Protein associated with aggressiveness in breast & ovarian cancer

A research team led by The University of Texas M. D. Anderson Cancer Center has found a potential new protein marker for prognosis of breast and ovarian cancer.

In the November, 2004 issue of the journal Nature Medicine, the researchers report tumor cells that "overexpress" the protein Rab25 are more aggressive and associated with poorer outcome. Thus, Rab25 could represent a novel therapeutic target or marker of tumor behavior, they say.

The researchers matched tumor samples to outcomes in about 100 patients diagnosed with either breast or ovarian cancer and found that a low level of Rab25 protein on a patient's cancer sample was associated with a better clinical outcome in both cancer types. For example, patients with early stage (I and II) ovarian cancer who had low Rab25 tumor expression had an 80 percent survival five years after treatment, compared to 50 percent survival if Rab25 expression was high. In women with advanced breast cancer, a low level of Rab25 protein expression was associated with a 60 percent five-year survival, compared to 40 percent if Rab25 protein expression was high.

Adding this protein to other known molecular markers of progression could contribute to a "highly predictive test of outcome in breast or ovarian cancer," says the study's lead investigator, Gordon Mills, M.D., Ph.D., a professor and chair of the Department of Molecular Therapeutics at M. D. Anderson.

He adds that the protein might also, one day, be a target for cancer treatment. "We are pursuing Rab25 both as a test for outcomes and as a possible treatment."

Researchers from Lawrence Berkeley National Laboratory, the University of British Columbia, the University of California San Francisco, and Northwestern University participated in the research study, which was funded by the National Cancer Institute and the U. S. Department of Defense.

The study is the first to link Rab25 to cancer, although several other members of the large Rab family of proteins, and the even bigger Ras protein superfamily to which it belongs, have been linked to the disease, says Mills. Members of the Ras protein family are mutated in a significant percentage of cancers, he says, and experimental drugs based on blocking Ras function are now being tested.

Rab proteins are anchored to intracellular membranes, and are activated when a receptor on the outside of the membrane is stimulated and the signal is brought into the cell. The "best current evidence" is that Rab25 is involved in deciding whether those internalized cell surface receptors "will either be degraded or will be returned to the cell surface," he says. Based on that knowledge, Mills and the team of researchers theorize that the receptors that Rab25 is deciding the fate of are those related to cell growth. "If you had more growth receptor going back to the surface instead of being degraded, you would have increased signaling, and more cell proliferation," says Mills. "But that working hypothesis has not yet been proven."