Researchers have identified a molecular mechanism by which breast cancer metastases promote bone destruction. Inhibition of this process may help prevent one of the most common—and most agonizing—complications of breast cancer.

Tumors of the breast are the most common form of cancer among women in developed countries. Breast cancer frequently spreads to the bones; indeed, more than half of patients develop osteolytic skeletal lesions. These women endure unrelenting pain and an increased risk of pathological fracture and hypercalcemia.

In a recent paper in Nature Medicine (January), Cun-Yu Wang at the University of Michigan (Ann Arbor) and coworkers have identified what purports to be the molecular culprits at the root of the bone resorption associated with breast cancer: nuclear factor- κB (NF-κB) and granulocyte macrophage-colony stimulating factor (GM-CSF). Researchers have long considered NF-κB a dangerous molecule that aids and abets developing tumors in many kinds of cancer. Wang and associates, however, are the first to report a causative connection between NF-κB, GM-CSF, and the bone destruction associated with breast cancer.

Two experiments were essential in leading Wang's team to these conclusions, both of which involve a murine model of osteolytic bone metastasis created by injecting breast cancer cells into the left cardiac ventricles of immunodeficient mice. In the first experiment, cancer cells modified to repress NF-κB were injected into mice; of these, far fewer developed bone lesions as compared to controls, and of those that did develop lesions, they were smaller than those of control mice injected with unmodified tumors.

Next, Wang and colleagues examined the gene expression differences between the two types of cells and determined that some genes, including the one for GM-CSF, were not expressed as much in the cells with NF-κB repression than in unmodified tumor cells. These findings were unexpected considering that GM-CSF is used in some instances as a therapeutic agent to stimulate the recovery and proliferation of the blood cells killed by chemotherapy. Therefore, in a second experiment, Wang and colleagues injected mice with the NF-κB-repressed tumor cells used before, as well as NF-κB-repressed cells that they had modified to artificially increase GM-CSF expression. The former cells caused little or no bone lesions, but the latter caused extensive bone lesions and damage.

The next step for researchers is to turn these findings into practical treatment regimes. It may be possible, for instance, to limit or prevent bone metastasis of breast cancer by blocking NF-κB or GM-CSF in cancer patients. Alternatively, increased GM-CSF might be used to flag patients with a high risk of bone metastasis.