Cancer comes full circle

BERKELEY, CA -- Researchers in the Life Sciences Division of the Department of Energy's Lawrence Berkeley National Laboratory have discovered a key molecular pathway by which an enzyme that normally helps remodel tissues initiates the pathway to breast cancer. The same molecular pathway, the researchers found, links both the loss of tissue organization in cancerous organs and the loss of genomic stability in individual cancer cells.

"This study demonstrates how structure and function in a tissue are intimately related, and how loss of structure could itself lead to cancer," says Mina Bissell, who pioneered the view that a cell's environment is as important as its genes in determining the formation and progression of tumors. "Thus the unit of function in organs -- which are made of tissues -- is the organ itself."

Enzymes known as matrix metalloproteinases (MMPs) are important during an organism's development and during wound healing, but they can also promote carcinogenesis. The new study shows that one type, MMP-3, causes normal cells to express a protein, Rac1b, that has previously been found only in cancers. Rac1b stimulates the production of highly reactive oxygen molecules, which promote cancer in two ways -- by leading to tissue disorganization and by damaging genomic DNA.

"What comes first in cancer, the mutations within the genome of the tumor cells or the loss of tissue organization?" asks Derek Radisky, a postdoctoral fellow in Bissell's laboratory who has focused on the molecular pathways mediating interactions between tumors and their surrounding tissues. "It's a chicken-and-egg problem. Our study shows that the relationship is reciprocal."

Lead author Radisky, with Bissell and their colleagues Dinah Levy, Hong Liu, Celeste Nelson, and Jimmie Fata of Berkeley Lab; Laurie Littlepage, Donna Albertson, and Zena Werb of the University of California at San Francisco; Devin Leake and Elizabeth Godden of Dharmacon, Inc.; and

Contact: Paul Preuss
DOE/Lawrence Berkeley National Laboratory

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