Abstract
Mouse models of human mammary intraepithelial neoplasia have been described in a number of contexts. In general, descriptions of early stages of progression in genetically engineered mice that go on to develop invasive and even metastatic carcinomas are compared with human ductal carcinoma in situ (DCIS). In some instances, lesions with phenotypic similarity to human DCIS are compared, even without evidence of progression. The terminology for these processes in the mouse mammary gland requires precise definition. Otherwise, it is impossible to compare the variety of available models for study utility. Experimentally driven operational definitions are optimal. We have studied a series of transplantable mammary intraepithelial neoplasia outgrowths (MINOs) derived from the transgenic mouse mammary tumor virus promoter-driven polyoma virus middle T oncogene FVB mice. We have characterized their behavior experimentally and morphologically. Experimentally, these MINOs meet the most stringent criteria to be considered premalignant. They are capable of orthotopic growth in the gland cleared mammary fat pad, are without being capable of ectopic (subcutaneous) growth, and have a consistent transformation to the fully malignant behavior (capable of ectopic growth)–defined therefore as invasive carcinoma. Morphologically, there is a high degree of heterogeneity both within and between individual MINO lines. Nevertheless, all consistently transform to behaviorally and morphologically similar carcinomas. MINOs therefore compare closely with human DCIS. Human DCIS is similarly defined by its universal potential (if incompletely treated) to progress to invasive carcinoma, despite heterogeneity within a given breast or between individual patients. We extend the comparison using immunophenotypic analysis, and gene expression analysis. Overall, our goal is to better model human DCIS, in a reproducible and robust mouse model system suitable for interventional studies. By creating a serially transplantable series of MINOs we have removed much of the variability which would otherwise confound such study. Derivation of MINOs from a variety of genetically engineered mice backgrounds may provide additional critical reagents for the preclinical study of DCIS.
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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