Mammary intraepithelial neoplasia outgrowths (MINO): MINO and human ductal carcinoma in situ

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.