A tiny protein called RhoC found in breast tumors may someday give doctors and patients an early warning system that could spot dangerously aggressive breast cancer long before it begins to spread, and identify the need for aggressive treatment.

A test to detect the protein is still more than a year away from clinical trials. But promising early results show that RhoC can serve as a marker for breast tumors that are most likely to spread, or metastasize-even identifying them when they're less than a centimeter in diameter.

RhoC, whose full name is RhoC-GTPase, is an enzyme involved in changing the internal skeleton of a cell-changes that allow a cell to polarize or move. That ability is important in muscle cells, which produce a lot of RhoC. But in cancerous non-muscle cells, RhoC is key to the structural changes that give a cell the ability to break off from a tumor, float through the body in the bloodstream, and take hold in a satellite location-in other words, to metastasize.

Researchers from the University of Michigan Comprehensive Cancer Center developed the test based on their prior research on the RhoC gene, and proved its effectiveness in 182 tissue samples from the U-M's breast cancer library. Their results were presented at the annual meeting of the American Association for Cancer Research.

The test detected invasive cancer that had the potential to metastasize with 88 percent specificity, and had 92 percent specificity for tiny tumors that had already metastasized. Samples of normal breast, benign breast cysts, or non-invasive breast cancer had little RhoC.

"This is a very promising marker for small but invasive breast cancers that may metastasize, which right now are hard to identify," said lead author Dr. Celina Kleer. "While more research is needed before clinical testing can begin, we hope it will help identify early-stage cancer that could be vulnerable to aggressive treatment, perhaps with drugs that target Rho protein."

Kleer and her colleagues embarked on the study to find out how much RhoC was produced in different kinds of breast cancer cells, compared with normal breast cells.

Previously, they had shown that the RhoC gene was overexpressed in inflammatory breast cancer, a particularly deadly variety that grows and metastasizes quickly. Overexpression of the gene, they believed, might also occur in other kinds of aggressive breast cancer-leading to larger quantities of the RhoC protein in cells of those cancers.

In finding the inflammatory breast cancer correlation, the Michigan team was the first to show that RhoC, already implicated in liver, pancreas and skin cancer, was also involved in breast cancer. They then showed that transplanting the RhoC gene into normal breast cells in mice transforms those cells into cancerous ones with metastatic potential.

"We found RhoC only in invasive cancers, and it almost always correlated with the presence of metastases. Very few non-metastatic cancers contained high levels of RhoC," she says. "The level of RhoC expression also increased as the stage of the breast cancer increased, which is another confirmation that it's a marker of more aggressive cancer. We had enough samples from invasive metastatic cancers of less than one centimeter in size to show that RhoC is highly specific for those tumors, but we'd like to look at more samples to be sure."

SOURCES:
93rd Annual Meeting of the American Association for Cancer Research, April 9, 2002, San Francisco, CA
University of Michigan Comprehensive Cancer Center (http://www.med.umich.edu)