Breast cancer is the second major cause of cancer death in American women, with an estimated 44,190 lives lost (290 men and 43,900 women) in the US in 1997. While ovarian cancer accounts for fewer deaths than breast cancer, it still represents 4% of all female cancers. For some of the cases of both types of cancer, there is also a clear genetic link.
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."
The other vital role of Rab25 is to activate the critical "PI3 kinase/AKT/PTEN" protein pathway involved in cell survival and growth. This pathway, however, is known to contain multiple tumor suppressor genes and oncogenes "and is targeted by genetic mutations in cancer more frequently than any other signaling pathway," says Mills. The fact that Rab25 is involved in this pathway "appears to be very important," and may provide a way to target the effects of Rab25, he adds.
The researchers discovered that the gene that produces the Rab25 protein is copied many more times than is normal in some breast and ovarian tumor cells, which then increases expression, or production, of the Rab25 protein. They then conducted laboratory in vitro cell line studies, and in vivo studies using human breast and ovarian tumor xerographs in mice, and were able to demonstrate that either increasing or decreasing expression of Rab25 altered tumor growth. Finally, using the human tumor samples, the researchers correlated Rab25 expression with survival.
"We know now that change in expression is associated with a poorer patient outcome in both breast and ovarian cancer, and that may help us predict outcomes in patients in the future" says Mills. "But we have a long way to go to understanding exactly what it is that Rab25 is doing, and how we might be able to use it in treatment."