Prevention: Ending the Danger of Breast Cancer
Prevention – Resuest for Applications (RFAs)
Innovative, Exploratory and Developmental Awards –
Type II
New Investigator Awards
Over 90% of breast cancers are non-hereditary (i.e., sporadic) and incidence might be reduced or avoided by alterations in diet, exercise, or hormonal modification. Identifying these prevention or risk reduction strategies and understanding how they interface with a woman’s underlying immunological, hormonal, cellular, and genetic makeup is the focus of this Priority Issue.
Dietary manipulation is an inexpensive and non-invasive approach to reducing human disease. A major role for diet in affecting breast cancer risk has long been suspected because of the vast differences in breast cancer incidence rates between different populations, and the relationship of this risk to place of residence, independent of ethnic or racial background. Especially appealing are hints that the addition of certain dietary elements, as opposed to large-scale changes in diet, may reduce risk. Once study (Shiuan Chen) is looking at the role of components of grape juice in preventing breast cancer. In another study, the potential for indoles (a dietary component of cruciferous vegetables) as a breast cancer prevention candidate is being explored through medicinal chemistry and computer modeling (Ling Jong). A third study (Pamela Horn-Ross) will test the hypothesis that estrogen-mimicking compounds (called phytoestrogens) in some foods may reduce the risk of breast cancer. Using a unique database containing the content of seven different estrogen compounds in a wide variety of foods, this project will be the pioneering study to examine in a detailed manner the relationship between plant estrogens and breast cancer risk.
Two studies are exploring new aspects of the relationship between hormones and breast cancer. One (Barbara Sternfeld) will use existing data from a study performed for other reasons to explore the relationship between physical activity (thought to reduce the risk of breast cancer) and ovarian function (one of the ways exercise is thought to result in a reduction of breast cancer). The other (Giske Ursin) will explore the hypothesis that use of oral contraceptives is especially detrimental for young women with mutations in the breast cancer susceptibility gene BRCA1.
Together, these studies will provide further clues to the factors that influence the development of breast cancer, and methods to reduce risk.
Prevention – Resuest for Applications (RFAs)
Breast Cancer Prevention with Phytoestrogens in Grape Juice
Shiuan Chen, Ph.D.
Beckman Research Institute of the City of Hope
Grape juice has been found to suppress breast cancer cell growth by preventing the synthesis of the female hormone estrogen, which plays a major role in the development of breast cancer. Approximately 60% of premenopausal and 75% of postmenopausal patients have estrogen-dependent tumors. In estrogen-dependent breast tumors, estrogen stimulates the formation of growth factors that are essential for breast cancer growth. In cells, a protein called aromatase produces estrogen, and in breast cancer patients, some tumors contain an abnormally high level of aromatase, which generates a large amount of estrogen. Therefore, an abnormal expression of aromatase in breast is considered to be a risk factor for breast cancer.
During the previous year, it was found that grape juice stopped the estrogen production in cells in a test tube. Recent experiments using mice demonstrated that the 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. These results suggest the possibility that drinking grape juice may prevent breast cancer.
In this study, more extensive animal studies using mice and rats will be performed to critically evaluate these preliminary findings. In addition, experiments will be designed to identify the active components in grape juice that are responsible for the suppression of breast tumor formation. The latter research will provide us with a scientific basis as to why grape juice is capable of suppressing breast tumor formation in mice. Such information could be very important for designing more selective and effective breast cancer prevention strategies given the ready availability of grape juice.
Innovative, Exploratory and Developmental Awards – Type II
Diet & Breast Cancer in the California Teachers Study Cohort
Pamela Horn-Ross, Ph.D.
Northern California Cancer Center
The specific relationships between a number of dietary factors and the development of breast cancer remain unclear. Clarification of these relationships is necessary to improve strategies for preventing the occurrence of this disease. The proposed research will evaluate several current and emerging hypotheses regarding nutrition and breast cancer risk in an established cohort of over 133,000 California teachers. The dietary components of interest include the role of plant estrogens, antioxidant vitamins, and the balance of dietary fat and fiber consumption.
This study will provide us with a better understanding of the interrelationships between dietary components and breast cancer risk, that is, information that will help guide strategies for breast cancer prevention. Using a recently developed unique database containing the content of seven different estrogen compounds in a wide variety of foods, this research project will be the first-ever prospective study to examine in a detailed manner the relationship between plant estrogens and breast cancer risk. In addition, the size of this study allows us to look at the joint role that other compounds found in fruits and vegetables (including antioxidant vitamins and fiber) play in what was recently described by an international expert review committee as the "probable" protective effect of fruits and vegetables on breast cancer risk. Finally, investigation of the balance of fat and fiber in the diet will provide insight into the controversy regarding the role of dietary fat in the development of breast cancer and thus, improve approaches to dietary prevention.
The California Teachers Study (CTS) cohort was established by investigators interested in environmental, genetic, and nutritional epidemiology, hormonal carcinogenesis, and public health. Participants in the CTS cohort were previously asked about their dietary intake and a wide variety of other lifestyle factors. Each year, approximately 480 members of the cohort will develop breast cancer. We will evaluate our hypotheses by comparing the dietary intake of those who development breast cancer during the next two years to those who don't, taking into account other lifestyle factors.
This project will provide important information on the recent effects of diet on the development of breast cancer and thus, on potentially promising avenues for breast cancer prevention through dietary modification in adult women. This is particularly important for California teachers who, for unknown reasons, have a higher than expected risk of breast cancer. In addition, the findings should add substantially to public health recommendations regarding dietary modification that are likely to be forthcoming in the next several years.
Oral Contraceptives, Hormonal Risk Factors and BRCA1
Giske Ursin, M.D., Ph.D.
