New study offers clues to how breast cancer spreads

Findings published in March issue of cancer research

Washington, DC – A new study published by researchers at Georgetown
University's Lombardi Cancer Center, in collaboration with researchers at Yale University, has identified two molecular predictors of breast cancer spread, or metastasis. This study may one day lead to tests of breast cancer tissue that will help physicians determine whether a woman's breast cancer is likely to spread, or metastasize.

Currently, physicians have no precise way of knowing which women's breast cancer will later spread. This new research may help doctors avoid use of chemotherapy in women who they identify as statistically unlikely to metastasize. In addition, the research may have identified a new target for future therapeutic drugs to treat and/or prevent the disease.

"Most women diagnosed with breast cancer that has not spread to their lymph nodes would do well in the absence of chemotherapy, but because physicians lack tools to precisely identify those women least likely to relapse, they often over-treat patients," said Dr. Robert Dickson, professor of Oncology and co-Director of the Breast Cancer Program at Lombardi Cancer Center. "This research may lead us to a place where we can test tissues taken during surgery and rule out a group of women whose cancer is unlikely to spread, saving them and their loved ones the added health and financial burdens associated with chemotherapy. The research may also lead us to a new targeted way to treat cancers at risk of spreading."

Dickson and his Lombardi colleagues, Drs. Baljit Singh and Chen Yong Lin, as well as colleagues at Yale University, honed in on two inter-related pairs of promising molecular predictors of breast cancer metastasis. The first pair is comprised of matriptase, a protein-cleaving enzyme which was first identified in Dickson's lab, and a protein known as HAI-1, that shields cells from toxic effects from matriptase. The second pair of proteins consists of HGF and c-Met, which comprise an important growth factor receptor system, already known to be involved in breast cancer.

Matriptase is found on the surface of healthy cells in the body and in some cancer cells, including breast cancer. Whereas in normal tissue, matriptase is only briefly activated under very specific controlled circumstances, it is always turned on in cancerous cells. In this new study, 330 women with non-metastatic breast cancer were followed for 30 years after surgical treatment of the disease. High levels of both matriptase and HAI-1 were found to be predictors of breast cancer that was likely to metastasize and cause early death.

The researchers also found that the presence of both c-Met and HGF, one a well-known cell receptor and the other a protein that turns on the metastatic switch in breast cancer – is associated with the spread of the cancer. In the new study, 3 of these proteins – HGF, c-Met, and matriptase – were commonly found in individual human breast cancers, another indicator that they will work together to help the cancer spread. "We have previously found that matriptase serves to activate HGF, which like flicking a light switch, flips on the metastatic switch in breast cancer," said Dickson. "Now we can think of it this way – if c-Met is the switch and HGF the finger that flips the switch, matriptase makes a hole in the mitten to let the finger stick out to touch the switch."

"The more we understand about the basis and predictors of metastasis, the closer we get to saving lives," said Dr. Claudine Isaacs, associate professor of Oncology and co-director of Lombardi's Breast Cancer Program. "People die from the spread of cancerous cells, not the initial cancer. This study gives us a better grasp of the molecular predictors of breast cancer metastasis, and may provide us a way to make more informed treatment decisions based on a woman's risk."

This work was supported by grants from the National Institutes of Health (to the Lombardi Cancer Center) and the William and Catherine Weldon Donaghue Foundation for Medical Research (to Yale University).

The Lombardi Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 39 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington DC area.

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