In the study of breast cancer, an astonishing proof-of-principle experiment graphically demonstrated the critical role played by a cancer cell's immediate surroundings. Malignant human breast cells were made to look and act like normal cells through manipulations of their microenvironment. This experiment proved that, in some cases, what is happening outside a cell can be equally if not more important than the presence of cancerous genes within.

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reast cancer is the most common and lethal malignancy in U.S. women between the ages of 40 and 45. Each year approximately 182,000 American women develop the disease, and each year approximately 46,000 die from it. What may prove to be an important discovery in the fight against this disease is a theory postulated by Berkeley Lab cell biologist Mina Bissell. The theory holds that there is an important link between the development of breast cancer and a network of fibrous and globular proteins surrounding breast cells called the "extracellular matrix" or ECM. Bissell and her colleagues have shown that the ECM is crucial to the normal functioning of cells, and loss of or damage to the ECM can lead to malignancy in transgenic mice.

Since it was first announced in 1982, the ECM theory has gained support from experimental results. This past spring, however, it was put to its most stern test. Bissell and Valerie Weaver, a post-doctoral scholar in cell and molecular biology, worked with unique lines of human mammary epithelial cells: one that remains normal, and one that becomes malignant following a known sequence of events. The malignant strain was treated in culture with an antibody that blocks one of the integrins-proteins which reside in the outer membrane of a cell and through which signals from the ECM are transmitted inside.

(Click on image to enlarge)

This image shows a cluster of normal breast cells on the left, tumor cells in the center, and reverted tumor cells on the right. The reverted cells were treated with an integrin-blocking antibody. Areas shown in red are cell nuclei, the green areas are cyto-skeletal protein. These images were produced by Carolyn Larabell.
Under the influence of the integrin-blocking antibody, the malignant cells reverted back to a normal appearance, their cancerous growth ceased, and they functioned as if they were healthy cells. Injected into mice, the same type of treated malignant cells yielded far fewer tumors that grew much more slowly than untreated cancer cells. By altering the pathways between the ECM and the nucleus, Bissell and Weaver were able to revert malignant cells back into almost normal form and function. When the reverted cells were examined with a fluorescent probe, the genes in their nuclei were still abnormal, indicating that the phenotype had been changed but not the genotype.

"These findings have vital implications for breast cancer diagnosis and prognosis," says Bissell. "Cancer is the result of not just genetic change, not just developmental regulation, or loss of growth regulation, but an interweaving of all of these factors."

The results of this experiment, even if in only one tumor cell population, help explain why breast cancer takes so long to develop even in women who are at high genetic risk. So long as cellular and tissue structure are maintained, tumor development can be suppressed despite the presence of cancer-inducing genes. Over the course of four decades in a woman's life, the ebb and flow of hormones and other contributors to a cell's microenvironment and genome take their toll. Eventually, through mechanisms not yet identified, the ECM is altered. This, in turn, alters the signals sent from the ECM into the cell's nucleus, and, if there are harmful mutations, the sum triggers the onset of malignancy.

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As a further proof-of-principle, Weaver, Bissell, and their colleagues also worked with the normal strain of their human breast cells. Again, altering cell microenvironments with integrin-blocking antibodies, they demonstrated that normal cells could be induced to look and act like cancer cells in culture.

Although this research does not offer a cure for breast cancer, it does point to the possibility that the disease may be treated or perhaps even prevented through means other than conventional genetic therapy.

"We've shown that even after cancer genes have been expressed and lesions have formed, it may still be possible to reverse the tumor process and restore cells to normal appearance and function," says Bissell.

For additional information, also see the Bissell Lab website.

- Lynn Yarris

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