Choosing a mouse model: experimental biology in context--the utility and limitations of mouse models of breast cancer

Abstract

Genetically engineered mice are critical experimental models for the study of breast cancer biology. Transgenic mice, employing strong mammary epithelial promoters to drive oncogenes, develop carcinomas with phenotypes corresponding to the molecular pathway activated. Gene-targeted (knockout) mice, in which tumor suppressors are deleted, develop mammary neoplasms with phenotypes primarily including patterns seen in spontaneous mouse mammary tumors, albeit at higher rates. Improved genetic engineering, using inducible gene expression, somatic gene transduction, conditional alleles, and crossbreeding for combined/compound genetic engineering yields precise molecular models with exquisite experimental control and phenotypes with comparative pathologic validity. Mammary gland transplantation technology adds a practical and validated method for assessing biologic behavior of selected mammary tissues. Overall, the many mouse models available are a rich resource for experimental biology with phenocopies of breast cancer subtypes, and a variety of practical advantages. The challenge is matching the model to the experimental question.

Figure 1.

The test by transplantation. Transplantation in orthotopic or ectopic sites provides an experimental definition for normal (A), hyperplastic (B), precancer (C), or cancer (D) in mammary epithelial tissues. Fresh tissue fragments can be harvested from a “donor” mouse and transplanted into a “recipient” mouse, either in the orthotopic site—a gland-cleared mammary fat pad—where the tissue proximal to the lymph node in the inguinal mammary stroma is removed at 3 weeks of age; or, in an ectopic site such as subcutaneous stroma. (A) Normal tissue transplanted into the orthotopic site yields a normal gland outgrowth, but does not grow ectopically. After sequential “serial” transplant generations, the normal tissue will senesce, eventually resulting in no outgrowth. (B) Hyperplasias, in contrast, will not senesce after multiple serial transplant generations, but they still will not grow ectopically. (C) Precancer tissues are defined by immortal growth in serial transplantation, but are also defined by a progression to a lesion that will grow ectopically. (D) Cancer tissues, meanwhile, are consistently able to grow in either the orthotopic or ectopic site.