BERKELEY, CA — 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).
|
PAUL YASWEN (AT MICROSCOPE) IS THE PRINCIPAL INVESTIGATOR WHO
FOUND THAT THE ZNF217 GENE PLAYS A ROLE IN BREAST CANCER.
GENEVIEVE NONET (STANDING) COLLABORATED ON THE STUDY.
|
"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
Lab’s 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 ZNF217’s
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 cell’s 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.
|