Two proteins that normally help cells move from place to place and are made in large quantities in breast cancer cells work together to promote the survival and spread of breast cancer, according to a new study by scientists at The University of Texas M. D. Anderson Cancer Center.
The finding, which appears in the June 2004 issue of the journal Cancer Cell, links together for the first time two proteins known to influence cell shape and survival of cancer cells. What’s more, when the scientists created a single change in a small 19-amino acid portion of one of the proteins, it stopped tumor formation. The results may lead to new strategies to trigger cell death in cancer cells, the scientists say.
“We can now target these 19 amino acids,” says Rakesh Kumar, Ph.D., professor of cellular and molecular oncology and the study’s lead investigator. “We might be able to develop a small molecule, a drug that could target the business end of this protein to interfere with the transformation process.”
The National Cancer Institute estimates that nearly 13 percent, about 1 in 8, of all women in the United States will develop breast cancer. It is the most commonly diagnosed malignancy among women. The proteins that Kumar and his research team studied appear to be involved in the process of transforming normal breast cells into cancer cells in the majority of breast cancer cases.
The research team discovered that when the two proteins, Pak1 and DLC1 (dynein light chain 1) interact, Pak1 chemically modifies DLC1 at a single site and changes the cell’s ability to respond to cell death signals. When DLC1 is modified it interferes with the cell death signaling pathway. As a result, cells no longer respond to death signals and instead continue to survive, multiply and spread. The loss of ability to respond to cell death signals is a hallmark of cancer.
When the scientists looked for DLC1 in breast cancer tumors, they found 54 out of 60 had elevated levels of DLC1. When they examined some of the tumors in greater detail, they found five out of six tumor samples studied had increased levels of the modified DLC1 that does not respond to cell death signals.
The scientists then used genetic methods to test the breast cancer cells in a mouse model that the scientists genetically altered to increase or over-express levels of DLC1. These mice developed tumors, and when they examined the cells that over-express DLC1, they also discovered that the cells could move faster than normal cells, they reproduced faster, and could grow without normal cell contacts – what is called anchorage independence.
“Taken together, these studies show cells that over-express DLC1 have enhanced cell survival and blockage of death signals, all of the characteristics required for successful tumor formation,” says Kumar.
But when the research team engineered a form of the DLC1 protein missing the crucial modification site, the protein could no longer block cell death signals and could no longer form tumors.
Kumar says that since DLC1 is a small protein and the research team has identified exactly how it becomes modified by Pak1, it may be possible in the future to block its activity through the use of drugs designed to inhibit its activity. Such inhibitors might restore the cell’s normal recognition of cell death signals, Kumar says.
However, he adds that more work needs to be done to understand how over-expression of DLC1 contributes to the development of breast cancer.
M. D. Anderson scientists Ratna Vadlamudi, Ph.D., Rozita Bagheri-Yarmand, Ph.D., Zhibo Yang, Ph.D., Seetharaman Balasenthil, Ph.D., Diep Nguyen, Aysegul Sahin, M.D., and Petra den Hollander, contributed to the study. The research was supported by NIH grants.