Cancer code-breakers: N.J. team pinpoints gene that helps tumors spread

The Record (Hackensack N.J.) (MCT) - A gene that makes breast cancer tumors more likely to resist chemotherapy and to spread to other organs has been identified by a team of New Jersey researchers.

The "metastasis gene" is turned on in 30 percent to 40 percent of breast cancer patients. When activated, it helps the tumor cells stick tightly to blood vessels in distant organs and makes them resistant to chemotherapy drugs traditionally used to treat breast cancer, according to researchers from Princeton University and the Cancer Institute of New Jersey.

Their study was published in Monday's edition of the journal Cancer Cell.

With more than 180,000 women a year hearing the dreaded diagnosis of breast cancer, the potential benefit of the research is great.

It could lead to the development of a test to screen for the gene in breast tumors and medication to block the gene's activity. A medication would not only help prevent metastases to distant organs, but enable chemotherapy to benefit more women, helping to prevent recurrences of breast cancer.

"There's the potential of coming up with one stone that hits two birds," said Dr. Yibin Kang, a molecular biologist at Princeton University who led the research. "If you come up with a therapy that inhibits the gene, it could make the tumor more susceptible to chemotherapy and at the same time reduce the chance for a tumor to spread."

The newly identified gene _ called Metadherin, or MTDH _ was found in 30 percent to 40 percent of the tumor samples examined.

"We are currently talking with companies like Johnson & Johnson for them to pursue development of antibodies to the gene," Kang said.

A test for the gene might be similar to the one that analyzes tumors for a variant of the HER2 gene, which makes cancer cells divide more rapidly. Women that test positive for HER2 can be treated with Herceptin, a targeted therapy that interferes with that gene's activity.

The gene also appears to play a role in prostate cancer metastases, said Kang, who is preparing an article on that research. The same genetic variant is found in about 20 percent of prostate cancer patients, he said.

The breast cancer study analyzed the genetic makeup of samples of breast cancer tumors from a tumor bank at the Cancer Institute of New Jersey.

The study found that tumors with the MTDH gene variant were more resistant to the common chemotherapy drugs paclitaxel, cisplatin and adriamycin.

Breast cancer is the leading cause of cancer death in women, claiming 40,000 lives a year in the United States. Metastasis, or the spreading of the cancer to another part of the body, and chemo-resistance are the two biggest challenges to curing breast cancer.

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More than 90 percent of deaths due to breast cancer result not from tumors in the breast, but from those that have spread to other organs _ most commonly the bones, lungs, liver and brain. If confined to the breast, breast cancer is seldom fatal: chances of survival are 98 percent after five years. Once the cancer has spread beyond the lymph nodes to other organs, chances of survival are reduced to 27 percent, according to the National Cancer Institute.

Understanding cancer's spread to other organs has long been a goal of researchers. Cells break away from the primary tumor _ usually found as a lump in the breast _ and travel elsewhere in the body where they "seed" new cancers in a complex process.

The same issue of Cancer Cell published Monday includes a separate study about a newly identified enzyme that also plays a role in breast-cancer metastases. The enzyme "works by sending out signals to prepare a new area of the body for the cancer to set up a camp," according to the lead researcher, Dr. Janine Erler of The Institute of Cancer Research in London.

Scientists now believe that "this breaking away and seeding new areas happens continuously throughout the disease," said Dr. Michael Reiss, another author of the genetic paper and director of the Breast Cancer Research Program at the Cancer Institute of New Jersey in New Brunswick.

Every cancer metastasis "starts off as a single cancer stem cell spawning," he said. "They're relatively resistant to chemotherapy and much harder to kill."

A person's genetic information is contained in 23 pairs of chromosomes, which normally contain two copies of a given gene, conveyed by the mother and the father. The study found that a very small area of human chromosome 8 contained multiple repeats of the MTDH gene. This "over-expression" of the MTDH gene resulted in production of certain proteins that made the cells stick more readily to blood vessel cells and to resist chemotherapy.

The strategy used to pinpoint this gene will be valuable in further cancer research, Reiss said. It relied on bioinformatics, or computer analyses of massive databases of genetic information on breast cancer tumors, as well as experiments with mice engineered to test the effects of the gene variation. Finally, the results were checked against human tumor specimens. Ten scientists are listed as authors of the study.

The three-year study was funded by grants from the Department of Defense, the National Institutes of Health, the American Cancer Society, the Susan G. Komen Foundation and the New Jersey Commission on Cancer Research.

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