October 1994, researchers identified the BRCA1 gene on chromosome 17. Inherited mutations to BRCA1 were linked to dramatically elevated risks of breast and ovarian cancers in women. The connection between the flawed gene and disease, however, was made through the statistical association techniques of gene mapping and not through any understanding of the molecular activity of the gene.
Now, in the September 11 issue of Nature, University of Pennsylvania Medical Center researchers report that one way functional BRCA1 limits tumor growth is by inducing p21WAF1/CIP1, another gene that inhibits cell division by blocking the DNA replication phase of the cell's reproductive cycle. A hallmark of cancer is uncontrolled cell division leading to rapid tumor growth, so that p21's regulatory role in maintaining healthy tissues is critically important.
"BRCA1 is clearly a tumor suppressor, because people who inherit mutations in this gene are much more likely to develop certain cancers," says senior author Wafik S. El-Deiry, MD, PhD, an assistant professor of medicine and genetics at Penn and an assistant investigator with the Howard Hughes Medical Institute. "But before now we had no idea how it functions to suppress cancer growth. In this study, we identify the first molecular target of action for BRCA1."
The findings suggest a number of approaches that might prove effective in treating breast and ovarian cancers. Scientists could screen drug compounds for the potential to activate p21 without the presence of BRCA1, for example, as a way to slow or stop tumor growth. Gene therapy tactics to reintroduce working BRCA1 where mutations have disabled the gene, or to replace missing p21 or enhance its activity might also prove useful in countering these cancers -- and, in fact, efforts to develop such strategies are currently under way, according to El-Deiry.
Sometimes called a universal inhibitor because of its potent ability to arrest cell division in all cells studied, the p21 gene was first cloned by El-Deiry in 1993 while he was a senior clinical fellow in the laboratory of Bert Vogelstein, MD, at The Johns Hopkins University in Baltimore. Vogelstein is widely recognized for his work on genetic abnormalities in colorectal cancer, in which the p53 tumor suppressor is frequently mutated.
"We found p21 as a target of p53," El-Deiry recalls. "At about the same time, investigators in the cell-cycle field found that the p21 protein interacts with and inhibits certain enzymes called kinases that drive the cell reproductive cycle. It then became evident that p21 was involved in inhibiting the cell cycle after DNA damage."
Such damage is often the precursor to cancer, he explains.
"Knowing about this interaction between p53 and p21, we decided to look to see if BRCA1 might also shut down the cell cycle by inducing p21 and discovered that it did."
Several experiments are described in the Nature paper. In one, mutant BRCA1 derived from patients with familial breast cancer failed to induce p21 in cultured human cancer cells and failed to inhibit progression of the cell cycle in those cells. In another, functional BRCA1 was unable to inhibit the cell cycle in cultured human cancer cells lacking the p21 gene.
"From those results, we concluded that p21 is required for the cell-cycle inhibitory effect of BRCA1," El-Deiry says.
The lead authors on the Nature study are Kumaravel Somasundaram, DVM, PhD, and Hongbing Zhang, MD. The laboratories of coauthors Barbara L. Weber, MD, an associate professor of medicine and genetics at Penn, and Jonathan D. Licht, MD, at Mount Sinai School of Medicine, collaborated significantly on the research.
"The close scientific cooperation over the last two years between our group, which studies p21, and Barbara Weber's group, which studies BRCA1, led directly to the success of our combined efforts," El-Deiry notes. Additional coauthors are Yi-Xin Zeng, MD, PhD; Yi Peng, MD; Hongxiang Zhang, MD, and Gen Sheng Wu, MD, PhD, at Penn, and Yariv Houvras, BS, at Mount Sinai. Weber and El-Deiry are also members of the Penn's Cancer Center.
Support for this work was provided by the National Institutes of Health, the Breast Cancer Research Foundation, and the Howard Hughes Medical Institute.
The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu) and to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.
Journal
Nature