BERKELEY, CA ó To the small list of genes that play a role in the development of breast cancer can now be added the name ZNF217. Multiple copies of this gene were found to remove natural restrictions on cell growth and thereby increase the chances for malignancy in a study jointly conducted by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California at San Francisco (UCSF).
"We hypothesize that over the course of evolution, the human body has developed an intrinsic molecular mechanisms to count and limit the number of times breast cells divide as a means of limiting the growth of abnormal cells," says Paul Yaswen, a cell biologist with Berkeley Labís Life Sciences Division who was the principal investigator in this study. "When expressed inappropriately, ZNF217 appears to compromise this mechanism, the net result being that the affected cells can continue dividing and accumulating additional changes necessary for malignancy."
Normal cells contain two copies of ZNF217 which are located on human chromosome 20. Amplification of the ZNF217 gene, meaning more than two copies are present, has been found in many different types of tumors, including some 40 percent of human breast cancer cell lines. The results of this latest study support the theory that over-activity of the ZNF217 gene contributes to the development of breast cancer by promoting cell "immortality." Cells are said to have become immortal when they grow past the point at which senescence and death is supposed to kick in.
Explains Yaswen, "Our data suggest that simple over expression of the ZNF217 gene product itself only allows cells to continue growing when they would otherwise stop. However, continued growth allows the cells to accumulate additional changes which may favor invasion and metastasis."
Collaborating with Yaswen on this study were Genevieve Nonet and Martha Stampfer of Berkeley Lab, and Joe Gray, Colin Collins, and Koei Chin of UCSF. Their results were published in the February 15, 2001 edition of the journal Cancer Research.
The National Cancer Institute estimates that nearly 13 percent (one in eight) of all women in the United States will develop breast cancer. It remains the most common malignancy among women in this country and the most lethal for those between the ages of 40 and 45. The Berkeley Lab-UCSF researchers began searching for possible oncogenes in a specific area of chromosome 20 that was known to be amplified in a large number of human breast cancers. They identified ZNF217 as a gene in this region of the genome whose level of expression consistently matched the levels of amplification found in breast tumors and cancerous cell lines.
"ZNF217 was relatively inactive in normal breast cells, but highly active in a number of breast cancer cell lines," says Yaswen. "The next logical step was to try to determine the role of the ZNF217 gene, if any, on breast cancer progression, by putting it into normal breast cells."
Introducing extra copies of ZNF217 into cultures of normal human mammary epithelial cells caused those breast cells to become immortal. The cells took on other characteristics as well that were similar to changes observed in cultures of breast cells exposed to chemical carcinogens. ZNF217-treated cells also displayed a new resistance to TGFb (Transforming Growth Factor beta), a substance that normally stops the growth of many different types of cells.
Yaswen says it may be possible in the future to block ZNF217ís activity through the use of antisense, drugs designed to inhibit the production of specific disease-causing proteins, or through the use of some type of molecular inhibitor. However, much more work needs to be done before the means by which over-expression of ZNF217 contributes to the development of breast cancer is fully understood.
"Ultimately, we want to know what other molecules, such as proteins or DNA, interact with ZNF217, and how do those interactions compromise a cellís normal growth controls," says Yaswen.
Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California.