Gene stifled in some lung, breast cancers

Many genes encode proteins whose job is to inhibit cell growth. Some of these genes suppress the growth of tumors, and a few have become household names, such as the BRCA1 gene, which inhibits breast cancer.

A gene called RASSF1A could become the next member of this rarefied club. A study in the May 2 Journal of the National Cancer Institute establishes that many lung and breast tumors lack a functional RASSF1A. The findings suggest that the protein encoded by RASSF1A helps choke off malignancies and could lead to new cancer therapies. Indeed, the scientists found that restoring RASSF1A function to implanted human cancer cells prevented them from developing into tumors in mice.

The precise role of the RASSF1A protein is unclear. Nevertheless, the protein may hold one of the molecular keys to disrupting runaway cell growth in cancer, says study coauthor John D. Minna of the University of Texas, Southwestern, in Dallas.

For cancer to grow, several tumor-suppressor genes may need to be turned off in unison, says coauthor Adi F. Gazdar, also of Southwestern. “You might reverse the malignancy by correcting just one of these defects,” he says.

The researchers used tumor cells surgically removed from lung and breast cancer patients to create cell lines that they could grow in the laboratory. RASSF1A was silenced in 32 of 32 cell lines grown from small-cell lung cancer patients, in 17 of 26 nonsmall-cell lung cancer lines, and in 15 of 25 breast cancer cell lines.

Since their earlier work suggested that RASSF1A hadn’t been mutated in cancerous cells, the researchers looked for a chemical modification of the gene. They found clusters of atoms, known as methyl groups, clinging to DNA in RASSF1A. This methylation occurs normally on some parts of chromosomes, but it doesn’t show up in RASSF1A of normal tissues.

Nearly all small-cell lung cancer cells and about half of the breast cancer cells that Minna’s group tested had aberrant methylation. Attaching to the RASSF1A promoter, the gene’s on switch, these methyl groups turned off the gene.

An analysis of a separate sample of 107 nonsmall-cell lung cancer patients showed that 32 had methylated promoter regions on RASSF1A in their tumor cells. The researchers checked hospital records of these patients and found that those without the aberrant methylation survived, on average, 49 months from the date of diagnosis, whereas those with a methylated RASSF1A promoter region survived only an average of 28 months.

In their mouse experiments, the researchers tested immune-deficient animals. The researchers injected one group of mice with lung cancer cells that lacked RASSF1A and another group with the same kind of cells containing added, functional RASSF1A. Whereas the first group of mice grew tumors, the others remained free of cancer.

Minna says, “The findings represent an early diagnostic tool for lung and breast cancer and will also lead to new therapy trials using drugs that block methylation in patients.”

“This work was very nicely done,” says James G. Herman, a medical oncologist at Johns Hopkins University Medical Institutions in Baltimore. As scientists improve their understanding of the human genome, they’ll encounter more genes that are switched on or off in cancer, he says.

Researchers investigating potential tumor suppressors will need to determine whether the proteins encoded by those genes play critical roles in the genesis of cancer or are simply signposts of the disease, says Herman. Putting such genes into human cancer cells and gauging whether they can stop cancer–as Gazdar and his colleagues did in mice–”is an important step,” Herman says.