The researchers implanted human breast cancer cells in mice and found metastasis activated by a quartet of genes working in tandem with each other.

Cancer is the uncontrolled growth of cells where the physiological death of cells is also impaired. Cancer is basically of two types. It is benign when the cancerous cells are confined to a boundary and do not invade adjacent cells. However most breast cancers are of a malignant nature, meaning they invade and spread through adjacent cells and tissues.

Metastasis occurs when cells from a primary cancer break off and enter the bloodstream or the lymphatic system to travel to far off organs where they begin dividing and proliferating once again. Whether it is in the blood or the lymph, the spreading cancer cell stops at the first place it gets stuck.  Because of the rich capillary network, lungs are a very common site of cancer spread.

The process of metastasis remains a mystery prompting scientists to speculate genetic involvement. In June 2004 researchers from the Whitehead Institute for Biomedical Research suggested in the journal Cell that cancer spreads by hijacking an existing cellular process and use it to disperse throughout the body.

But specific gene involvement came to light in 2005 when Dr Joan Massagué from the Memorial Sloan-Kettering Cancer Center and colleagues identified 18 genes that help in spreading breast cancer to the lungs.

In the current study Massagué and his colleagues at Sloan-Kettering worked with researchers from Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain to hone in on the activity of four of these genes.

The details are reported in the April 12 issue of the journal Nature.

The four genes identified are EREG, MMP1, MMP2 and COX2. They code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2. Massagué says these genes were already playing a prominent role in regulating growth and remodeling of blood vessels.

“Our understanding of the genes for these four proteins and their behavior in metastasis led us to hypothesize that they might be cooperating with each other in a way that would give an advantage to cells in the primary tumor,” said Massagué.

In order to test if these genes could be silenced, the researchers used a technique called RNA interference. Here RNA or ribose nucleic acid molecules are tailored to suppress expression of target genes.

“The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumor growth and spread," Massagué said.

Furthermore microscopic analysis on the tumors revealed that switching off all four genes managed to reduce the tangle of blood vessels typically seen inn cancer cells. “These findings provide a beautiful explanation for how the genes that we identified in breast cancer patients as being associated with lung metastasis manipulate blood vessels to give them an advantage both in the primary tumors and in the lung,” Massagué said.

In additional step researchers studied the effect of three drugs in silencing the four genes involved in spreading breast cancer to the lungs. They used the cancer drug Erbitux, the anti-inflammatory drug Celebrex, and an experimental anti-inflammatory drug to target the four genes. A control group of mice was not given any drug.

The drug combination halted the spread of breast cancer to the lungs in the mice. “We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective,” said Massagué. “This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis."

In an article published in the Proceedings of the National Academy of Sciences, Massagué and his colleagues examined how a group of 18 genes called `lung metastasis gene-expression signature' (LMS) works in growth and spread of breast cancer.

The next step according to the researchers is to identify if the same genes are involved in spreading breast cancer to the bones, colon and the brain.