U-M researchers identify gene involved in breast cancer

July 26, 2007

ANN ARBOR, Mich. -- Researchers at the University of Michigan Comprehensive Cancer Center have identified a gene linked to the development of an aggressive form of breast cancer.

The researchers found that the gene, FOXP3, suppresses tumor growth. FOXP3 is located on the X chromosome, which means a single mutation can effectively silence the gene. This is unusual, as only one other gene linked to cancer has been found on the X chromosome.

When one copy of the FOXP3 gene is silenced, the researchers found in studying mice, 90 percent of the mice spontaneously developed cancerous tumors. The researchers also looked at FOXP3 in human breast tissue cells, comparing cancerous and non-cancerous cells. FOXP3 was found to be either deleted or mutated in a substantial portion of the cancer sample: about 80 percent of the cancer tissues studied did not express the gene at all.

In addition, the researchers found FOXP3 to be a repressor of HER-2, a protein that typically marks a more aggressive form of breast cancer. The researchers believe FOXP3 suppresses the HER-2 gene. HER-2 can be activated by many different factors, but the researchers found that when FOXP3 is normal, it keeps HER-2 levels low; when FOXP3 is missing or mutated, HER-2 levels are likely to rise.

The researchers have shown that FOXP3 was reduced or missing in about 80 percent of the more than 600 cases of breast cancer tissue examined. At this point, the researchers do not know if FOXP3 can predict breast cancer risk, like the BRCA1 and BRCA2 genes, both of which are linked to a higher risk of breast cancer.

"FOXP3 defects promote cancer development. We do not know whether this is a genetic defect that puts women at higher risk. For treatment, this gene could be quite important, but for diagnosis, it's too early to tell," says study author Yang Liu, Ph.D., deNancrede Professor of Surgery at the U-M Medical School and co-director of the cancer immunology program at the U-M Comprehensive Cancer Center. Results of the study appear in the journal Cell.

Initially, the researchers were studying FOXP3's role in autoimmune disease, when they noticed that female mice with one copy of the mutated form of the gene were developing breast cancer. Moreover, the tumors expressed high levels of ErbB2, the mouse equivalent of HER-2. Breast cancer is rare in mice, and ErbB2-positive breast cancer is even more rare.

"FOXP3 is the first X chromosome-linked gene that suppresses breast cancer and represses the HER-2/ErbB2 oncogene. Given the significant role HER-2 plays in breast cancer and the widespread defects we found on FOXP3, it is likely that this gene play an important role in suppressing breast cancer," says Pan Zheng, M.D., Ph.D., associate professor of surgery and pathology at the U-M Medical School.
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The research is still in early stages. No predictive or diagnostic test is available involving this gene finding. More than 180,000 women will be diagnosed with breast cancer this year, and 40,900 will die from the disease, according to the American Cancer Society. For information about breast cancer and currently available genetic tests, visit www.mcancer.org or call the U-M Cancer AnswerLine at 800-865-1125.

In addition to Zheng and Liu, U-M study authors were Lizhong Wang, Xing Chang, Huiming Zhang, Weiquan Li, Yan Liu, Yin Wang, Bae Keun Park and Cun-Yu Wang. Additional authors are Tao Zuo, Carl Morrison, Michael W.Y. Chan, Jin-Qing Liu, Chang-gone Liu, Rulong Shen, Xingluo Liu, Tiany Yang, Tim H.-M. Huang, and Richard Love from Ohio State University; and Virginia Godfrey from the University of North Carolina, Chapel Hill.

Funding for the study was from the National Institutes of Health and U.S. Department of Defense.

The University of Michigan has filed a patent application on this research technology, and is currently looking for a corporate partner to help bring the technology to market.

Reference: Cell, Vol. 129, issue 7, pp. 1275-1286

University of Michigan Health System

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