TRENDS IN RESEARCH AND TRIAL UPDATES FOR BREAST CANCER DETECTION AND TREATMENT IMPLICATIONS FOR SURGEONS

COX-2 Inhibition in Breast Cancer

It is well known that cyclooxygenase-2 (COX-2) is overexpressed in colorectal and other types of cancer. Furthermore, from animal and epidemiologic studies, it appears that certain non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit tumorigenesis and reduce the incidence of some cancers, including gastrointestinal cancers. According to Timothy Hla, PhD, Professor of Physiology, Genetics, and Developmental Biology, University of Connecticut School of Medicine at Farmington, researchers have begun to investigate the potential role of COX-2 in breast cancer and the mechanism by which certain NSAIDs may disrupt breast cancer cell pathways.

The Potential Role of COX-2 in Breast Cancer
In one Finnish study, Ristimaki and colleagues investigated COX-2 expression in about 1500 patients with breast cancer. Using rigorous immunohistochemical techniques, these re-searchers found that 37% of breast cancer tissue expressed high levels of COX-2, and 90% expressed moderate levels of COX-2. “These findings are significant in that normal breast tissue does not express COX-2, and high COX-2 expression is correlated with poor distant disease-free survival,” Dr. Hla explained.

Hla and colleagues then investigated whether COX-2 overexpression in breast tissue is sufficient to induce tumorigenesis. After introduction of human COX-2 gene via a mammary tumor virus promotor into mice, the researchers found COX-2 expression in the mammary gland to be zero in normal control mice, minimal in virgin transgenic mice, and high in pregnant and lactating transgenic mice. In mice expressing COX-2, high levels of prostaglandin, particularly prostaglandin E2, were also found. In female virgin transgenic mice, minor precocious lobuloalveolar differentiation and increased expression of prostaglandin-dependent B-casein gene were observed, and this was reversed by treatment with the COX-2 inhibitor indomethacin. In addition, a delay in mammary gland involution was correlated with decreased apoptosis of mammary epithelial cells in transgenic mice. “Overall, if the transgenic animals did not become pregnant, they did not develop high levels of COX-2 expression and did not develop cancers. However, after cycles of pregnancy and lactation, almost all transgenic mice developed mammary tumors,” Dr. Hla explained. Data further suggested that “COX-2 expression in the mammary gland can lead to invasive carcinoma development, and this appears to require prostaglandin synthesis. Further, when the transgenic mice were placed on COX-2 inhibitors, tumor development was suppressed in 80% of cases.”

Conclusion
According to Dr. Hla, the mechanism of COX-2 in inducing tumor growth requires further study, but may include angiogenesis or dysregulation of apoptosis. Indeed, COX-2 tumor cells showed reduced levels of Bax and Bcl-x proteins and increased levels of Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells may be sufficient to promote tumorigenesis. “These and other data suggest a scientific basis for further study of NSAIDs, particularly COX-2 inhibitors, for their potential effects on tumor biology. Clearly, whether this effect will have a role in breast cancer prevention or treatment needs to be determined,” Dr. Hla concluded.