HARVARD GAZETTE ARCHIVES

Stairway to discovery: Kornelia Polyak (right) and Dale Porter found that a protein they discovered in invasive breast tumors plays a role in protecting the brain from Alzheimer's disease and stroke. (Staff photo Kris Snibbe/Harvard News Office)

Now they have an answer. The gene produces a protein that evidently protects cancer cells in the same way it shields brain cells from damage caused by diseases like Alzheimer's and strokes. "The same substance can be doubly harmful to some people with invasive breast cancer because it protects the tumor cells from death," notes Kornelia Polyak, an assistant professor of medicine at Harvard Medical School.

Fragments of this Janus-like protein, dubbed dermcidin or DCD, have also been found in the blood of people with cachexia, a muscle-wasting disease that afflicts some terminally ill cancer patients.

Such revelations have excited a number of drug companies about the potential uses of DCD. Since Polyak and her colleagues published their findings last month in the Proceedings of the National Academy of Science, several drug companies have contacted them about the possibility of using DCD as a means of diagnosing invasive breast cancer, the most common form of the malignancy.

In terms of treatment, everyone wants to find a way to stimulate the protein's activity in the brain while blocking it in breast tumors.

"DCD is a growth factor that can bind tightly to either brain or breast cells," explains Polyak. "For this to happen, it needs a receptor on the surface of those cells. Our next major goal is to identify that receptor. Once found, it becomes a target for drugs that can either activate or block it." She has already received a grant from Novartis Pharmaceuticals in Cambridge to support the search.

A second chance to survive

DCD came to light while Polyak, who heads the Breast Cancer Genetics Lab at Dana-Farber Cancer Institute in Boston, was looking through a library of genes active in tumors. "We found the DCD gene present in 10 percent of the invasive breast cancer cells we checked," she recalls. "But it did not appear in normal breast cells or in early-stage breast cancer."

Most breast cancers involve tumor cells that have escaped from milk ducts and invaded other parts of the breast. They have not yet spread or metastasized to other areas of the body, but will do so if not treated aggressively.

Polyak's team, which includes Dale Porter, a research fellow in medicine, then tested 76 tissue samples from other parts of the body. "We couldn't find it anywhere else but in the brain, and that really surprised us," Polyak says.

Apparently, the DCD protein protects cells damaged by Alzheimer's or Parkinson's diseases and strokes. It gives them a second chance to survive. DCD's exact role in breast cancer remains unknown, but Polyak believes it helps tumor cells to grow. "Growing cells sometimes outpace their blood supply," she explains. "Ordinarily, these cells would die, but DCD may help them grow to a larger size.

"It may also enhance their ability to spread beyond the breast," she continues. Poyak and her colleagues are now testing this idea by injecting human cancer cells into mice. Half of the rodents would also receive DCD to see if it enhances lethal spreading compared with the mice who do not get the protein.

Polyak is also interested in whether DCD helps other types of cancer cells to grow. Since her paper was published, different research groups have told her about evidence for the protein that they found in two other types of cancer.

Looking ahead

On the brain side, investigations into the role of DCD in Parkinson's disease have begun. Polyak's group is collaborating with researchers at Mt. Sinai School of Medicine in New York City to determine if the protein can stem the loss of brain cells that produce the trembling, rigidity, and progressive degeneration caused by this malady.

Meanwhile, British investigators have found fragments of the DCD protein in cancer patients suffering from cachexia. These patients, particularly those with pancreatic cancer, lose fat and muscle no matter how much they eat.

"It's pretty sad," Polyak comments. "The body just destroys itself. We don't know what initiates it. Perhaps studies of the DCD gene will lead to new information to help these people."

Yet another researcher group has come across the gene in sweat glands. "That doesn't surprise me," says Polyak. "The mammary gland is a kind of modified sweat gland; they both arise from the same tissue during embryonic development. That's interesting because there might be stem cells in both glands from which arise tumors that express the DCD gene.

"This is something else we want to look into. But in terms of immediate importance for treating patients we want to find the receptor that binds to brain and breast cells, giving them desirable protection in one case but unwanted protection in the other."