Development of Spontaneous Mammary Tumors in BALB/c-p53+/-Mice: Detection of Early Genetic Alterations and the Mapping of BALB/c Susceptibility Genes

摘要

Breast caner is the most common cancer type in women carrying p53 germline mutations which lead to multiple cancer types. Frequent observation of mammary tumors in BALB/c-Trp53+/- (p53) female mice but rare in C57BL/6-Trp53+/- females suggested that inherited breast cancer susceptibility also exists in mice. p53 heterozygosity in these mice provides a sensitized background for screening alleles that contribute to cancer susceptibility. By multiple genetic crosses, we conducted a mouse genome scan and isolated the SuprMam1 region on mouse chromosome 7 that could be linked to mammary tumor susceptibility in BALB/c-Trp53+/- mice. Microarray gene expression profiling identified Deleted in Malignant Brain Tumors 1 DMBT1 as a leading candidate. Loss or down- regulation of DMBT1 has been found in many cancer types as well as in breast cancer. Furthermore, the basal level of DMBT1 mRNA in the mammary glands was dramatically reduced in the susceptible BALB/c mice compared to C57BL/6. In normal human breast tissues, an overall reduction DMBT1 protein was statistically linked to women with breast cancer history compared to those who had no breast cancer before. The data Suggests that DMBT1 could be a low- penetrance allele that contribute to breast cancer susceptibility.