Silencing a gene slows breast-tumor fighter

Just as every actor needs a director to shout “Action,” each gene in the body needs a promoter—nearby DNA that switches on the gene at appropriate times. The promoter’s cue can take on life-or-death importance when the gene is p53, a tumor suppressor.

Researchers now report that a protein that activates the p53 promoter is frequently missing in breast cancer cells. Of tumor samples taken from 30 women with breast cancer, 20 were devoid of the protein, called HOXA5, says study coauthor Saraswati Sukumar, a molecular biologist at the Johns Hopkins Medical Institutions in Baltimore.

The p53 gene itself encodes a protein that signals cells to commit programmed suicide, or apoptosis, when their growth patterns run amok, as in cancer. Try as it may, however, p53 can’t always play the hero. In at least one-fifth of breast cancer cases, for example, p53 has been mutated and its protein rendered ineffective. Sukumar also suspects that p53 is silenced in some breast tumors.

To ascertain whether HOXA5 plays a vital role in activating p53, Sukumar and her colleagues infused either functional or defective HOXA5 genes into breast-tumor cells in laboratory dishes. The working genes induced cell death, whereas flawed HOXA5 genes permitted the tumor cells to keep thriving, the researchers report in the June 22 Nature.

HOXA5’s cancer-fighting capabilities may not be limited to activation of the p53 promoter, Sukumar says. The protein also spurred production of another tumor-suppressing protein, encoded by the p21 gene. “We have a feeling that more genes are [switching] on,” she says.

Further experimentation suggested a mechanism by which the HOXA5 gene might come to be disabled in cancer patients. The researchers took breast cancer cells lacking p53 protein from 20 patients. In 16 cases, they found that hydrocarbon fragments, or methyl groups, had latched onto the promoter region for the HOXA5 gene.

While methylation is a common occurrence in DNA throughout the body, the promoter DNA next to the HOXA5 gene “is normally not a methylated region,” says Sukumar. If methylation has silenced HOXA5, the gene couldn’t direct a cell to produce the protein needed to activate p53‘s promoter, she concludes.

Meanwhile, none of the breast cells from 10 healthy women showed a methylated promoter for HOXA5, she says.

“This . . . is potentially a very interesting finding,” says Louise C. Strong, a cancer geneticist at the University of Texas M.D. Anderson Cancer Center in Houston. Scientists are now examining the effects of removing methyl groups from portions of DNA. By demethylating HOXA5 promoter DNA, scientists might be able to fight breast cancer by activating p53 in patients, she says.

HOXA5 belongs to the Hox family of genes, which guide formation of certain body parts. Sukumar notes that the new study is the first to link a Hox protein to apoptosis. Future research might delve into ways of delivering functional HOXA5 genes to tumors in patients lacking the protein.

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