Mouse Mammary Cancer Models - Mechanisms and Markers

Abstract : We have focused on two mouse models for mammary cancer, the p53-deficient Wnt-1 transgenic model and the Chk1-defident Wnt-1 transgenic model. Both bitransgenic models are dependent on the Wnt-1 transgene to initiate mammary adenocarcinomas within 3-12 months after birth. Our goal was to determine what effect deficiency of the p53 tumor suppressor or the cell G2 checkpoint gene Chkl would have onWnt-1 initiated mammary tumorigenesis. Characterization of the biology of the p53-deficient Wnt-1 transgenic model had shown that p534- mice develop tumors that arise sooner, grow faster, have more anaplastic histopathology, and have more chromosomal instability than p53+1+ mice. To identify genes which might be involved in the different tumor phenotypes, we compared their global RNA expression patterns by various approaches. We identified six genes consistently upregulated in p53+I+ mammary tumors and one consistently upregulated in p534- tumors. All of these genes are relevant either to cell cycle control or differentiation state and may in part be responsible for the less aggressive p53+I+ tumor phenotypes. Comparison of tumor incidence in the Chkl+/- and Chkl+/+ Wnt-1 transgenic mice revealed a significantly earlier appearance of Chkl+/- tumors, consistent with the hypothesis that Chk1 is a real tumor suppressor.