Abstract
Comparative genomic approaches have been used extensively to identify DNA sequences involved in the regulation of conserved human genes. These approaches are indeed powerful, permitting the ~5% of the genome that is comprised of critical functional elements to be distilled from the background of non-conserved DNA. Using genome alignment tools, promoters, enhancers and other types of regulatory sequences can be identified, providing ready access to DNA sequence elements that are difficult to identify by other means. Comparative genomic alignments can also reveal the presence of novel genes. However, while most studies focus on sequences that are similar between the human and the mouse, the differences between the two genomes are also revealing, exposing different mechanisms of gene regulation and function and even gene-content differences in humans and rodents. Both the similarities and differences in genomic structure are critical to the interpretation of rodent models for human disease. We are using comparative genomic approaches to define genes and regulatory elements associated with imprinting and developmental disorders in the mouse model system. I will discuss new data arising from the analysis of mouse mutant models expressing developmental disorders and susceptibility to cancer. In each case, comparative genomics approaches have been critical to identification of genes and regulatory elements that are central to development of disease-related symptoms in the animals. Differences in gene regulation and structure revealed by these studies will also aid in exptraloting results from these mouse models to similar diseases in human patients.
Highlights
The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer
We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERαnegative tumors. p53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells
Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors
Summary
Transgenic Oncogenesis Group, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA. The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, remain problematic. P53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells. These tumors have a high rate of metastasis that is independent of tumor latency. Since it is feasible to isolate ERα-positive epithelial cells from normal mammary glands and tumors, molecular mechanisms underlying ERα-positive and ERα-negative mammary carcinogenesis can be systematically addressed using this model
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