University of Southern California- Norris Comprehensive Cancer Center
A large number of breast cancers diagnosed at an early age may be due to genetic changes (mutations) in the breast cancer susceptibility gene, BRCA1. Recent evidence suggests however that not all women with one of these mutations will develop breast cancer. It is possible that other genetic or non-genetic factors play a role in whether or when breast cancer occurs in women with a BRCA1 mutation.
A number of studies have suggested that women who use oral contraceptives at an early age may be at increased risk of breast cancer. There are now a growing number of studies suggesting that use of oral contraceptives may be particularly detrimental in young women with a family history of breast cancer. We have preliminary data suggesting that women with a BRCA1 mutation may have a much higher risk of breast cancer if they have used oral contraceptives than women with no such mutations. However, these findings were based on small numbers, and must be replicated in a larger study.
We propose to conduct a large study to determine to what extent use of oral contraceptives increases the risk of breast cancer in women with a BRCA1 mutation. We also propose to determine whether reproductive factors and physical exercise influences the risk of breast cancer in women with a BRCA1 mutation, and whether women with a BRCA1 mutation have different mammographic density profiles than women with no such mutations.
This study will provide valuable information regarding the role of BRCA1 in breast cancer development, and could yield important results in developing intervention regimens and appropriate counseling for women with a BRCA1 mutation.
New Investigator Awards
Dietary Indole Analogs for Breast Cancer Prevention
Ling Jong, Ph.D.
SRI International
Prevention is the best way of dealing with any disease, and this is particularly true of cancer, with all of its complexities and its often devastating course. Numerous studies suggest an effective role for fruits and vegetables in the prevention of human cancer, especially breast cancer. Such preventive effects are very likely to come from tumor inhibitors that occur naturally in food and plants. Dietary natural products are presumably safe, and thus are very attractive as the lead compounds for developing novel cancer preventive agents.
Indole-3-carbinol (I3C), a dietary component found in cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts, has a striking ability to prevent breast cancer in various laboratory models, and it is currently undergoing Phase I clinical trials for breast cancer prevention in humans. However, I3C itself is far from an ideal breast cancer preventive agent. One serious drawback is that the compound itself is not active against cancer but must be acted on by gastric acid in the stomach to produce the active forms, and it is not known which of its many digestion products is the most important for cancer prevention. Furthermore, the cancer preventive effect may vary considerably between individuals, and at different times in the same individual, because variation in gastric contents could substantially affect the formation of the active forms. Clearly, there is room for improvement.
This research project aims to develop a safe, effective reliable breast cancer preventive agent based on I3C and four of its known active forms. We have found some important structural similarities in the four active forms by using computer modeling and analysis, and we plan to use one active form as the framework and modify it with carefully designed changes. Our goal is an I3C derivative that can be taken orally, retains the ability to inhibit activities associated with cancer onset, and has improved stability, increased clinical effectiveness, consistent results, and minimal toxicity and side effects. This novel breast cancer prevention candidate will be unique because it is a derivative of a dietary natural product whose history of consumption by humans for centuries indicates it is likely to be safe for long-term use.
Our multidisciplinary approach combines lead-based compound design, medicinal chemistry, computer modeling, cell culture biological screening, and tumor biology. The systematic development of compounds is coupled with basic research into mechanisms of action and feedback of the findings to guide design and discovery of improved compounds. Achievement of our goals could have a significant impact on reducing the human and economic costs of breast cancer in California.
Epidemiology of Physical Activity and Ovarian Function
Barbara Sternfeld, Ph.D.
Kaiser Foundation Research Institute
Female athletes often experience changes in their menstrual cycles and generally have decreased levels of the ovarian hormones, estrogen and progesterone. Because lifetime exposure to ovarian hormones is thought to increase the risk of breast cancer, it is reasonable to hypothesize that the hormonal and menstrual cycle changes associated with exercise could reduce the risk of breast cancer. However, the extent to which these changes occur with more moderate levels of recreational and occupational activity typically seen in the population at large is not known. This proposal is for a study of the influence of self-reported physical activity on reproductive hormonal milieu, using available data from the Semiconductor Health Study (SHS). Briefly, the SHS was a large study of adverse reproductive outcomes among workers in the silicon wafer manufacturing plants. One component of the SHS followed a sample of 402 ethnically diverse women for up to six menstrual cycles. The women were interviewed at baseline and then completed daily menstrual diaries and collected daily urine specimens, which were used to measure daily levels of reproductive hormones.
The basic objective of this grant is to further understand the potential role that physical activity, a modifiable behavior, may have on the development of breast cancer. Although we will not directly examine the relationship of physical activity to breast cancer, we will evaluate whether changes in ovarian function occur in the general population in association with such activity. If we find alterations in reproductive hormonal levels in women not engaged in athletic training, this will give additional impetus to public health strategies aimed at promoting physical activity as a preventive measure against breast cancer.
The proposed study is innovative in two respects. First, the SHS itself developed and implemented several innovative methodologies, such as the collection of daily urine samples in a large-scale epidemiological study. Secondly, by utilizing existing data, it allows for a cost efficient, but methodologically sophisticated investigation of physical activity and ovarian function. In addition, the project is multidisciplinary, bringing together the expertise and perspectives of exercise physiology, physical activity epidemiology, reproductive epidemiology, reproductive endocrinology, and occupational health and medicine.
Finally, the project has a potential for translational impact in that it could provide additional impetus for the development of public health strategies aimed at promoting regular participation in physical activity. Although this proposed study will not directly benefit the many women who have already developed breast cancer, it may benefit their daughters, their sisters, their friends and the community at large by giving further motivation on both the individual and community level for adoption of an active lifestyle.
