Abstract
Premalignancy in mouse models has been studied for the past 50 years. These present as epithelial hyperplasia; several types of which occur in the mouse mammary gland depending on the initiating stimulus. Alveolar hyperplasias are frequently observed in models where mouse mammary tumor virus, hormones or chemical carcinogens are the initiating agents. Ductal hyperplasias are frequently observed in genetically engineered models where specific oncogenes have been deregulated. The premalignant nature of these lesions can be verified by transplantation into the mammary fat pads of either syngeneic or immunocompromised mice. The alveolar hyperplasias generate tumors that are frequently estrogen-receptor negative and diploid, although metastatic to lung. Estrogen receptor expression is downregulated early in premalignant progression, often when the hyperplastic lesion is first identified. The ductal hyperplasias progress through ductal carcinoma in situ and generate tumors that are frequently estrogen-receptor negative but the tumors are aneuploid. In recent years, premalignancy in genetically engineered mice has been extensively characterized at the biological level in p53 null mammary epithelium and in polyoma MT mammary gland, and to a lesser extent in the SV40LT antigen mammary gland. The molecular alterations in these lesions are beginning to be analyzed by array methodologies. These models provide the opportunity to identify early events causal in premalignant progression as well as to test the efficacy of agents that prevent progression.
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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