"Since the use of a selective COX-2 inhibitor caused a significant delay in the onset of breast cancer in mice, there is a potential role for using COX-2 inhibitors to prevent human breast cancer," according to Louise Howe, Ph.D., assistant professor of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, and lead author of the study.
The study, recently published in AACR's journal, Cancer Research, involved the use of genetically bred HER-2/neu mice that overexpress or overproduce the protein HER-2, a condition that occurs in 20-30 percent of breast cancer patients and is associated with poor prognosis for the patient. While advances have been made, there are still not enough therapeutic approaches to treat breast tumors that overexpress HER-2/neu. Recent studies suggest that COX-2, which is overexpressed in about 40 percent of human breast cancers, may be important for mediating HER-2/neu-induced breast tumor formation. COX-2, an inducible enzyme that generates prostaglandins (PG), may be implicated in several biological events throughout the process of tumor development. Therefore, it may be considered a potential target for preventing and possibly treating a number of cancers, including colorectal and now breast.
The first study, from Weill Medical College, randomly tested 50 mouse mammary tumor virus (MMTV)/neu mice that were fed either a diet containing 500 ppm (parts per million) celecoxib or a control diet. Mammary tumors were detected in 50 percent of the control mice at 32.3 weeks of age versus 39.6 weeks of age in the celecoxib-treated mice. The incidence of breast tumors was lower at all subsequent ages for the celecoxib-treated mice relative to control mice. This protective effect was achieved at drug levels that can be safely administered in humans.
The study also showed that MMTV/neu mice express COX-2, which is overexpressed in HER-2/neu positive human breast cancers, allowing researchers to investigate the chemopreventive activity of COX-2 in this mouse model.
A second study, conducted by researchers at Jefferson Medical College, Thomas Jefferson University, confirmed these findings by evaluating the effectiveness of celecoxib in protecting against the development of spontaneous mammary tumors in HER-2/neu mice. At four weeks of age, the mice in this study were fed a diet supplemented with 900 ppm celecoxib, 64 ppm of a COX-1 inhibitor, or an unsupplemented control diet. Tumor incidence was significantly less in the celecoxib-fed mice (74 percent) than the control (97 percent) and COX-1 (91 percent) fed mice. Breast tumors began appearing at 142 days in the control mice, at 160 days in the mice fed the COX-1 inhibitor, and at 200 days in the mice fed celecoxib. The median time for tumor development was 265 days in the mice fed COX-1 inhibitor, 266.5 days in the control mice, and 291 days in the celecoxib mice. Tumor incidence was significantly less in the celecoxib mice (74 percent) than the control (97 percent) and COX-1 (91 percent) mice.
"The results of our study show that celecoxib protects against the development of spontaneous mammary tumors in mice that overexpress HER-2/neu," according to Susan Lanza-Jacoby, Ph.D., professor of surgery, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, lead investigator of the study. "The mice also experienced a significant reduction in the number of tumors, as well as a longer time to disease progression."
Additional epidemiological and human studies are needed to further define the potential implications of these studies for the treatment of breast cancer. "Studies should be conducted to determine whether the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors as protective agents varies according to the HER-2/neu status of breast cancer," said Andrew Dannenberg, MD, Director of Cancer Prevention, New York Presbyterian Hospital-Cornell, New York. "Studies also should concentrate on whether the use of selective COX-2 inhibitors may be more effective in combination with other agents for the treatment of HER-2/neu-overexpressing breast cancers."
More than 203,500 new cases of breast cancer will be diagnosed and more than 39,600 women will die in 2002, according to the American Cancer Society. Breast cancer is the second leading cause of cancer-related death in women.
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 19,000 laboratory and clinical scientists engaged in cancer research in the United States in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention