UCSC Review Winter 1996

The Genetic Riddles of Breast Cancer

by Robert Irion

At the end of World War II, when few doctors bothered to study medical issues unique to females, an American woman could expect to live to age 65. Half a century later, women's health is a vibrant field, and the average life span is 79 years. But this rosy picture masks a grim statistic: The odds that a woman will face the specter of breast cancer before she dies have climbed from one in twenty in 1945 to a startling one in eight today.

Much of this trend results from better detection of breast cancer and from the growing percentage of women in their 80s and 90s, when the disease is far more likely to strike. Even so, the rising number of new cases (an estimated 182,000 in 1995) has prompted grassroots women's groups such as the National Breast Cancer Coalition to demand that the government pay more attention to the problem--which, they believe, is a health crisis of epidemic proportions.

Three years ago, the government listened. Congress earmarked $210 million in additional money for research on the causes and treatment of breast cancer, more than doubling the 1993 budget in that field. Through an odd twist of political maneuvering, the U.S. Army, not the National Institutes of Health (NIH), called for proposals to distribute the windfall. Nervousness about the military's role gave way to relief among scientists as the Army set up a panel of respected medical advisers to oversee the awards. By January 1995, more than 250 groups around the country had funds in hand to refresh their assault on the vexing disease.

One of the beneficiaries was UCSC biologist Charles Daniel, whose four-year, $1.1 million grant from the Army is among the largest of his distinguished career. Ironically, Daniel--one of UCSC's founding faculty members--retired in 1994 during the last and largest of UC's early-retirement waves. But the Army grant and a separate four-year grant from NIH will keep the Daniel team hopping in Sinsheimer Laboratories through 1998.

Daniel couldn't be more pleased, as his lab is making real progress toward fingering some of the genetic triggers in cells that may fire the breast-cancer bullet.

"Cancer is almost certainly the most complex problem that biomedical science has tackled," he says. "Our research is part of a broad effort to understand the basic processes behind breast cancer. These approaches do not offer an immediate hope for curing cancer, but they may lead to an arsenal of tests that would help identify people at high risk."

The crux of Daniel's project is to explore the roles of special genetic controls, called "homeobox genes," in the growth of both normal and cancerous breasts. Homeobox genes are the master regulators of the fate of a living cell. Virtually all animals share this family of genes, which have kept the same basic molecular structure through billions of years of evolution.

Studies of fruit flies and mice have shown that homeo-box genes dictate basic body patterns in an embryo, such as how the nervous system gets wired or where arms and legs end up. Errors in these genes can cause changes in the cell that damage or kill the embryo. Further, it appears that homeobox genes also control proper tissue growth in adults. If the genes somehow go haywire, cancer may result.

In 1994, Daniel's lab group was the first to show that homeo- box genes are active in breast tissues. Led by former graduate student Yael Friedmann (now at the Hebrew University Sharet Institute in Israel), the researchers studied the mammary glands of mice. They found that certain homeobox genes in the glands switch on or off in response to changes in the levels of estrogen and other hormones. Moreover, mice with breast tumors had homeobox genes that appeared to function abnormally.

This work was the primary reason Daniel's proposal to the Army earned the highest possible rating from the review panel. With the new infusion of money, his team is advancing its work along two different, yet intersecting, avenues.

First, again using mice, the researchers are studying which of the dozens of known homeobox genes control how breasts grow and function at various stages of life. By inducing changes in some of the genes, the team is testing whether homeobox genes can act as cancer-causing catalysts. Scientists already know that other types of genes can spark cancerous growth by going into overdrive or shutting down prematurely.

Second, the team is extending its work to human breast cancer. Mice have long served as reliable animal models for humans, but homeobox genes may behave a bit differently in the two species. The researchers cannot use people in their experiments. They can, however, study tissues from women with breast cancer to search for the same kinds of cellular and genetic changes that they create in mice.

Daniel is collaborating with Dominican Santa Cruz Hospital for this purpose, the first such tie between a local hospital and UCSC researchers. Dominican provides tissue samples from the diseased breasts of patients who undergo surgery--tissues that the hospital would otherwise discard. The scientists do not preserve the tissues in a living state. Rather, they extract genetic material from normal and cancerous cells, then study it using the techniques of molecular biology. Already, the team has found hints that similar genetic mechanisms are at work in the breast tissues of both mice and women.

Daniel says his team's project is far removed from inventing a new medicine for breast cancer or manipulating the body's genes to prevent it. "The medical research establishment is based on understanding how things work at a very basic level, and for breast cancer that is not well known," he says. "Learning more about which genes control these processes might help us detect people at risk. That's a big promise, because prevention is much more important than a cure when it comes to cancer."

With his own career nearing a close, Daniel is excited about the foundation his lab may establish for others. "There are dozens of labs working on homeobox genes and dozens working on breast cancer, and a small but growing number at the intersection," he says. "We were the first. If our work ultimately shows that these genes do play a key role in the development of breast cancer, labs all over the world will pounce on it."