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Researchers identify gene set linked to breast cancer's spread to lungs

July 28, 2005

In a potential advance for the treatment of aggressive breast cancer, scientists at Memorial Sloan-Kettering Cancer Center (MSKCC) have identified a set of genes in breast tumors that appear to predict if the disease will spread to the lungs and, once there, how virulent it will become. The findings shed new light on the biology of breast cancer metastasis, and could lead to a possible prognostic tool and new targets for breast cancer treatment.

"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. The findings appear in the July 28, 2005 issue of Nature.

In a 2003 study, Dr. Massagué and his colleagues identified a gene pattern in breast cancer cells that are prone to spread to bone. 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. This finding is surprising as it had been previously assumed that genes that dictate metastases to specific organs did not exist.

To uncover 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.

Using a microarray - or "gene chip" - the researchers were able to analyze the cells to see how their genetic activity differed from that of breast cancer cells that did not show a proclivity for lung metastases in the rodents. Some genes function more vigorously than usual while the activity of others was suppressed.

The gene "thumbprint" was then 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.

"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 is also looking for similar patterns of gene activity in other cancers with a proclivity to spread to the lungs.

Dr. Massagué added that there are drugs already on the market that target a few of the genes discovered in the new study. "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 said.

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 are also searching for gene patterns in other forms of cancer that often spread to the lungs.

Memorial Sloan-Kettering Cancer Center