Posted January 31, 2014
Donald McDonnell, Ph.D., Duke University Medical Center
Novel strategies for chemopreventive or lifestyle approaches to reducing breast cancer incidence are urgently needed. Several studies have shown a correlation between obesity and the development of breast cancer. Furthermore, breast cancer patients taking statins, drugs that inhibit cholesterol synthesis, demonstrate an increased time to recurrence. To decipher the mechanisms by which obesity and cholesterol affect breast cancer incidence and progression, Dr. Donald McDonnell conducted a research project supported by an FY09 Idea Award.
Dr. McDonnell's team found that 27-hydroxycholesterol (27HC), the main metabolite of cholesterol, induces breast cancer cell proliferation by activating the estrogen receptor (ER). Additionally, 27HC was found to activate those nuclear receptors that act as cholesterol sensors and help regulate cholesterol levels in the body, called liver X receptors (LXRs). This finding is one of the first to highlight a role for LXR in breast cancer. Using both genetic and pharmacological approaches, Dr. McDonnell demonstrated that elevation of circulating 27HC significantly increased tumor growth and metastasis in mouse models of breast cancer. These findings and other compelling data form the foundation of an FY12 Idea Expansion Award recently granted to Dr. McDonnell thus enabling him to expand upon this innovative research.
Dr. Erik Nelson, a postdoctoral fellow in Dr. McDonnell's lab and the recipient of an FY08 BCRP Postdoctoral Fellowship Award, conducted studies that show 27HC promotes breast cancer through differential effects on ER and LXR. In contrast to the effects on the growth of primary tumors, the actions of 27HC on metastasis do not appear to involve ER, but instead occur through LXR activation. Moreover, gene expression analysis showed that 27HC modulates the levels of ER and LXR target genes, suggesting that the receptors may mediate not only the downstream activation of cancer-causing genes, but also the pathogenic effects of 27HC directly. Work conducted in the McDonnell lab also showed that macrophages, which express high levels of CYP27A1, a catalyst of 27HC production from cholesterol, promote tumor growth. These findings suggest that lowering total cholesterol may be a way to reduce breast cancer risk, and that interfering with 27HC production may be a useful strategy to prevent and/or treat breast cancer.