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December 4, 2000

Vertino discovers 'cell-death' gene/breast
cancer link

By Holly Korschun

Emory scientists have discovered that a mistake in the way DNA is labeled and packaged could lead to the abnormal silencing of a gene that plays an important role in keeping breast cancer cells in check, thus contributing to cancer progression.

Results of the work were reported in the Nov. 15 issue of Cancer Research.

Paula Vertino, assistant professor of radiation oncology, and her colleagues at the Winship Cancer Institute, discovered that a gene called TMS-1, which is normally involved in apoptosis (programmed cell death), the process the body uses to help eliminate damaged or cancerous cells, is abnormally silenced by the overexpression of a particular type of enzyme that serves as a marker for DNA.

The enzymes, called methyltransferase enzymes, work as a marking crew for DNA by using a chemical reaction to transfer a methyl group onto the cytosine base regions of DNA molecules. Methylation serves as a flag for proteins that read and interpret the information contained in DNA. Genes marked by methylation are normally turned off, or down-regulated; unmethylated genes are expressed, or up-regulated.

“Methylation is a modification of DNA, and the pattern of which cytosine bases are methylated and which are not adds another level of information to the DNA sequence,” Vertino said. “While the DNA sequence determines a gene’s function, its pattern of methylation can dictate whether it is on or off.”

In contrast to the DNA sequence, however, methylation is not built into the DNA and is not necessarily permanent. Methylation markers are not inherited in the same way as genetic sequences and genetic mutations, and they must constantly be replaced by methyltransferase enzymes. One variety of methyltransferase enzymes has the job of placing methylation markers on DNA during human development in the embryo; another variety of enzymes has the job of replacing the methylation markers each time a cell divides.

Vertino screened DNA to find genes that were down-regulated in response to aberrant methylation. She discovered that when a particular methyltransferase enzyme, called DNMT-1, is experimentally overexpressed, it mistakenly turns off the TMS-1 gene (the target of methylation-induced silencing). She then found that the same gene was aberrantly methylated and silenced in human breast cancers.

Since TMS-1 is a gene partly responsible for ridding the body of breast tumor cells through apoptosis, this silencing could lead to unrestricted tumor growth and progression of breast cancer.
Since most drugs and radiation used to treat human cancers work by inducing apoptosis, the silencing of a gene such as TMS-1 that promotes apoptosis could also lead to resistance to conventional cancer therapies.

Scientists have discovered other alterations in methylation patterns that are present in tumors, including undermethylation of places in the DNA that normally are methylated.

“We now know that abnormal increases in methylation can lead to aberrant silencing of important tumor suppressor genes,” Vertino said. “Loss of methylation groups also may contribute to tumor progression by causing chromosomes to become unstable, which can lead to genetic alterations. A major focus of our work is determining what is responsible for this abnormal placement of methylation.”

In addition to DNMT-1, several other methyltransferase enzymes recently have been identified, but their exact roles and interactions with each other are not yet understood. Vertino also wants to clarify whether aberrant methylation is a cause or a consequence of tumorogenesis. She believes the answer will be a combination of the two.

“Some abnormal methylation events will cause silencing of a very important gene, or genes, and contribute directly to tumor formation,” she said. “And some of the changes we see may be consequences of the fact that the tumor is genetically unstable. Aberrant methylation is propagated during cell division, just as a mutation in a DNA sequence would be.”

Unlike a mutation, in which a gene is permanently damaged, methylation is a reversible reaction. Vertino has been able to reverse the silencing of TMS-1 using drugs that inhibit DNA methyltransferases, leading to re-expression of the gene. She hopes to accomplish the same thing in humans and thus re-establish growth control of tumor cells and sensitize resistant cells to chemotherapy or radiation.


Back to Emory Report Dec. 4, 2000