A gene 'thumbprint' was found in a group of 82 early stage breast tumors removed from patients. More than half of the patients whose primary tumors showed the genetic thumbprint went on to develop lung metastases, compared with only 10 percent of those whose primary tumors did not carry the gene set.

The findings shed new light on the biology of breast-cancer metastasis, and could lead to a possible prognostic tool and new targets for treatment, say the researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) who identified the genes.

"Our work shows that the ability of a tumor to form metastases depends on the combined action of multiple genes -- and a different set of genes is required for each organ the tumor spreads to," said Joan Massagué, PhD, Chairman, Cancer Biology and Genetics Program, at MSKCC, who led the study.

"Based on these insights, we can now seek genes for metastasis by other tumors and to other organs," added Massagué, who is also a Howard Hughes Medical Institute investigator.

Gene 'Thumbprint'

Prior to this research, it was assumed that genes that dictate metastases to specific organs did not exist. In a 2003 study, Dr. Massagué and his colleagues identified a gene pattern in breast-cancer cells that are prone to spread to bone. Surprisingly, the latest work shows that the genes that prompt breast tumors to spread to the lungs are almost entirely different from the earlier set, with only six genes in common.

In order to pinpoint the genes involved in breast-cancer metastasis, Dr. Massagué’s group used a cell line from a breast cancer patient treated for aggressive tumors that had spread to many other organs. From this line, they identified cancer cells that showed a propensity for migrating to the lungs, but not the bone, when transplanted into mice.

To see how the genetic activity of those cells differed from breast-cancer cells that did not show a tendency to spread to the lungs, the researchers used a microarray, or "gene chip." They observed that some genes functioned more vigorously than usual, while the activity of others was suppressed.

The gene "thumbprint" was verified in a group of 82 early stage breast tumors removed from patients at MSKCC. More than half (55 percent) of patients whose primary tumors showed the genetic thumbprint went on to develop lung metastases, compared with only 10 percent of those whose primary tumors did not carry the gene set.

How Metastatic Ability Is Acquired

"Metastasis, particularly to visceral organs, such as the lung, accounts for the majority of breast-cancer related mortality," said Andy J. Minn, MD, PhD, a radiation oncologist at MSKCC and first author of the Nature paper.

The new research "may provide genetic markers to aid oncologists in clinical management, offer potential therapeutic targets to develop drugs against metastasis, and give basic researchers a paradigm to understand how metastatic ability is acquired," Dr. Minn said.

As the gene thumbprint is narrowed to as small a set as possible, researchers could develop diagnostic tests that incorporate this genetic information, Dr. Massagué noted. The research team also is looking for similar patterns of gene activity in other cancers with a proclivity to spread to the lungs.

There are drugs already on the market that target a few of the genes discovered in the new study, Dr. Massagué pointed out. "If you can successfully target these genes with a drug, you are helping slow the growth of any primary tumor and also blocking the growth of any tumor cells that have spread to the lungs," he explained.

The next step for the researchers is a study involving a larger number of breast cancers, including those from patients at other medical centers. They also are searching for gene patterns in other forms of cancer that often spread to the lungs.