Prevention and Risk Reduction: Ending the Danger of Breast Cancer

Prevention is the ultimate solution to the breast cancer crisis; however, our lack of understanding of what actually causes breast cancer hampers the development of effective prevention strategies. Nevertheless, CBCRP-funded researchers are using several plausible theories about causes of breast cancer to devise new ways to prevent the disease:

Research Conclusions

Safer Preventive Drugs: Investigating Naturally Occurring Compounds

Dietary Indole Analogs for Breast Cancer Prevention. Indole-3-carbinol—found in cruciferous vegetables, such as cabbage, broccoli, and Brussels sprouts—is a promising breast cancer preventive. However, when it appears naturally in food, indole-3-carbinol isn't potent enough for use as a preventive therapeutic. Ling Jong, Ph.D., at SRI International, Menlo Park, modified the structure of indole-3-carbinol to create more potent anti-cancer agents. These indole analogs work against various human breast cancer cell lines. In animals, they shrink tumors and can be given orally. These are two highly desirable properties that make indole analogs good candidates for testing as a breast cancer prevention drug. Dr. Jong's team found that their most promising indole analog compounds inhibit the growth of human breast cancer cell lines that require estrogen for growth, as well as those that don't. The indole analogs are highly potent against breast cancer cells that do not respond to tamoxifen, a drug currently used to prevent breast cancer. Against one type of human breast cancer cell, an indole analog was more potent than tamoxifen. The researchers fed low doses of indole analogs to mice; this prevented the growth of mammary tumors (the mouse equivalent of breast tumors) that depend on estrogen. At high doses, the indole analogs stopped the growth of mouse mammary tumors. None of the mice showed any adverse effects. This research shows that indole analogs are strong candidates to be developed into drugs that women-especially those at high risk-could safely take for long periods of time to prevent breast cancer.

Diet and Other Active Lifestyle Modification: What Women can do Now

Diet and Breast Cancer in the California Teachers Study Cohort. Pamela Horn-Ross, Ph.D., of the Northern California Cancer Center, Union City, investigated diet as a possible breast cancer prevention strategy. In 1995—96, as part of the California Teachers Study, over 133,000 female teachers and administrators answered a 16-page questionnaire about their intake of over 100 foods and beverages, and also of vitamins. Dr. Horn-Ross analyzed data from over 111,000 of these women. By the end of 1997, 711 had been diagnosed with invasive breast cancer. No food or beverage appeared to prevent or stimulate breast cancer, except one. Women who drank 20 grams or more of alcohol per day (the amount in two glasses of wine) were more likely to develop breast cancer than women who didn't drink alcohol. The only dietary change this study's findings suggest will help prevent breast cancer is reducing alcohol intake to a drink per day or less.

Exercise, Hormones, and Cancer Prevention. Donna Williams-Hill, Ph.D., of the University of Southern California Keck School of Medicine, Los Angeles, investigated the roles of exercise, hormones, pregnancy, and Vitamin E in the development of breast cancer using the Wistar Furth rat as a model. This rat carries at least three genes that make it susceptible to mammary cancer (the equivalent of breast cancer in humans) and no genes that make it resistant. It is highly susceptible to tumors when given a single dose of a chemical compound called DMBA. The research team found that rats that were exercised had fewer tumors, and the tumors developed later, compared to rats that weren't exercised. The more intense the exercise, the stronger the effect. Pregnancy decreased the number of tumors, but did not increase the amount of time before the first tumor appeared. However, pregnancy was not as effective as exercise alone. Vitamin E had no impact; in fact, rats that exercised and were fed Vitamin E had more tumors than rats that simply exercised. These results indicate that exercise—an amount equivalent to jogging 15 minutes per day, five days per week—is a simple, non-invasive, inexpensive means of cancer prevention. The research team also removed the ovaries of some of the rats and gave them replacement estrogen. These rats did not get tumors at all. This indicates that in order to grow, tumors need some substance the ovaries produce in addition to estrogen, possibly progesterone. This result is interesting in light of the controversy surrounding hormone replacement therapy in post-menopausal women.

