A genetic 'gang of 4' drives spread of breast cancer

Studies of human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies by Howard Hughes Medical Institute researchers reveal that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.

Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis. Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis.

In the newly published experiments, the researchers also found that they could reduce the growth and spread of human breast tumors in mice by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. The researchers are exploring clinical testing of combination therapy with the drugsЧcetuximab (trade name Erbitux) and celecoxib (Celebrex)Чto treat breast cancer metastasis.

The research team, led by Howard Hughes Medical Institute investigator Joan Massaguй at the Memorial Sloan-Kettering Cancer Center, published its findings in articles in the April 12, 2007, issue of the journal Nature and in the online early edition of the Proceedings of the National Academy of Sciences on April 9, 2007.

In an earlier study, Massaguй and his colleagues had identified 18 genes whose abnormal activity is associated with breast cancerТs ability to spread to the lungs. In the new study published in Nature, Massaguй and his colleagues at Sloan-Kettering, along with researchers from Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, focused on four of these genes. These genes, which code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to help regulate growth and remodeling of blood vessels, said Massaguй.

"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 Massaguй. "These same genes, we believed, might also be used for some related purpose in the target organ, the lung."

To test this idea, the researchers silenced various combinations of the four genes in human breast cancer cells that had metastasized to the lung, and then tested these cells in mice. To silence the four genes, the scientists used a technique called RNA interference, in which RNA molecules are tailored to suppress expression of target genes.