Etiology and Prevention

Although our foundation of knowledge for the basic science aspects of breast cancer has expanded greatly over the past decade, gaps still remain in our strategies for large-scale prevention due to uncertainties over the underlying causes of the disease and their relative importance. There is an extensive list of factors associated with increased and decreased risk for breast cancer. However, the relative importance of diet, exercise, family history, pregnancy, alcohol, hormone replacement therapy, and other factors remains controversial.

The CBCRP’s newly launched Special Research Initiatives seeks to increase knowledge of and create solutions to the environmental causes of breast cancer.

Two research topics are represented in this section:

Research Conclusions

Common Genetic Variation & Breast Cancer: A Genomic Approach
DNA, the long double-stranded molecule found in a cell’s nucleus, contains the thousands of genes that store hereditary information and controls how a cell operates. Humans are 99.9% identical to each other at the level of their DNA. The remaining 0.1 percent is responsible for differences in our physical features as well as disparities that may increase breast cancer risk. The majority of these differences are DNA sequence variations called single nucleotide polymorphisms (SNPs, pronounced snips). SNPs occur when a single nucleotide—A, T, C, or G—in the genome is altered; many SNPs are quite common. Christopher Haiman, Sc.D., at the University of Southern California, Los Angeles, and colleagues tested a novel genetic (haplotype) approach to identifying genetic markers of non-inherited breast cancer risk. (A haplotype is a combination of genotypes on the same chromosome that tend to be inherited as a group.) Using data from the MultiEthnic Cohort Study, they characterized common SNP patterns in five DNA repair pathways genes: ATM, BRCA1, BRCA2, TP53 and PTEN. Modest evidence of an association between a common haplotype pattern and breast cancer risk was found for the BRCA2 gene. No relationship was seen between SNPs or haplotypes in BRCA1 or PTEN, and no markers were found for TP53 or ATM. These findings advance our understanding of the role that genetic variation plays in breast cancer. Results from this research were published in Human Molecular Genetics 2004; 13(20):2431-41.

Control of Aromatase Expression in Breast Cancer
Most postmenopausal women with breast cancer have tumors that are hormone-sensitive. These tumors are fueled by the hormone estrogen. A class of drugs called aromatase inhibitors is now widely used to treat hormone-sensitive breast cancer in postmenopausal women. These drugs work by blocking the aromatase enzyme and keeping it from converting androgens into estrogen. However, because aromatase inhibitors block the complete production of estrogen, their use can lead to side effects associated with estrogen deficiency, such as bone loss. Ikuko Kijima, M.S., at the Beckman Research Institute of the City of Hope, Duarte, and colleagues studied regions in the human aromatase gene called promoters I.3 and II. These regions regulate aromatase expression in breast cancer. The team identified several protein binding sites in these promoters. They found that one of these proteins, called CCAAT/enhancer binding protein delta (C/EBPD), increased aromatase activity. The team intends to continue to study how promoters I.3 and II regulate aromatase expression. This work could lead to the development of hormone therapies that suppress estrogen production in breast tissue without decreasing estrogen where it is needed. Results from this research appeared in the Journal of Steroid Biochemistry and Molecular Biology 2005; 95(1-5):17-23, and Cancer Research 2006; 66(11):5960-7.

Genetics, Obesity, and Breast Cancer Risk
Obesity appears to decrease breast cancer risk in premenopausal women but increase risk in postmenopausal women. Obesity occurs for complex reasons. Catherine Carpenter, M.P.H., Ph.D., at the University of California, Los Angeles, and colleagues explored whether three genes that appear linked to obesity, LEP-R, beta3AR, and PPARgamma2, also increase breast cancer risk. The team observed a sizeable association between waist-to-hip ratio and the LEP-R variant, K109R, among white pre- and postmenopausal women that confirmed an association between K109R and percent body fat observed in their previously funded CBCRP study. They found associations between measured waist, waist-to-hip ratio, and the Pro12Ala PPAR-gamma variant among African American premenopausal women. They also observed associations between Body Mass Index (BMI) and measured waist and the Pro12Ala PPAR-gamma variant among Hispanic premenopausal women. These findings could help to identify groups of women who are susceptible to obesity and an increased risk of breast cancer.

Preventing Breast Cancer with Ginseng
Ginseng has been used in traditional Chinese medicine for several thousand years to treat numerous ailments. Some scientists have suggested that it may have a role in breast cancer chemoprevention. Michael DeGregorio, Pharm.D., at the University of California, Davis, explored whether ginseng is capable of preventing the development of chemically-induced breast cancer in mice. Dr. DeGregorio divided the mice into four groups: a control group that received no treatment; a group that received ginseng; a group that received the breast cancer drug tamoxifen; and a group that received an investigational breast cancer drug called ospemifene. The mice were treated daily for one year. Dr. DeGregorio found that the number of mice that developed breast cancer in the ginseng group was the same as that in the control group. This finding does not support a role for ginseng in breast cancer chemoprevention. However, other studies have suggested that purified components of crude ginseng, known as ginsenosides, may be useful in cancer prevention. Future studies of these purified active components of ginseng will provide more information as to whether ginseng has any value in breast cancer prevention.

