St. Louis (Oct. 25, 2004) -- High levels of a protein called LRP6 can make cancer cells more aggressive, according to Washington University researchers affiliated with the Siteman Cancer Center. The protein's ability to enhance tumor development suggests that the gene that codes for LRP6 is an oncogene--a gene that contributes to tumor development when overactivated.
"Because no one has ever connected LRP6 to proliferation in tumors, we believe we may have identified a new oncogene," says Guojun Bu, Ph.D., associate professor of pediatrics and of cell biology and physiology. The findings will be reported in the December 2nd issue of the journal Oncogene. The article is available online Oct. 25.
"In several types of human cancer, such as breast and colon cancer, a key cell signaling pathway that regulates cell growth and development is overactive because a gene coding for a pathway component has mutated," Bu says.
Increased signal activity from this pathway can lead to abnormal cell proliferation and ultimately to cancer, but researchers have been unable to identify the pathway component responsible for certain types of cancer such as breast cancer. "We believe LRP6 may be the missing link, the long-sought component that turns up the activity of this signaling pathway," Bu says.
To uncover LRP6's role in cancer, Bu's team took slow-growing cancer cells and altered the LRP6 gene so that it made more of the protein. They found that the cancer cells began proliferating more rapidly as a result. When the researchers introduced these aggressive cells into mice, the animals developed tumors twice as large as those caused by the original, slow-growing cancer cells.
Having seen the effect of high-levels of LRP6 in laboratory experiments, Bu and his team looked for higher-than-normal LRP6 gene activity in human tumor samples. "We used patient-matched tumor specimens from the Siteman Cancer Center," Bu says. "We found both colon and breast cancer samples with increased LRP6 gene activity."
"The most interesting was breast cancer," he says. "We found the LRP6 gene had higher than normal activity in five of the eight breast tumors we tested. So, it appears that an increase of LRP6 alone may lead to breast cancer in these cases."
Next Bu and his colleagues plan to screen a larger group of breast cancer samples to see how frequently the LRP6 gene is overactivated in tumor tissue. Because LRP6 is an essential component of a key signaling pathway and located in an exposed position on the surface of cells, Bu believes the protein may be a good target for drugs that decrease its function to slow down or prevent the progression of some types of cancer.
Li Y, Lu W, He X, Schwartz AL, Bu G. LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering -catenin subcellular distribution. Oncology, Dec 2, 2004.
Funding from the American Heart Association and the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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