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Mammary Cancer Projects

1. We are using the mouse as a model system to study oncogene cooperativity and to identify new genes involved in breast cancer. In our eariler work, we tested whether two genes commonly involved in human breast cancer, p53 (aka TP53) and ERBB2 could cooperate to promote mammary cancer in mice, using different transgenic mouse models. We were able to show that indeed there is cooperativity, and that as expected, a dominant negative allele of p53 contributes to tumorigenesis by promoting genomic instability. Unexpectedly, we also found it promoted increased rates of apoptosis within the tumor.

2. In a second series of experiments, we wished to determine if the mutant p53 allele that we used, harboring an arginine to histidine mutation at position 172, had the ability to function as a dominant active allele, as has been suggested by A. Levine and coworkers. We tried to address this by crossing the mutant p53 allele onto a p53 null background, on which it would not be able to interact with wildtype p53, and could only function as a dominant active rather than a dominant negative allele. However, due to the high penetrance of lethal thymic lymphomas in the p53 null mice, we were unable to directly test this hypothesis. See Zelazny E, Anagnostopolous A-M, Coleman A, Perkins A. Cooperating oncogenic events in murine mammary tumorigenesis:assessment of ErbB2, mutant p53, and MMTV. Exp Mol Pathol. 2001;70:183-193.

3. In a third series of experiments, we attempted to find new genes involved in breast cancer, and specifically those that could cooperate with mutant p53. We used the mouse as a model system, and used the mouse mammary tumor virus (MMTV) to mutate/activate cooperating oncogenes. Using MMTV as a mutagen has the advantage that the mutated genes can be readily cloned by inverse PCR. This study led to the identification of a number of new sites of proviral insertion that heretofore had not been directly implicated in mammary tumorigenesis. It may be that these genes play a role in human breast cancer as well. A review that highlights our work has been written by Emmet Schmidt.

For a review of the value of mouse mammary tumor virus studies for human breast cancer, see review by Callahan and Smith.

4. We are currently expanding our screening of our mammary tumors for common sites of MMTV proviral integration as a way of identifying genes that may also play a role in human breast cancer, and that may be targets for therapeutic intervention. We have the unique advantage of having performed MMTV mutagenesis on a variety of mouse backgrounds, with and without different oncogenic transgenes. We believe that the use of these varied mouse backgrounds has allowed us to obtain a different spectrum of insertion sites than what has been identified previously. This work is ongoing.

Funding

US Army IDEA Award, Grant BC021042. “Rapid Genomic Approach to Discovery of Oncogenes in Breast Cancer.”