations that c-src activity is elevated in a large percentage
of human breast cancers, these observations suggest that activation of the c-Src pathway
may be a crucial step in mammary tumor progression. We are current testing the role of the
PI-3' kinase and SHC pathways in PyV middle T mediated tumorigenesis.
key words
c-src, other proteins, adenocarcinoma
Contributed By
Dr. W. J. Muller
Phone: 905-525-9140 ext 27306
Fax: 905-521-2955
e-mail: ( mullerw@mcmail.cis.mcmaster.ca
contributed: March 11, 1996
last update: December 1998