Prevention and Risk Reduction: Ending the Danger of Breast Cancer
The CBCRP is supporting two main approaches to breast cancer prevention. The first aims at improving our understanding of risk factors as a basis for lifestyle changes to reduce the impact of these factors. Elucidating the precise role of exercise, diet, early pregnancy and other hormone-affecting events, are important examples of this approach.
The second approach aims at developing products that directly prevent or help repair the early cellular changes that can lead to breast cancer. Here, investigation into natural products offer the prospect of discovering nontoxic, efficacious compounds without adverse side effects, that might relatively quickly become available.
Conclusions
There is a great deal of experimental, clinical and epidemiologic evidence that hormones play a major role in breast cancer. Viewed in this way, the known risk factors for breast cancer can be understood as those affecting the cumulative exposure of the breast to estrogen and, perhaps, progesterone. Thus, many of grants funded by CBCRP examine ways this exposure can be beneficially modified. Catherine Carpenter, Ph.D., at the University of Southern California School of Medicine, Physical Activity: Impact on Hormones and Breast Cancer Risk following up on her previous reports of the benefits of exercise for postmenopausal women, found that breast cancer risk was substantially reduced among women with stable weight (less than 17% gain) who maintained a high level of exercise both before and after age 40. One explanation for this reduction may be that strenuous exercise, by promoting a leaner body mass, may affect hormone levels known to be associated with the presence of excess body fat. Satyabrata Nandi, M.P.H.,Ph.D., at the University of California, Berkeley, reported on the Identification of Pregnancy—Associated Breast Cancer Genes. In this 1-year IDEA pilot grant, he compared the gene expression of virgin and previously pregnant rats. It is known that pregnancy in women by the age of 18 provides a significant (30%+) lifetime reduction in breast cancer risk. However, the genetic basis for this protection has not been identified. In this project a novel candidate gene, termed RMT1, was identified and gene was found to be expressed in a majority (74%) of rat tumors compared to normal mammary cells. The RMT1 sequence was not present in DNA/protein databases, and it appears to be mammary glandspecific. Dr. Nandi was funded in 1998 through a 3-year RFA award from the California CBCRP to conduct further studies on RMT1 and to search for additional pregnancy-associated breast cancer genes.
Research in Progress
Pamela L. Horn-Ross,Ph.D., of the Northern California Cancer Center, conducted a study to address two questions relevant to our understanding of the etiology of breast cancer: (1) whether estrogens found in plant foods reduce breast cancer risk in amounts commonly consumed by non-Asian postmenopausal women; and (2) whether obesity increases breast cancer risk only when a woman's diet does not contain a sufficient amount of these plant estrogens. Preliminary analyses suggest that recent consumption (i.e., within the year prior to breast cancer diagnosis) of foods containing plant estrogens did not impact breast cancer risk either positively or negatively in the study group of non-Asian postmenopausal women. Consistent with her second hypothesis, she found a slight suggestion that obesity increased a woman's risk of breast cancer only when her diet did not include a substantial amount of plant estrogen-rich foods. However, this association was not statistically significant. While further analyses are underway to verify these initial observations, at present her study suggests that foods rich in plant estrogens do not appear to be useful in breast cancer prevention at levels commonly consumed by non-Asian California women.
How hormone levels may be affected by exercise is being investigated by Lisa Shames, Ph.D., M.P.H., at the University of Southern California School of Medicine, who is investigating the relationship of exercise to ovarian function across a range of physical activity—a range that non-athletes might reasonably be expected to maintain. She has to date just finished collecting all of the blood and urine samples necessary and will complete the hormone assays and data analysis during the coming year.
Women who have breast cancer do not die from the primary cancer in the breast but from the consequences of its metastasizing to other parts of the body; how to prevent this is a key question being investigated by Kent Erickson, Ph.D. of the University of California, Davis. Dr. Erickson has shown that when animals were fed high levels of fish oil, breast tumor growth was slower and the level of metastasis to the lung was decreased when compared to animals fed a diet containing a vegetable oil, safflower oil. The continuation of their work will focus on the possible mechanisms underlying this phenomenon: whether fish oils decrease a tumor's ability to stimulate growth of its own blood vessels, and decrease the specific enzymes necessary for metastasis.
Nurulain Zaveri, Ph.D., at SRI international is continuing the chemical synthesis of derivatives from a component of green tea, epigallocatechin-3-gallate and testing them for their ability to prevent breast cancer. Several of these newly-synthesized compounds are showing biological activity of cell growth inhibition equal to or greater than the parental compound from green tea. These will be tested in mouse models of breast cancer. Gary Firestone, Ph.D. at the University of California, Berkeley is examining how a compound produced in Brussels sprouts, cabbage and broccoli, called indole-3-carbinol (IC3), actually works to inhibit cancer cell growth. He is finding that IC3 causes a decrease in the cellular amounts of proteins that regulate the ability of cells to divide. Interestingly, the growth inhibition appears to be effective in both tamoxifen-resistant and tamoxifen-sensitive cells. IC3 has a low toxicity and, because of its presence in the natural diet, there is a promising potential for its use as a long-term preventative agent.
Recently Initiated Research
In 1998 CBCRP awarded 4 grants for the study of prevention of breast cancer. Pamela Horn-Ross, Ph.D., of the Northern California Cancer Center will conduct the first prospective study to investigate in detail the relationship between plant estrogens and breast cancer risk using a recently developed unique database containing the content of seven different estrogen compounds. She will examine the role of plant estrogens, antioxidant vitamins, and the balance of dietary fat and fiber consumption, among other factors. Ling Jong (SRI International) and Shiuan Chen (Beckman Research Institute of the City of Hope) will focus on specific dietary components. Dr. Jong's goal is to develop a safe, effective reliable breast cancer preventive agent based on Indole-3-carbinol (I3C), (a dietary component found in cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts), which is currently undergoing Phase I clinical trials. Dr. Chen will investigate the chemopreventive action of grape juice using two animal models, and try to identify the active components in grape juice. He is following up on intriguing laboratory experiments showing that grape juice (in particular red seedless grape juice) stopped estrogen production in cells in a test tube and that tumors implanted in mice fed with a very small amount of grape juice daily for 5 weeks were one-third the size of those in similarly implanted mice not given grape juice.
Giske Ursin, M.D., Ph.D., of University of Southern California's Norris Comprehensive Cancer Center, following up on some preliminary indications, will investigate whether women who have a BRCA 1 mutation and who use oral contraceptives have a much higher risk than women without this mutation who use oral contraceptives.
