Loss of Gene in Breast Cancer Signals More Aggressive Disease
DURHAM, N.C. -- Breast cancer cells that lose an important "genetic switch" on their surface are highly likely to spread to other parts of the body, scientists at Duke University Medical Center have found.
Cancers that spread, or metastasize, often prove deadly, so identifying genetic changes that promote metastasis may help in developing better tools for preventing this aggressive behavior, said the study's senior investigator, Gerard Blobe, M.D., Ph.D., an associate professor of medicine, pharmacology and cancer biology.
The findings appear online in the Journal of Clinical Investigation and are published in the January 2007 issue. The study was funded by the National Institutes of Health, the National Cancer Institute, the Department of Defense Breast Cancer Research Program and the Komen Foundation for Breast Cancer Research.
In the study, the researchers analyzed cancer cells taken from the tumors of over 200 breast cancer patients. More than half of the tumors lacked particular "docking sites," called type III TGF beta receptors, on their surface. The sites are where the TGF-beta protein binds and ignites a series of chemical signals that regulate cell growth and mobility.
Breast cancer cells that had none or few of the type III TGF beta receptors were more likely to return and spread after treatment, the study showed. Cancer cells that retained ample numbers of the receptor were significantly less likely to spread, the researchers found by comparing a tumor's receptor levels to the woman's eventual health outcomes.
"If further studies confirm our findings, physicians could use the presence or absence of this receptor as a marker to identify women who should be treated more aggressively in an effort to eradicate their cancers before they spread," Blobe said.
However, even the most aggressive chemotherapy treatments can leave behind errant cancer cells that later regrow and metastasize, he said.
To overcome this problem, Blobe said, it ultimately may prove possible to restore the type III TGF beta receptors in women prior to their receiving chemotherapy in order to inhibit the cancer's propensity to spread. He said this approach has proven successful in laboratory studies, in which researchers were able to reverse the loss of type III TGF beta receptors in various types of cancer cells by administering a drug called 5 azacytidine.
Blobe's team tested a similar approach by restoring type III TGF beta receptors in mice that lacked these receptors. Armed with their new complement of receptors, the mouse tumors were far less likely to metastasize, the study showed
"Restoring expression of this receptor in animals with breast cancer dramatically inhibited cancer cell invasion, metastasis, and the growth of blood vessels that nourish tumors," Blobe said.
Scientists have long known that TGF-beta receptors and their proteins are critical regulators of cell growth, differentiation and death within nearly all normal cells in the body.
But in cancer cells, TGF-beta protein has a unique and contradictory role, Blobe said.
Early in cancer, the protein acts as a tumor suppressor, inhibiting the uncontrolled growth of cells. But as the cancer progresses, the protein switches sides and begins to promote the metastasis of cancer. Cancer cells begin to produce more TGF-beta protein and, in turn, the protein promotes the aggressiveness of the tumor.
Scientists have not understood this dichotomous role of TGF-beta, Blobe said.
The Duke researchers proposed that loss of type III TGF-beta receptors can serve as an accomplice to the cancer cell's changing response to the TGF-beta protein.
Under normal circumstances, type III TGF-beta receptors cleave off of the cell surface and serve as a vacuum of sorts, taking up the excess TGF-beta protein floating outside the cell, Blobe said. But when the receptors are missing or present at low levels, they cannot perform their clean-up role and TGF-beta floods the cell. The abundance of TGF-beta protein triggers the cancer's invasiveness.
The loss of the receptors can be traced back to loss of the gene that controls their production, Blobe said. As is the case with all genes, the type III TGF-beta receptor gene is present within each cell's genetic code as two copies, one inherited from the individual's mother and the other from the father. When a cancer cell loses both copies of this gene, the cell is rendered incapable of producing its receptor proteins, he said.
"Our data support the theory that loss of the type III TGF-beta receptor expression is a frequent and important step in breast cancer progression that directly promotes breast cancer invasion and metastasis," Blobe said.
The team now is conducting studies to identify other possible mechanisms by which type III TGF-beta receptors can inhibit cancer's invasiveness and the growth of blood vessels that nourish the tumor, Blobe said.
He said the team also is trying to determine whether measuring the levels of the type III TGF-beta receptors in cells can serve as a guide to making treatment decisions among cancer patients, and whether the TGF-beta pathway is altered in prostate, lung and ovarian cancers.