Prevention and Risk Reduction: Ending the Danger of Breast Cancer
Only a maximum of 20% of breast cancer is thought to be due to inherited genes. Thus, as much as 80% of breast cancer is caused by factors other than inherited genes; namely environmental and lifestyle factors. The incidence of breast cancer thus has the potential to be reduced or avoided by alterations in our environment, our diet, physical exercise or hormone levels. Identifying prevention strategies and understanding how they interface with a woman's underlying immunological, hormonal, cellular, and genetic makeup is a CBCRP Priority Issue. Much of the work that CBCRP funds that looks at risk identification and risk reduction is now aimed at understanding the individual lifestyle differences between women who contract breast cancer and women who do not. Many funded projects examine specific dietary factors to understand the molecular basis for their possible components into preventative agents.
Research Conclusions
Gary Firestone, Ph.D. from the University of California, Berkeley completed a 2–year IDEA project to study Dietary Indole Inhibition of Breast Cancer. A naturally occurring compound, called indole–3–carbinol (I3C), produced in cabbage, broccoli, and Brussels sprouts can inhibit the growth of human breast cancer cells grown in the laboratory. Dr. Firestone found that I3C works by causing a drop in the amount of a critical protein (CDK6) needed for cells to pass through a cell division checkpoint, and also causes an inhibition of a functionally related protein, called CDK2. Importantly, I3C was found effective for both tamoxifen–sensitive and tamoxifen–resistant breast cancer cells. I3C has promise both as a preventative compound and as a treatment option. For example, it could be used as adjunct therapy with tamoxifen and for breast cancers where the only current options are surgery and radiation therapy. The results of this project were published in the Journal of Biological Chemistry (Feb 13,1998; 273(7): 3838–47) and in Cancer Research (Mar 15, 1999; 59(6): 1244–51). In 1999, the CBCRP funded Dr. Firestone and a postdoctoral fellow in his lab for new grants to continue the development of this project in a pre–clinical direction.
Research in Progress
Shiuan Chen, Ph.D. at the Beckman Research Institute of the City of Hope is looking further into some intriguing findings that show that grape juice suppresses breast cancer cell growth. Grape juice seems to prevent the synthesis of estrogen, the female hormone linked to breast cancer. Previous experiments had demonstrated that tumors implanted in mice fed grape juice daily for 5 weeks were one–third the size of those in mice not fed grape juice. Dr. Chen is performing more extensive animal studies using mice and rats to critically evaluate these preliminary findings. During the last year, he has worked out details of the animal experiments, initiated the separation of the active components in grape juice, and found that red wine extract, but not white wine extract, contains similar chemicals that can suppress estrogen formation.
Kent Erickson, Ph.D. at the University of California, Davis is continuing a project to determine how dietary fat could be altered to reduce the growth and spread of breast cancer. His first aim is to test the effects of dietary fat on metastasis, because most deaths from breast cancer are due to the spread of the tumor. He has found that when animals are fed high levels of fish oil, breast tumor growth is slower and the level of metastasis to the lungs is decreased compared to animals fed a diet containing safflower oil. This suggests that the effect of fish oil may be to decrease levels of the protein that stimulates growth of new blood vessels into tumors. Dietary fat may also alter levels of specific enzymes associated with tumor growth and metastasis. For example, breast tumors produce an unique enzyme that is increased in animals fed the vegetable oil diets, whereas the levels of a natural inhibitor of that enzyme are increased in tumors of animals fed the fish oil diet.
Pamela Horn–Ross, Ph.D. of the Northern California Cancer Center is addressing two questions relevant to our understanding of diet and breast cancer. First, do estrogen–containing plant foods eaten in amounts commonly consumed by non–Asian postmenopausal women reduce breast cancer risk? Second, does obesity increase breast cancer risk only when a woman's diet does not contain a sufficient amount of plant estrogens? Preliminary analyses suggest that recent consumption (i.e., within the year prior to breast cancer diagnosis) of foods containing plant estrogens does not impact breast cancer risk in non–Asian postmenopausal women. Second, there was a tendency for obesity to increase a woman's risk of breast cancer, but only when the diet did not include a substantial amount of plant estrogen–rich foods. At present, this 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 women.
Ling Jong, Ph.D. from SRI International is developing a safe, effective, and reliable breast cancer preventive agent, without the undesirable side effect of tamoxifen, based on a tumor–inhibiting compound that occurs naturally in cruciferous vegetables, such as cauliflower and Brussels sprouts. This compound, called indole–3–carbinol (I3C), is known to be converted into several different active forms in the body. Dr. Jong designed and synthesized variations of 3–3'–diindolylmethane (DIM), which is a major active form of I3C, and discovered four active analogs. One analog has 15 times the growth inhibitory activity of DIM. Computer–aided molecular modeling is being used to correlate bioassay results with molecular structure. Understanding how structural changes in the compound affect anti–tumor activity will help generate more active and promising cancer preventive agents in the future.
Nurulain Zaveri, Ph.D. from SRI International is continuing a New Investigator project to develop and test more effective compounds based on an active anti–cancer agent from green tea, called epigallocatechin–3–gallate (EGCG). Many breast cancer survivors practice alternative therapy by using naturally occurring dietary compounds. In many cases, it is proving very difficult to extract, purify, and study these compounds using the pharmaceutical methods of Western medicine. However, these compounds, including EGCG, are excellent starting points for rational drug design. Dr. Zaveri's project is addressing the critical issues of potency and absorption properties to select EGCG derivatives as new candidate breast cancer therapeutics.
Recently Initiated Research
Three grants awarded in 1999 also address the Prevention and Risk Reduction Priority Issue. Donna Williams-Hill, Ph.D. at the University of Southern California, is investigating the mechanisms by which exercise may reduce risk of breast cancer. Many studies have been conducted, but it is not yet known what types, durations or intensities of exercise are sufficient and most effective, and for whom. By using a rat model, Dr. Hill is controlling for several of the factors that have made human studies on exercise difficult. Next, Vicki Davis, Ph.D. at the Cedars Sinai Medical Center, is investigating whether it is possible to obtain protective effects against breast cancer by inhibiting estrogen action in the breast, while maintaining the important beneficial effects of estrogen on the rest of the body, such as protecting against heart disease and osteoporosis. She is looking closely at a natural variant of the estrogen receptor, called estrogen receptor alpha. Finally, there are indications that certain dietary patterns are associated with lower breast cancer risk. Most notable of these is a diet rich in soy products, which seems to lessen the impact of estrogen on breast cells. Anna H. Wu, Ph.D. from the University of Southern California, is conducting a case-control study to investigate soy-estrogen metabolizing gene interaction, specifically variants of the CYP17 and COMT genes. This large study (which will result in a sample size of approximately 1300 cancer cases) is necessary to sort out the complex and interrelated lifestyle/environmental and genetic factors in breast cancer development.
