Special considerations in mouse models of breast cancer.

Literally thousands of specifically engineered mice have been created to study the pathology, molecular biology, natural history and response to therapy in breast cancer. The incredible success of mouse models of breast cancer stems from several important foundations in mouse mammary biology. First, the biology of the mouse mammary gland has been studied for many years. The normal development, lactation related changes and spontaneous tumors in the mouse mammary gland are well characterized. Second, several mammary specific gene promoters have been characterized, permitting ready transgenic engineering to incorporate genes into the mammary glands of mice [1]. Third, the mammary gland of mice is transplantable, using technology pioneered in the 1960’s where mammary tissue is transplanted into the gland cleared mammary stroma [2]. The only other organ system where this has been possible until very recently is the hematopoetic system, and this has also been a great boon to the study of leukemia for the same reasons. Chiefly, this orthotopic transplantation permits the experimental evaluation of the growth and malignant behavior potential of isolated tissues or cells [3]. Much more recently, transplantation technology has been developed for the CNS and prostate [4,5]. Nevertheless, several important challenges to the validity [6] of the mouse models of breast cancer remain. Few of the models are accurate representations of the estrogen receptor (ER) positive human breast cancers. Metastases which occur in several models are hematogenous and almost exclusively pulmonary, whereas human breast cancers metastases are characterized by nearly universal lymphatic spread and nodal metastasis which precedes or is synchronous with disseminated hematogenous metastasis. Human breast cancer does metastasize to the lung, but also commonly to the liver and bone, and these sites are rarely affected in the mouse models without specific designs to adapt the cells for this homing. Many of the extant genetically engineered mouse models have been previously reviewed and categorized [7,8]. As a gross oversimplification, the existing models can be grouped into two categories: (1) transgenic models, those with specific oncogene expression, usually through highly active mammary specific promoter driven expression, and (2) gene targeted models, those with an increased susceptibility to mammary tumorigenesis, usually through gene targeting (knockout) of a tumor suppressor. Each of these methods has specific strengths and problems. The overexpression of an oncogene in the mouse mammary gland results in multifocal (nearly diffuse) expression throughout the luminal epithelium of all of the mammary glands of the genetically engineered mouse. As a result, multifocal tumorigenesis is the rule in these animals. The tumor phenotypes are directly related to the oncogene such that “signature” phenotypes are now recognized for a handful of molecular activation “pathways” [9]. In many instances, individual genes within a given pathway have been shown to result in tumors with identical phenotypes. This has provided functional proof, in fact, that the molecular models are correct. In contrast, tumor suppressor knockout mice typically develop tumors after longer latency. Even with-