Michael Press, M.D., Ph.D., is on the phone with a physician whose patient, a woman with an aggressive case of breast cancer, is hoping to qualify for a clinical trial of a drug that seems to work best in women who have a specific gene mutation. Press, coordinator of the USC/Norris Comprehensive Cancer Center's breast cancer research program and the Harold E. Lee Chair in Cancer Research, is acting as a sort of gatekeeper for the trial, analyzing cell sample after cell sample to ensure that only those women with the cell types most likely to respond to the drug in question are admitted.

After assuring the physician that the results of the cell sample analysis should be available soon, Press hangs up the phone with a slight grimace. "It's hard," he admits. "There's so much at stake."

Press knows that the results of this trial may be critical in determining the future treatment of thousands of women with breast cancer. But he also knows that the results of this single cell typing are equally critical to the woman whose physician just called. It is difficult to balance these often-competing interests, but Press, a scientist with a physician's gift for compassion and empathy, does it almost effortlessly.

Gone fishing
One of Press' longest pursuits of genetic links to women's cancers has centered on a gene for a protein called HER2/neu.

The HER2/neu protein is a cell-surface receptor that plays a role in sending growth signals to the cell's nucleus. When this gene is overexpressed-prompting the production of several times the normal number of receptors-the cells carrying that gene tend to grow faster than usual. As it turns out, HER2/neu is overexpressed in 25 to 30 percent of human breast cancers, making them unusually aggressive and more likely to metastasize and recur.

Press is involved in HER2/neu research in a number of ways. For one, there is that clinical trial the concerned doctor was calling about-a trial under the auspices of the Breast Cancer International Research Group (BCIRG) that hopes to determine whether the drug herceptin-a monoclonal antibody that grabs onto the HER2/neu protein receptor and prevents its signal from being sent-is truly the best way to treat newly-diagnosed breast cancers that overexpress the gene. Press' lab is the international testing site for that trial-the laboratory through which samples from all over the world are routed, and where it is determined whether the breast cells in those samples actually overexpress HER2/neu. To date, says Press, they have screened more than 2,000 patients' cancers.

"We're excited about being part of this trial," he says. "I really think it will improve our approach to breast cancer therapy."

The Press laboratory was chosen as the testing site for the trial because Press and his colleagues were recently involved in getting one of the most accurate methods to characterize these sorts of cell-surface receptors that has been approved by the Food and Drug Administration-a process called fluorescence in-situ hybridization, or FISH.

"Although most places don't use FISH as yet," says Press, "when it comes to gene amplification and overexpression, this is the way to go." Clearly, the BCIRG agrees.

Another collaborative effort, with Leslie Bernstein, Ph.D., the AFLAC Chair in Cancer Research and professor of preventive medicine at the Keck School, is a study of about 1,500 women with invasive breast cancer as part of the large-scale Women's Contraceptive and Reproductive Experiences Study. Bernstein and Press are examining a number of genes and hormones that might play a role in making one individual's cancer more belligerent than another's. And, along with Shelley Enger, an epidemiologist from Kaiser Permanente, Press is working to characterize breast cancer's cellular and genetic alterations and determine whether those changes can be linked to either positive or negative responses to various chemotherapy drugs.

"We're looking to see if we can show a correlation between genetic alterations and a patient's potential for responding to the different forms of therapy," Press says.

Press is equally involved in pursuing basic scientific questions-what he calls "the really exciting stuff"-such as determining precisely why an overexpressed HER2/neu gene makes tumor cells so
aggressive and dangerous. To do that, Press has engineered HER2/neu overexpressing cells in laboratory dishes and is finding that overexpression of the gene has an impact on some of the cell's most basic processes such as the ways cells adhere to various tissues in the body.

"Cells that overexpress HER2/neu actually adhere less tightly to the tissues," he says, "which makes sense if you realize that in order to metastasize, a cell needs to be able to move more easily. HER2/neu seems to permit the cell to do this."

Press has also found that a revved-up version of HER2/neu can make it easier for cancer cells to migrate from place to place and to invade new tissues. And from preliminary studies, he says, it looks as if too much HER2/neu also decreases apoptosis-the cellular version of suicide.

"The goal is to try to understand what HER2/neu does to cells to change those behaviors," Press says. "Then, once we know the steps, we can see if we can intervene-and where."

Inherited cancer
The story of breast cancer, and of Press' pursuit of a cure, neither begins nor ends with HER2/neu. He actually entered the breast cancer arena studying the estrogen receptors in the nucleus of women's cells. "We would look at estrogen receptors in the clinical setting to determine whom to treat with hormones-and whom not," he explains. Breast cancer cells that sport these receptors are more likely to proliferate out of control in response to female hormones; cancers without the receptors can be more safely treated with hormones.

He began to realize that estrogen alone is only part of the equation. "The estrogen receptor's function is to recognize the presence of the hormone and cause other genes to be turned on in the cell," he says. "But they don't do it alone. They require co-activators-other enzymes and proteins that make the expression of the estrogen receptor much stronger." To pursue this area, Press collaborated with Michael Stallcup, Ph.D., Keck School professor of pathology and a leading scientist in the study of steroid hormone receptor co-activators.

Among those co-activators is one of the genes that is considered responsible for the inherited forms of breast cancer-BRCA1. Mutated BRCA1 is linked to about 10 percent of breast cancers; women with the mutated gene have an extremely high risk of developing breast cancer relative to women who lack the mutation.

But Press believes that is not the entire story of BRCA1 and breast cancer. "We assume that it not only has a role in hereditary cancers, but also a role in breast cancers that are not hereditary," he says.

That is why Press' laboratory is looking into the role of "wild-type" BRCA1-the non-mutated version of the gene. What they have found is that women with non-hereditary breast cancers tend to have a reduced or a complete loss of expression of the BRCA1 gene. In other words, the non-mutated BRCA1 seems to play a role in controlling the expression of growth signals in cells. When paired with estrogen and other hormone receptors, says Press, wild-type BRCA1 may play a more critical role in spontaneous breast cancer than it does in its mutated form in inherited breast cancer. And that, he adds, may soon lead to new therapeutic options for women with the disease.

That sort of thinking is typical of Press. When he investigates a potential breast cancer culprit, he never forgets that his job is to help bring findings from the laboratory to a patient's bedside. "We're very interested in translational medicine at the Norris," Press notes. "It's the logical next step when you're doing any phase of cancer research."