The work also provides further evidence about how estrogen helps activate a disease that afflicts thousands of American women each year.
Dr. Ellis Levin, a professor of medicine, biochemistry and pharmacology at UCI, and colleagues at the Long Beach Veterans Administration Medical Center and Georgetown University Lombardi Cancer Center have identified how the healthy BRCA1 gene prevents the growth and survival of breast cancer cells. The gene accomplishes this by keeping estrogen and growth factor molecules from sending chemical messages through specific signaling pathways on the surface of breast cancer cells – signals that can cause a tumor to grow.
When the BRCA1 gene is mutated, however, it can no longer block this signaling activity from stimulating the growth and survival of cancer cells. The findings suggest that drugs developed to block estrogen signaling at these specific pathways can help curb the incidence of breast cancer in women. The study appears in the July issue of Molecular and Cellular Biology.
Levin said that the findings give further insight into how estrogen can interact with mutant BRCA1 to promote the development of breast cancer. This discovery is important, he added, because women who take estrogen supplements for more than five years to treat menopause symptoms increase their chances of developing breast cancer by about 25 percent.
"The therapeutic goal is to develop estrogen inhibitors that would prevent these types of undesirable effects, yet preserve the positive effects that prevent osteoporosis or hot flashes. Alternatively, enhancing or restoring normal BRCA1 protein function is another approach to consider in women with such BRCA1 mutations," said Levin, who also is chief of endocrinology at UCI and at the VA Medical Center.
It has been long established that mutations in BRCA1 genes strongly increase the risk of breast and ovarian cancer in women and prostate cancer in men; up to 80 percent of women who have this mutated gene ultimately develop breast cancer. Healthy BRCA1 genes are involved with repairing DNA damage, promoting chromosome stability and regulating cell growth activity, but this study has identified a novel and potentially important role as a tumor suppressor. The researchers only studied the tumor-suppressing role of BRCA1 in breast cancer.
Mahnaz Razandi and Ali Pedram of UCI and Dr. Eliot Rosen of Georgetown assisted with the study. The Department of Veterans Affairs, Department of Defense, the National Institutes of Health, the Avon Products Breast Cancer Research Foundation and the Susan B. Komen Breast Cancer Foundation provided support.
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Journal
Molecular and Cellular Biology