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Mammary pathology of the genetically engineered mouse

Human breast cancer has been modeled in well over 100 types of genetically engineered mice (GEM). Many of the mutated or overexpressed genes found in human breast cancer also initiate mammary cancer in GEM. The histopathology of GEM models of breast cancer have proved to be unique. Most GEM tumors do not resemble the spontaneous tumors induced by the mouse mammary tumor virus (MMTV) or by carcinogenic agents. The pattern of some GEM tumors closely resembles that seen in some human breast cancers. The most provocative and most thoroughly studied GEM group belongs to the ERBB2 (HER2) signal transduction pathway. GEM bearing ERBB2, various forms of mutated ERBB2 and ERBB2-related genes produce tumors via similar molecular mechanisms, and also have a remarkable morphological resemblance to some forms of human breast cancer. Tumors associated with tumor suppressor genes, such as Brca1 and SV40 Tag (that suppresses expression of Rb and p53) tend to resemble poorly differentiated tumors and, in some cases, medullary carcinoma of the human breast. Many of the GEM develop mammary tumors with characteristic or unique gene-specific 'signature' phenotypes that readily can be identified microscopically. The principle that genotype predicts phenotype can be applied to other GEM and extended to include entire molecular pathways. Studies of tumor kinetics in bi-transgenic mice suggest that some combinations of genes are synergistic while others are inhibitory. Although the majority of breast cancer models have been induced using the MMTV-LTR as a promoter, C3(1), WAP, and BLG promoters frequently have been used. Tumors retain the phenotype characteristic of the oncogene, for the most part, regardless of promoter. In some cases, inserting the transgene behind the native promoter or 'knocking-in' an oncogenic variant at the normal gene locus has also resulted in tumors characteristic of the oncogene. GEM with inactivation of tumor suppressor genes generally die with tumors other than mammary tumors. The mammary tumors that do develop tend to be more poorly differentiated, aneuploid tumors with a wider range of phenotypes. However, when crossed with GEM bearing activated transgenes, the tumors are most likely to resemble the phenotype of the transgene. The tumors in bigenic mice do, however, have more pleomorphic and aneuploid cells. The great majority of mouse mammary tumors are hormone independent. This is in contrast to human breast carcinomas, 50% of which express the receptors for estrogen and progesterone, and are dependent (at least partially) on these hormones for growth. The biology of metastasis is also quite different with mouse carcinomas displaying a hematogeneous spread almost exclusively to the lung and with human carcinomas displaying regional lymph node involvement with preferential systemic spread to the bone, brain and liver.

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Borowsky, A. Mammary pathology of the genetically engineered mouse. Breast Cancer Res 5 (Suppl 1), 11 (2003).

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