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Genetically Altered Mice

Technology Development

Mice are desirable as cancer models because of the discovery in 1981 that the mouse germline can be changed to accept the delivery and consistent expression of foreign genes.  This followed the demonstration in 1976 that normal cells have proto-oncogenes that are defective in tumor cells; these defective genes are called oncogenes, and many have now been associated with the development of human tumors.  The first publications about transgenic cancer models appeared in 1984.  One model of brain tumors was derived by delivering a viral oncogene called SV40 T-antigen into mouse eggs.  The other was produced by delivering a mutant human oncogene called c-Myc by MMTV, a mouse virus that infects mouse mammary tissue; the mice developed mammary tumors that resemble human breast tumors.  These first models were the impetus for development of a large number of transgenic cancer models, using oncogenes that many laboratories discovered to be associated with human cancers in a variety of organ systems. 

Numerous strategies employed

In 1984, researchers implicated another type of gene, a tumor suppressor gene, in the development of cancers.  This cancer-causing mechanism requires that the activity of the tumor suppressor gene be lost in order for a tumor to develop.  However, generating a cancer model that is based on loss of gene expression (as opposed to the over-expression or mutation mechanism by which oncogenes act) presented a technical challenge.  It was difficult to conceive of approaches that would work to result in loss of expression.  However, in 1987, a new technique emerged that subsequently revolutionized mouse cancer modeling.  The procedure - homologous recombination in mouse embryonic stem cells, or ES cells, allows researchers to remove a gene (knock out), or replace it (knock in), or perform a variety of other alterations of mouse DNA segments that replicate the different types of genetic aberrations or mutations that the research community has found to be associated with human tumors.  Because cancer researchers are able to alter the genetics of laboratory mice with great precision, it allows them to test how, when, where, and in which combinations particular gene alterations are involved in the initiation and progression of cancer to invasive, metastatic tumors.

 

Technical aspects

For additional details on the process of generating mouse models with genetic modifications, explore the Generating Models Genetic Modifications area of this site.