Cooperating Oncogenic Events in Murine Mammary Tumorigenesis: Assessment of ErbB2, Mutant p53, and Mouse Mammary Tumor Virus

Abstract

We are investigating cooperating genetic events in the genesis of breast cancer, using the mouse as a model system. We have shown cooperativity between a mutant allele of p53 (p53-172H) and overexpressed ErbB2 in mammary tumorigenesis in transgenic mice. We are now performing additional crosses to further examine oncogene cooperativity with ErbB2 and p53-172H. We attempted to test the dominant oncogenic potential of p53-172H in an in vivo setting by crossing the p53-172H transgene together with ErbB2 onto either a p53−/− or a p53+/− background. We show that the p53-172H allele and the heterozygous p53 genotype have an identical impact on the latency of ErbB2-induced mammary tumors; there was no evidence of additivity or synergy between p53-172H and the p53+/− genotype. On the p53−/− background, we obtained no mammary tumors due to the early onset of lymphomas and sarcomas, thus precluding assessment of the effect of the p53-172H transgene on mammary tumorigenesis in a p53-null background. Thus, in this in vivo model for breast cancer, we failed to find evidence that p53-172H can function as a dominant oncogenic allele, but rather found support for its being essentially equivalent to a null allele in its impact on ErbB2-induced mammary tumorigenesis. By comparative genome analysis, we showed that a common feature of tumors arising in ErbB2/mutant p53 mice (p53-null allele with or without p53-172H) is a loss of chromosome 4, a feature of many epithelial tumors in mice and one that is consistent with a role for loss of INK4a/ARF in such tumors. We also attempted to accelerate ErbB2-induced mammary tumorigenesis with mouse mammary tumor virus (MMTV) proviral tagging mutagenesis, but we were surprised to find that mice with MMTV alone had the same latency as mice with both MMTV and ErbB2, indicating no cooperativity between ErbB2 and MMTV. This may have been due to the mixed C3H/HeN × FVB strain background used in this cross.