The numbers are frightening enough. Each year approximately 182,000 women in America develop the disease, and each year approximately 46,000 die from it. No other malignancy is as common among our nation's female population, and none more lethal to those between the ages of 40 and 45. The anxiety and fear generated by these statistics is intensified by the confusing and often conflicting reports from medical researchers.

Genetics, for example, has been identified as one important risk factor-mutation of a gene called BRCA1 is a known source of inherited breast cancer. But breast cancer in women with a family history of the disease accounts for no more than 6 percent of all new cases. Diet and environmental elements also appear to pose a risk-epidemiological studies consistently show that American and western European women are five-to-six times more likely to develop breast cancer than Asian or African women. Experimental evidence, however, has been inconclusive. The fact is, almost half of all breast tumors are diagnosed in women who have none of the medical community's established risk factors. This spotty rate of predictability is indicative of how much remains to be learned about the disease and its underlying causes.

Progress, however, is being made. Through the fog of controversial research findings and claims, there is at least one theory that has withstood the tests of time and scrutiny. The theory implies that there is a direct link between the development of breast cancer and a network of fibrous and globular proteins surrounding breast cells (as well as cells of other organs and tissues) called the extracellular matrix, or ECM. Since its inception more than 15 years ago, the ECM theory has steadily gained in scientific acceptance and has yielded a growing volume of fundamental knowledge about both normal and breast cancer cells. The ECM theory is the brainchild of Mina Bissell, an award-winning researcher in cell biology and the director of the Life Sciences Division at Berkeley Lab. She also gives much credit to Glenn Hall, who was working for her as a post-doctoral student at the time.

Bissell proposed her ECM-theory in 1980 shortly after she and colleague James Bartholomew had established the first cell biology laboratory at Berkeley Lab. Cell biology is the field of research in which cells are studied as living entities that take on specialized shapes, sizes, and functions, organize into communities, and interact with their environment. The Holy Grail of cell biology is solving the mystery of differentiation-the process by which cells that start out with the same genetic information in the DNA of their nuclei change into the vast and distinctly different specialists that make up living organisms. For example, all new cells are identical in appearance, but a mature brain cell in the body looks nothing at all like a heart cell, which looks nothing at all like a skin or muscle cell. Likewise, a cell from the retina will produce a pigment that constitutes eye color, and a breast cell can be induced to express milk.

What is behind these differences in form and function? Activation of certain genes and deactivation of others as the cell develops is the obvious answer, but what factors regulate the expression or repression of these genes? Bissell was among the first to make the connection between the regulation of cell growth and development and the cell's surrounding environment. This recognition stemmed from her days as a graduate student at Harvard University in the late 1960s when she studied bacteria under the noted microbiologist Luigi Gorini.

"When one works with bacteria as I did, one is aware of the profound effects that small molecules such as sugars have on the activation and repression of genes," Bissell says. "When I began to work on animal cells (she came to Berkeley Lab in 1972 after a post-doctoral fellowship in UC Berkeley's Molecular Biology Department), I was continually frustrated by the fact that there seemed to be very little appreciation by cell biologists of how profoundly environmental factors could change the behavior of cells."

Having been trained in chemistry and molecular genetics, Bissell turned to cell biology because of her interest in understanding how things develop-processes rather than static states. This curiosity led her off the "beaten track" of cancer research and onto a somewhat unorthodox approach. While most cancer researchers were searching for new types of oncogenes (cancerous genes carried by viruses), Bissell began studying the behavior of healthy and malignant cells in culture with an eye on the relationship between function and morphology-the changes in structure and form that a cell undergoes as it develops. Her ultimate idea was to define precisely what for cells is "normal."

Using the radioactive tracer techniques developed at Berkeley Lab by Nobel prize-winning chemist Melvin Calvin to study the carbon cycle in plants, Bissell examined a variety of cells grown in culture-a standard medium of nutrients and serum. Like other researchers before her, she observed that all cells, upon removal from their natural habitat in a living organism, begin to lose their morphological and functional differences. Within hours of growth in a culture, for example, breast cells and retina cells will lose their respective abilities to express milk or pigment. The cells will go on to beget subsequent generations of cells that have no specialized function and are virtually indistinguishable from one another.

This loss of differentiation posed a severe problem for Bissell's plan to study cell morphology and function in culture, but it also intrigued her with its implied relationship between a cell's microenvironment and its development. She was one of the few scientists in the 1970s and 1980s who felt that genes could be profoundly influenced by cell-microenvironment and that an aberration in the microenvironment could play a role in cancer development.

"I have argued in the past that to understand the mechanisms involved in cancer induction, one has to understand the factors that allow the cells to retain their normal phenotype," Bissell says. "Given that all cells have the same genetic information and almost all retain the ability to grow, what tells the cells (in their natural habitat) to stop growing? What allows them to retain form and function? What makes a liver cell a liver and a breast cell a breast?"

A cancer cell and a healthy cell share much of the same basic biology and biochemistry. The difference between them is that the expression or repression of the genes in a cancer cell is not properly regulated. As a result, the cancer cell exhibits uncontrolled growth and abnormal differentiation. It is Bissell's contention that the cancer cell loses the ability to "sense" its microenvironment properly. In the belief that normal cells lose differentiated functions in culture because their microenvironment is "incorrect," Bissell undertook experiments in which she manipulated the microenvironments of her cultures. She and other researchers in her laboratory worked mainly (but not exclusively) with breast cells from pregnant mice.

The mouse is a valuable model for medical research in humans, and one of the few mammals (along with other rodents and dogs) other than humans that can develop breast cancer. Breast cells are prized experimental subjects by cell biologists because the mammary gland is one of the few tissues that undergoes dramatic changes in form and function after adulthood. During pregnancy, breast cells, under the influence of hormones, will differentiate into a milk-producing stage. After the off-spring is weaned, breast cells will quickly "involute" back into their non-milk producing stage. This process can be readily followed by tracking the expression of milk proteins.

What Bissell and her colleagues found was that cancerous breast cells grew at the same rate as healthy cells when placed in standard cultures and both quickly took on the flat appearance of generalized tissue cells. If ECM was added to the culture, however, the healthy breast cells once again became plump and round and began secreting milk, while the cancerous cells once again grew wildly into a tumorous mass.