Surrogate Markers for Green Tea
Chemoprevention is the use of drugs, vitamins, or other agents to prevent cancer occurrence. Epidemiologic and laboratory data suggest that green tea may prevent breast cancer by suppressing the growth of tumor cells and their blood supply. Because chemoprevention clinical trials require thousands of patients and decades of follow up, researchers are looking for surrogate markers that can be used to assess in months, rather than years, whether an agent is having an impact. To test four potential biomarkers, Mai Brooks, M.D., and Jian Rao, M.D., at the University of California, Los Angeles, randomized 72 high-risk women to either a daily dose of 800 mg green tea tablets or placebo tablets for three months. Ductal lavage was performed on all of the women before and after they began using the green tea or the placebo. Drs. Brook and Rao will now analyze the fluid obtained through ductal lavage to see whether the green tea had an affect on the four candidate surrogate biomarkers: nipple fluid basic fibroblast growth factor (bFGF), cellular proliferation marker Ki67, and DNA S-phase values. This work will advance our understanding of the role green tea may play in breast cancer prevention and could lead to new ways of assessing the effectiveness of chemopreventive agents in clinical trials.

Studying the Interaction of an Essiac Tea and Food Mutagen
Women who are diagnosed with breast cancer often choose to use complementary and alternative medicines (CAMs) as treatments to supplement conventional therapies or as prevention against another cancer diagnosis. Essiac herbal extract formulations are one of the most commonly used products. Kristen Kulp, Ph.D., at the Lawrence Livermore National Laboratory, and colleagues explored whether Essiac could have a protective effect on breast tumor formation by evaluating the ability of the tonic to prevent tumors caused by PhIP, a dietary carcinogen that is formed in well-cooked meats. The team found that Essiac did not increase or decrease PhIP-induced DNA damage in breast cancer cells. They also found that Essiac had no statistically significant effect on PhIP-induced tumor formation in rats. Overall, the results of this project suggest that Essiac does not protect breast cells from DNA damage or subsequent tumor formation from exposure to the breast carcinogen PhIP. However, the affects of Essiac may be different in humans. Findings from this research were published in Breast Cancer Research and Treatment 2006; 98(3):249-59.

Grants in Progress: 2006

Androgen Receptor Gene and p21 Gene in Breast Cancer
Wei Wang
University of Southern California

Birth Characteristics and Breast Cancer in Young Women
Peggy Reynolds
Northern California Cancer Center

Breast Cancer Lymphedema: Role of Insulin Resistance/FOXC2
Stanley Rockson
Stanford University

Breast Cancer Breast Cancer Chemoprevention with Dietary Herbal Estrogens
Dale Leitman
University of California, San Francisco

Breast Cancer Prevention with Estrogen
Satyabrata Nandi
University of California, Berkeley

Breast Cancer Prevention with Phytochemicals in Mushrooms
Shiuan Chen
Beckman Research Institute of the City of Hope

Breast Cancer Risk Associated with High Mammographic Density
Thea Tlsty
University of California, San Francisco

Estrogen Receptor Beta Agonists to Prevent Breast Cancer
Peter Kushner
University of California, San Francisco

Epstein-Barr Virus in Breast Cancer Tissues
Sally Glaser
Northern California Cancer Center

Grape Seed as a Natural Breast Cancer Chemopreventive Agent
Melanie Ruth Palomares
Beckman Research Institute of the City of Hope

HER-2/neu Gene Variations and Breast Cancer Risk
Michael Press
University of Southern California

The Hygiene Hypothesis and Breast Cancer Risk
Christina Clarke Dur
Northern California Cancer Center

The IGF Pathway & Breast Cancer Risk in African Americans
Susan Neuhausen
University of California, Irvine

PBDEs In Tissues of Women with and Without Breast Cancer
Myrto Petreas
California Department of Health Services

Structural Characterization of Aromatase
Yanyan Hong
Beckman Research Institute of the City of Hope

Targeted Chemoprevention in a Mouse Model for DCIS
Jeffrey Gregg
University of California, Davis

Tea, genes and their interactions on breast cancer
Anna H. Wu
University of Southern California

USC/NCCC Breast Cancer Research Training Program
Ronald Ross
University of Southern California

Research Initiated in 2006

Breast Cancer Metastasis: a Heritable Trait?
Alice Whittemore
Stanford University

Hereditary Breast Cancer and Novel Hispanic BRCA Mutations
Jeffrey Weitzel
Beckman Research Institute of the City of Hope

A Novel Biological Framework for the Role of Xenoestrogens
Shanaz Dairkee
California Pacific Medical Center Research Institute