New Path from
Estrogen to Survival in Breast Cancer Cells Described
Behind the Cancer Headlines®
After years of research, scientists at The University of Texas M. D. Anderson Cancer Center are now able to explain, in exquisite molecular detail, how the estrogen hormone can help keep breast cancer cells alive.
Writing in the journal Nature Cell Biology, they assign roles to a number of genes and proteins thought to play a part in breast cancer cell survival, and in the process, have identified potential molecular drug targets.
"It's a very complex story, but we have been able to bring together a number of basic discoveries from different fields of research to work out the basic mechanism by which estrogen can exert a pro-life effect on cancer cells," said the study's lead author, Edward T. H. Yeh, M.D., professor and chair of The University of Texas M. D. Anderson's Department of Cardiology.
Along the way, the researchers have provided some novel insights. One is that they have determined a role for breast cancer-associated protein 3 (BCA3), which had been recently found to be over-expressed in both breast and prostate cancers. Yeh and his team show that this protein, by itself, doesn't have any relationship to the cancer, but when modified by the protein NEDD8, can act like a tumor suppressor.
The researchers also found that SIRT1, a key protein involved in this molecular pathway, is a member of a family of proteins responsible for prolonging life span in both yeast and worms. "The fact that these molecules, which maintain life span in other species, has been found to be involved in suppressing cancer development seems important to us," Yeh said. "The reason people live longer is that they don't develop cancer as readily."
Players in this newly defined pathway are:
·
BCA3, which had no known function.
·
NEDD8, a protein that can bind to other proteins
and alter their function.
·
SENP8, a protease (enzyme) that can break bonds
between other molecules.
· SIRT1
· NFkB (Nuclear Factor kappa B), a family of proteins that turn on genes involved in cell death (apoptosis) and cell proliferation. When over-expressed, NFkB can protect cells from undergoing apoptosis, and in general, the more NFkB is expressed, the more resistant the cell is to apoptosis.
Now that this cancer-promoting molecular pathway has been described, Yeh says it might be possible to interfere with a number of the players to inhibit cancer growth. "NEDD8 is key," he said. "It may be possible to design drugs that block the removal of NEDD8 from BCA3." By increasing the amount of NEDD8-modified BCA3, there will be a corresponding decrease in the level of NFkB and the cancer cells will be more sensitive to chemotherapy, Yeh says.
"There is a lot we need to sort out, of course, but this
is a model of how estrogen may function to promote growth in breast cancer that
we can all now work from," Yeh says.
SOURCES:
Nature Cell Biology,
University of