Research in Progress

Safer Preventive Drugs: Investigating Naturally Occurring Compounds

Breast Cancer Prevention with Phytoestrogens in Grape Juice. Grape juice suppresses breast cancer cell growth by preventing the synthesis of the female hormone estrogen. About 60% of breast tumors in pre-menopausal women and 75% of those in postmenopausal women depend on estrogen for growth. This suggests that drinking grape juice may prevent breast cancer. Shiuan Chen, Ph.D., at the Beckman Research Institute, City of Hope, Duarte, is isolating compounds from red grape juice and red wine and testing them for their ability to prevent tumor formation in animal cell lines. Dr. Chen's team has found that red wine extract completely stops the action of aromatase, an enzyme that generates estrogen in cells. They have started to study the action of purified extracts from grape juice and red wine in animals. The goal is an affordable preventive medication.

Breast Cancer Prevention by Inhibition of Estrogen Action. Many types of breast cancer need the female hormone estrogen to develop and grow. However, estrogen has enormous benefits to most other tissues in the body. So researchers are looking for ways to reduce estrogen action in the breast, without reducing estrogen in the rest of the body. Vicki L. Davis, Ph.D., at Cedars-Sinai Medical Center, Los Angeles, is studying mice that have been genetically engineered to develop tumors in the mammary gland (analogous to the breast in humans). The test group of mice also have a gene, ERdelta3, that appears to block estrogen action in the breast, inhibit the growth of tumors, and work in the presence of normal estrogen levels. If this turns out to be true, it might be possible eventually to devise a therapy that turns on the ERdelta3 gene to inhibit estrogen action in the breast, while maintaining normal estrogen levels in the rest of the body. So far, the mice with the ERdelta3 gene have fewer tumors than control group mice, and the tumors appeared at later ages.

Breast Cancer Prevention by Analogs of EGCG from Green Tea. Nurulain Zaveri, Ph.D., at SRI International, Menlo Park, is building on previous successful CBCRP-funded research to improve the breast cancer preventive action of a compound found in green tea, epigallocatechin-3-gallate (EGCG). Because of the way EGCG is absorbed and digested in the body, a woman has to drink 8-10 cups of green tea per day to get a preventive effect. Since each cup contains 70 mg. of caffeine, drinking large amounts of green tea leads to caffeine-related side effects, a problem in current studies where women are drinking green tea. This year, Dr. Zaveri has synthesized a chemically-modified version of EGCG. In the lab, this EGCG analog inhibits the growth of breast cancer cells, both those that need estrogen for survival and those that do not. Dr. Zaveri has also set up a method for testing whether this EGCG analog might be better absorbed in the human body. During the coming year, her team will synthesize more chemicallymodified versions of EGCG and test them for action against breast cancer cells and potential ease of absorption in the human digestive tract.

Mechanisms of Reduced Metastasis by Conjugated Linoleic Acid. Conjugated linoleic acid is a naturally-occurring compound found in some sources of dietary fat, including beef and dairy products. In small amounts, it has been shown to reduce the spread of mammary cancer in mice. Kent L. Erickson, Ph.D., of the University of California, Davis, is investigating how conjugated linoleic acid can reduce the growth and spread of tumors. Dr. Erickson has found that mice fed various amounts of conjugated linoleic acid produced lower levels of proteins that are known to enhance the formation of tumors. It took longer for tumors to form in mice fed conjugated linoleic acid than in mice with a diet free of the substance. Fewer tumors spread to the lung in mice fed conjugated linoleic acid, even at a level of 0.1% of the diet. Conjugated linoleic acid also appears to keep breast cancer cells from lodging in the lung and growing, even after they have spread. At the levels it was fed to mice, conjugated linoleic acid does not appear to be harmful to humans; this study is providing additional evidence to support testing it in humans.

Diet and Other Active Lifestyle Modification: What Women can do Now

Bovine Leukemia Virus Infection and Human Breast Cancer Risk. Gertrude Buehring, Ph.D., at the University of California, Berkeley, is testing the speculative hypothesis that bovine leukemia virus is associated with an increased risk of breast cancer. She has previously shown that a majority of women have antibodies to bovine leukemia virus. This virus is found in beef and milk and can be transmitted to humans. It causes mammary tumors in animals (the equivalent of human breast tumors). The antibodies in women may be a response to a live virus, or to a harmless, de-activated part of the virus, and it isn't possible to determine which through laboratory testing. Dr. Buehring is using a case-control study of 338 women to see if women with breast cancer are more likely to have the virus in their breast tissue than women with no history of breast cancer. So far, she has collected 40 tissue samples and solved some of the technical problems of detecting the virus in the samples. If the rate of infection with the bovine leukemia virus is significantly higher in breast tumors than in normal breast tissue, this would justify launching a larger study to determine if the virus can cause some breast cancer.

