Mechanisms of breast cancer brain metastasis
Authors: Brunhilde Felding-Habermann, Emily Chen, Joseph Krueger, Mihaela Lorger, Karin Staflin, John Yates, Patricia Steeg, Diane Palmieri, Joan Kroener
Journal: Cancer Research (2008)

3674   Brain metastases are among the most feared complications in breast cancer without effective therapies. Successful prevention and treatment will depend on specific knowledge of mechanisms that allow breast cancer cells to enter and colonize the brain.  We established novel models for human breast cancer brain metastasis in immune deficient mice, following the tumor cells by non-invasive bioluminescence imaging. After injecting the tumor cells into the venous circulation or internal carotid artery, the tumor cells colonize the brain and disseminate within the central nervous system as seen in breast cancer patients. Our unique cell models allow us to investigate mechanisms that circulating breast cancer cells use to arrest within the cerebral microcirculation, penetrate the blood brain barrier, and thrive within the brain tissue.  Large scale proteomic profiling of in vivo selected brain homing variants of our new cell lines and direct implantation of the tumor cells into the brain tissue revealed that tumor cell entry into the brain, and survival and growth within the brain microenvironment require distinct functional pathways. We found that expression of certain genes can compensate for each other in promoting tumor cell survival, once the cells have reached the brain. Survival and growth supporting genes that can act in concert, or independently, are b3 integrin and Her-2. Regardless of the proliferation driving genes, however, the tumor cells apparently adapt their metabolic properties to the unique energy metabolism of the brain. We found significant alterations in protein expression profiles and associated functions in breast cancer cells from brain lesions, indicating stable changes in the energy metabolism of these cells. Brain metastatic cells show pronounced increases in enzymes involved in oxidative glucose metabolism, tricarboxylic acid cycle and oxidative phosphorylation pathways suggesting that the brain metastatic cells - like neuronal cells - derive energy at high efficiency almost exclusively from glucose oxidation. This contrasts most other tumor cells from primary tumors and extracranial metastases, as these cells follow the less energy efficient Warburg pathway and metabolize glucose to lactate. A very important change that the brain metastatic breast cancer cells also undergo allows them to detoxify reactive oxygen species which result as byproducts from the oxidative pathways and mitochondrial activity. Thus, a subset of breast cancer cells may evolve during malignant progression that is capable of gaining entry to the protected environment of the central nervous system. Once there, surviving tumor cells depend on the expression of key genes and can differentiate along pathways that allow the cells to adapt and thrive within the brain microenvironment. Our study raises the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy.