NEW YORK (Reuters Health) - Breast and ovarian tumors that overexpress the RAB25 small GTPase are more aggressive and associated with a poorer outcome than tumors that do not overexpress this protein, researchers report in November issue of Nature Medicine published online October 24th.
These studies for the first time “implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers,” Dr. Gordon B. Mills from The University of Texas M. D. Anderson Cancer Center in Houston and multicenter colleagues write.
“Our studies demonstrate that RAB25 is aberrant in both breast and ovarian cancer,” Dr. Mills told Reuters Health. “This suggests that it is a novel and unexpected target for therapy,” he added.
Increased DNA copy number of chromosome 1q is often seen in ovarian and breast cancers and is associated with a high relapse rate in invasive ductal breast carcinoma, the investigators explain in their report, “but the driver of the regional copy number increase in 1q has not been identified.”
Using array comparative genomic hybridization, they were able to pinpoint an increase in DNA copy number centered on the RAB25 small GTPase in chromosome 1q in roughly half of ovarian and breast tumors analyzed.
When they matched tumor samples to outcomes in about 100 patients with either breast or ovarian cancer, they found that increased DNA copy number or RNA level of RAB25 correlated with markedly reduced disease-free or overall survival.
This shows that RAB25 “is an indicator of prognosis,” Dr. Mills pointed out, and “in combination with other markers, it may provide a method to determine which patients need particular types of therapy.”
It is noteworthy, the authors point out, that RAB25 mRNA levels were selectively increased in stage III and IV ovarian tumors, “suggesting a potential role of RAB25 in tumor progression.”
The team also reports that in cultured ovarian and breast cancer cells, forced expression of RAB25 markedly increased cell proliferation and prevented apoptosis, even that induced by chemotherapy, and increased tumor aggressiveness. Decreasing RAB25 levels consistently increased the number of apoptotic cells. Similar results were obtained in vivo using human ovarian and breast xenografts in mice.
Source: Nat Med 2004. [ Google search on this article ]
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