Estrogen Metabolizing Genes, Soy, and Breast Cancer in Asians. Anna H. Wu, Ph.D., at the University of Southern California, Los Angeles, is studying genes that may interact with soy foods in the diet of Asian women to affect the development of breast cancer. Building on two studies previously funded by the CBCRP, Dr. Wu is collecting and analyzing blood specimens from 1,300 Asian women with breast cancer and an equal number from women who don't have the disease. She is investigating whether the risk of breast cancer is higher in women with particular types of CYP17 and COMT genes, two genes that metabolize the female hormone estrogen, and whether these genes interact with soy in the diet to cause breast cancer. Preliminary results suggest that women with one type of CYP17 gene have a small increased risk for breast cancer.

How Hormones or Environmental Contaminants Interact with Other Known Risk Factors

Upregulation of BRCA1 as a Cancer Preventive Strategy. Colin K. Hill, Ph.D., and Donna Williams-Hill, Ph.D., at the University of Southern California, Los Angeles, are investigating how tumor suppressor genes interact with hormones in the breast, and how these interactions might translate into breast cancer risk. Normal BRCA1/BRCA2 genes help to prevent cancer. The hypothesis of this study is that cells need a minimum level of the proteins produced by these genes to keep from forming tumors, and hormone levels may be associated with how much BRCA1 protein cells produce at various stages of development. The team is analyzing the amount of BRCA1 protein in cells from the mammary glands of rats (the mammary gland in rats is the equivalent of the breast humans) at various stages of development. They eventually propose to study the level of BRCA1 protein in breast tumor tissue and normal breast tissue. The ultimate aim is to understand the critical points in breast development where risk is greatest so that strategies can be designed to offset that risk. It may be possible, for example, to increase the amount of BRCA1 protein in cells during susceptible years of development, or later in life.

Mammographic Density, HRT, and Hormonal Activity Genes. Women whose breast tissue appears denser than average on a mammogram have a higher risk of breast cancer. Thomas Mack, Ph.D., of University of Southern California, Los Angeles, is investigating whether density of breasts is inherited and how certain hormones affect breast density. Dr. Mack's team will compare the breast density of identical twins who are taking or have taken various kinds of hormone replacement therapy. After adjusting for any other pertinent characteristics, they will determine if the hormones are causing any difference in breast density. The team is also investigating how estrogen metabolism genes influence breast density, by comparing breast density among sets of identical twins (who have identical estrogen metabolism genes) and fraternal twins (who are more likely to have different estrogen metabolism genes). The team has collected mammograms and interviewed approximately 700 pairs of twins. They are in the process of comparing the mammograms, collecting medical records about the twins' intake of hormone replacement therapy, and collecting saliva samples for DNA analysis.

Genetic and Environmental Modifiers of Breast Cancer Risk. Argyrios Ziogas, Ph.D., of the University of California, Irvine, is investigating how three types of genes interact to raise or lower breast cancer risk. The first type of genes are BRCA1 and BRCA2, on which abnormalities are already known to increase a woman's risk of breast cancer. The second type of gene interacts with cancer-causing chemicals in the environment and may elevate breast cancer risk. The third type of gene is involved in the metabolism of the hormone estrogen. Dr. Ziogas is using data from the unique resource of a breast and ovarian cancer registry of 1,176 families, a questionnaire providing environmental exposure and lifestyle information, and analysis of the families' genes. Results should add to our understanding of the BRCA genes' role in breast cancer, and of interactions between BRCA genes and genes that interact with environmental contaminants and estrogen. This could lead to improved individualized risk prediction, and targeted preventive strategies.

Research Initiated in 2001

Safer Preventive Drugs: Investigating Naturally Occurring Compounds

Evaluation of Essiac Tea to Prevent Mammary Tumors. Essiac tea, an herbal mixture introduced in the 1920s to treat cancer, is commonly used today by breast cancer survivors to try to prevent recurrence. The individual herbs used in one Essiac tea mixture have biological activities associated with decreasing cancer risk. Many herbs used in Essiac tea have long histories of use in Asian diets and medicine. Yet there are no published scientific studies evaluating Essiac tea's effectiveness in preventing breast cancer. Michelle Bennett, Ph.D., of the Lawrence Livermore National Laboratory, will investigate whether Essiac tea inhibits mammary tumor growth in mice and rats.