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An Immunotolerant HER-2/neu Transgenic Mouse Model of Metastatic Breast Cancer

Authors' Affiliations: Divisions of ¹ Nuclear Medicine, ² Neuroradiology, ³ Magnetic Resonance Research, and ⁴ Medical Imaging Physics, ⁵ Russell H. Morgan Department of Radiology and Radiological Science, Department of Molecular and Comparative Pathobiology, and ⁶ Sydney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: George Sgouros, Johns Hopkins University School of Medicine, Cancer Research Building II, Room 4M.61, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-614-0116; Fax: 413-487-3753; E-mail: gsgouros{at}jhmi.edu.

Purpose: Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies.

Experimental Design: The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry.

Results: Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody.

Conclusion: The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.