Advances in Clinically Relevant Metastatic Breast Cancer Models

Once breast cancer has been diagnosed, the most important question is whether the cancer is confined to the breast or has spread to distant sites. The majority of the death of women with breast cancer result from the growth of metastases that do not respond to therapy.(1) The development of more effective therapies should be based on a better understanding of the mechanisms responsible for the spread of cells from the breast to distant sites, including lymph nodes, bone, brain, liver and lungs. A variety of in vitro and in vivo models have been developed to study the biology of metastasis.(2) In general, in vitro assays have been designed to model distinct steps in the process, for example, invasion through the reconstituted basement membranes,(3) or specific binding to endothelial cells isolated from organs where the cancer cells commonly form metastases.(4,5) Such in vitro assays have great practical value for evaluating specific tumor cell behaviors, yet their limitations for predicting in vivo malignancy should always be considered. It is probably impossible to simulate accurately all the events of the metastatic process with in vitro models, especially considering the events that involve interactions with components of the microenvironment at the site of metastasis.(6) Thus, animal models using transplantable tumors that can grow and metastasize predictably in a suitable host have become standard systems for analyzing the metastatic phenotype and testing the efficacy of anti-metastatic therapies. The most common animal models are rodent tumor models, using transplantable tumors, or spontaneously arising or carcinogeninduced mammary tumors of rats and mice.(7) More recently, transgenic mice with different oncogenes targeted to the mammary epithelium have become available and some are suitable for testing specific forms of therapy, such as those designed for tumors that overexpress HER2/neu.(8,9) Immunodeficient rodents, most commonly athymic (also known as nude) of SCID mice, have been used widely for xenograft studies with human cancers. Not all human cancers or established tumor cell lines will successfully grow in immunodeficient mice, at least from a subcutaneous (s.c.) route of inoculation, the most common and for practical purposes the easiest technique to use. The approach of injecting human tumor cells into the normal equivalent mouse organ, known as orthotopic injection, has been adopted as a way to improve tumor take and growth, and has also been shown to increase Despite advances in surgical and clinical management, metastatic disease, notably to the lungs, liver, bone, and brain is the most common cause of death from breast cancer. Two basic principles govern the process of metastasis. First, that the tumors are heterogeneous populations of cells, and second, that the process of metastasis is a sequence of events that depends on tumor cell properties and interactions with the microenvironment at the sites of metastasis. In theory, inhibitors targeted at any of the steps of metastasis have the potential to inhibit metastatic progression. In vitro assays cannot simulate accurately the complex process of metastasis, and the use of appropriate animal model is necessary to model the process, and to test the impact of targeted inhibitors on the growth and development of breast cancer metastasis. Animal models for growth and metastasis of rodent and human breast cancer cells have been developed, including models that target the metastatic growth in key organs such as the bone and brain. (Journal of Korean Breast Cancer Society 2004;7: 141-147) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