Elucidation of the molecular mechanisms underlying breast cancer progression and metastasis has gained tremendously from mouse models in which the multiple stages of tumor progression are recapitulated. However, despite their obvious convenience in basic cancer research and in the testing of experimental therapies, the use of mouse models carries several limitations. There are obvious differences between human and mouse tumorigenesis, among which are the kinetics of carcinogenesis and the final size of tumors, differences in cell intrinsic features such as the requirements to transform cells, and differences in organ-specific gene expression, in physiology, metabolism, pathology, and in the immune system. Moreover, metastatic dissemination occurs mainly via hematogenous spreading to lungs and lymph nodes in MMTV-PyMT and MMTV-Neu mice, as opposed to the initial spreading of cancer cells to local lymph nodes via the lymphatics in human breast cancer.
Another important aspect to the understanding of breast cancer metastasis is the role of different subpopulations of breast cells, including cancer stem cells. A great effort is put into their isolation by means of molecular markers or functional assays. The use of transplanted breast cancer stem cells isolated from mice harboring different genetic modifications thereby offers a valuable tool not only in the unraveling of breast cancer development but also in designing effective therapeutic strategies.
Recent technological advances have greatly improved the use of animal models in breast cancer research, such as the use of bioluminescence and fluorescence systems, magnetic resonance, positron-enhanced tomography scans or in vivo confocal analysis to image tumor development in live animals, also allowing observation for long periods. Moreover, extended time-lapse observation of labeled tumor cells in vivo provides new insights into the actual dynamics of tumor growth, extravasation, cell migration, and organ colonization, as well as the contribution of the tumor stroma and subsets of immune cells. Finally, gene expression analysis of tumor samples matched with normal tissue from patients will provide gene signatures that will have to be tested in vivo by proof-of-concept experiments in reliable mouse models of breast cancer metastasis.
In the future it will be necessary to generate mouse models that more accurately recapitulate human breast carcino-genesis, while offering the advantages of model systems, such as easy genetic or pharmacological manipulation and imaging. The quest for such improved models has just begun.