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

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, studied mice that were genetically engineered to develop tumors in the mammary gland (analogous to the breast in humans). The test group of mice also had a gene, called ER.3, that appears to block estrogen action in the breast. The mice with the ER.3 gene had fewer tumors than control group mice, probably because the tumors appeared at later ages. Late age at onset of tumors is a benefit to the test group; a comparable delay in women would allow them to remain tumor-free for more years of life. This research could potentially lead to a therapy that turns on the ER.3 gene to inhibit estrogen action in the breast, while maintaining normal estrogen levels in the rest of the body. The team also treated both groups of mice with isoflavones, substances found in soy products, at levels 3 times higher than the equivalent amount generally recommended to postmenopausal women. This provided no protection from mammary tumors for either group of mice.

Research in Progress

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 cancer. Michelle Bennett, Ph.D., of the Lawrence Livermore National Laboratory, fed one group of rats with water and another with a 3% solution of an Essiac herbal tonic. All rats were then exposed to the same cancer-causing substance. Eighty-two percent of the rats fed the Essiac tonic had mammary tumors, which are the equivalent of breast tumors in humans, compared to 71% of those fed water. The rats fed Essiac also had twice as many tumors as the rats fed water. The Essiac tonic appeared to promote, rather than prevent, the formation of tumors. The researchers plan to test Essiac tea on rats whose Her-2/Neu genes have been altered to cause the mice to spontaneously form mammary tumors.

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 called matrix metalloproteinases 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

Upregulation of BRCA1 as a Cancer Preventive Strategy.

Colin K. Hill, Ph.D., at the University of Southern California, Los Angeles, is 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 produce proteins, also called BRCA1 and BRCA2, that help to prevent cancer. The team has found that, in rats, levels of the BRCA1 protein rise as the animals enter puberty. They also found that rats bred to be susceptible to mammary cancer (the equivalent of breast cancer in humans) have lower levels of BRCA1 than rats bred to resist mammary cancer. In addition, the team found strong evidence that hormones control the levels of BRCA1. The ultimate aim of this research 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.

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. 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 also has evidence that this EGCG analog might be better absorbed in the human digestive tract than the EGCG found in green tea.

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 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. The team has collected and analyzed blood samples from 90% of the women. So far, the researchers have found that eating soy foods during teenage and adult years lowers the breast cancer risk of Asian women, and that physical exercise can reduce one's breast cancer risk.

Active Lifestyle Modification: What Women Can Do Now

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 is comparing 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). So far, the team has collected mammograms and interviewed approximately 700 pairs of twins, received DNA samples from 239 women, and documented hormone replacement therapy from medical records from 155 physicians.

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 types 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. Preliminary results show that starting menstruation at an early age changes the breast cancer risk posed by two genes called CYP1A1 and COMT. Another gene, called GSTT, is associated with breast cancer risk. In this population-based sample, 3.3% of women with breast cancer have cancer-promoting mutations in their BRCA1 genes, and 1.2% of women have this type of mutation in their BRCA2 genes. Results from this study could improve risk prediction for individual women.

Research Initiated in 2002

Safer Preventive Drugs: Investigating Naturally Occurring Compounds

Breast Cancer Prevention with Estrogen.

Having a baby before age 20 protects a woman from breast cancer. Satyabrata Nandi, Ph.D., at the University of California, Berkeley, is testing in mice and rats a 7-21 day hormone treatment with levels of estrogen comparable to those during pregnancy. Those mice and rats, along with mice and rats that haven't had the hormone treatment, will then be given a cancer-causing substance, to see if the hormone treatment provides protection from mammary cancer (the mouse/ rat equivalent of breast cancer).

Fiber, Estrogen, and Breast Cancer in Mexican American Women.

Mexican American women in the US have the lowest rate of breast cancer of any major ethnic group. Malcolm C. Pike, Ph.D., at the University of Southern California, Los Angeles, is investigating whether the high-fiber diet these women eat affects the way their bodies process the hormone estrogen and whether this is responsible for their low rates of breast cancer.

Risk Reduction and Identification

Using Scientific Text to Identify Breast Cancer Risk Factors.

Breast cancer risk factors are characteristics women have—such as a type of gene or not having a baby before age 20—that raise their risk for the disease. Catherine L. Blake, M.S., at the University of California, Irvine, will construct an interactive computer system to search thousands of scientific articles for information about various characteristics women with breast cancer may have. She will then compare the frequency of these characteristics among women with breast cancer to the frequency in the general population. The goal is to find new risk factors for the disease.

Using Microarrays to Estimate Breast Cancer Risk.

Bradley C. Ekstrand, M.D., Ph.D., at Stanford University, is testing the hypothesis that breast cancer is associated with abnormal genes that govern the mechanisms cells use to repair DNA damaged by x-rays. His research team will expose blood samples—from women with breast cancer and those without the disease—to x-rays, and use a technology called microarrays to measure how the genes respond. The team will then see if differences in the way genes respond can be used to predict which women have cancer.