Tumor Suppressor Gene Protects Against Pre-cancerous Development

Cav-1 is involved in breast cancer onset and progression, and it's present in epithelial cells and mammary "fat pads," or stromal cells. The researchers, led by Michael Lisanti, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University and Jefferson's Kimmel Cancer Center, showed striking effects in mice that lacked Cav-1, particularly in stromal cells.

Reporting November 1, 2006 in the American Journal of Pathology, Dr. Lisanti, Kimmel Cancer Center director Richard Pestell, M.D., Ph.D., professor and chair of cancer biology at Jefferson Medical College, and their co-workers showed in a series of experiments that tumor cells grew larger in mammary fat pads lacking Cav-1, and that metastatic breast cancer cells transplanted to fat pads with Cav-1 failed to grow.

"There could also be human conditions where loss of Cav-1 in the stroma could be predisposing patients toward increased risk," Dr. Lisanti says. "This provides the hard genetic evidence of a cause-effect relationship between loss of Cav-1 in the stroma and tumor growth. This could be predictive by looking at Cav-1 in the stroma and seeing if this is a bad risk factor."

The researchers found that mice lacking the Cav-1 gene showed a cell thickening in the breast duct and hyperplasia -- or excessive cell growth -- in the lobulo-alveolar area. Both are locations where breast cancer can begin.

In one study, they took a tumor from a mouse and put it in a stromal fat pad in both a normal mouse and in a mouse lacking Cav-1 and discovered that the tumor grew twice as large in the latter. "The stroma clearly has effects on normal mammary growth, hyperplasia and tumorigenesis," Dr. Lisanti says.

Dr. Lisanti and his team performed another experiment in which they compared the effects of implanting metastatic breast cancer cells in mice with Cav-1 and those lacking the gene. When they implanted such cells in the mouse flank, which is not a location at which tumors grow, nothing happened. But when they put the cells in the mammary fat pad, tumors formed. When they implanted metastatic breast cancer cells with Cav-1 in the fat pads, "it had a huge effect," Dr. Lisanti says, blocking tumor growth.

"This tumor suppressor effect of Cav-1 depends on the location of the cells," he explains. "This means it is specific to the mammary fat pad. The mammary stromal and epithelial cells somehow sense the microenvironment and respond to the Cav-1 gene."

The researchers believe that the effect also depends on the activity of the cyclin D1 gene, a cancer-causing gene overexpressed in about half of all breast cancers. Using a mouse model of premalignant growth in mice carrying the cyclin D1 gene but lacking Cav-1 -- which worsens the condition -- the researchers added Cav-1 and found "it completely represses the phenotype, meaning it can not only suppress the tumor, but also the premalignant state caused by cyclinD1 upregulation."

Turning down cyclinD1 activity relies on the cellular microenvironment, Dr. Lisanti says. "We think Cav-1 can block the transforming effects of cyclinD1," he says. "It could be a very important therapeutic candidate for developing caveolin mimetic drugs suppressing cyclinD1 activity."

Dr. Lisanti believes that Cav-1 "could be important for early intervention because patients with epithelial cell hyperplasia could be given Cav-1 mimetic drugs to see if they could suppress this."