Gene Suggests New Route To Cancer
NEW YORK, NY, Dec. 9 -- An important part of cellular housekeeping is the bulk degradation of the cell's own proteins, known as autophagy. In a report to be published in the Dec. 9 issue of Nature, researchers at Columbia University College of Physicians & Surgeons identify the first mammalian gene known to participate in autophagy. The gene, beclin 1, also appears to play a role in breast cancer. It can inhibit tumor growth and is expressed at decreased levels in human breast cancer. These findings suggest a new route to the development of cancer, via defects in autophagy pathways.
"Cells undergoing autophagy essentially eat themselves. They digest their own proteins to remodel themselves, to survive during periods of starvation and to limit growth, " says Dr. Beth Levine, assistant professor of medicine and lead author of the study. "It appears that beclin 1 may provide a genetic link between autophagy and negative control of tumor growth. This raises the possibility that treatments that restore autophagy in cancer cells could be beneficial."
Dr. Levine and her colleagues originally discovered beclin 1 while searching for novel proteins that bind to the cell-death inhibitor, Bcl-2. They noted that beclin 1 is similar to a yeast gene controlling autophagy and that it maps to a chromosomal section deleted in 40 percent to 75 percent of sporadic breast and ovarian cancers. This led them to study the gene's function and role in breast cancer.
They inserted beclin 1 into a human breast-cancer cell line known as MCF7 cells. The cell line was originally derived from a patient lacking one copy of a chromosomal section deleted in many breast and ovarian cancers. The MCF7 cells do not normally express detectable levels of the Beclin 1 protein.
They then subjected genetically unaltered MCF7 cells and the MCF7 cells containing beclin 1 to starvation conditions that normally trigger apoptosis. The MCF7 cells containing beclin 1 displayed characteristics of autophagy, while the unaltered MCF7 cells did not. Tumors formed three to four times as often in mice injected with normal MCF7 cells as they did in mice injected with the MCF7 cells containing beclin 1.
Dr. Levine and her colleagues also showed that beclin 1 was expressed in all 32 samples of normal breast epithelial cells but was reduced significantly in 18 of 32 samples of breast cancer cells.