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.

Two research topics are represented in this section:

Research Conclusions

Epstein-Barr Virus in Breast Cancer Tissues
While some studies have reported a link between breast cancer and the Epstein-Barr virus (EBV), others have not. This could be because it is very difficult to measure EBV in breast tumors. Sally Glaser, Ph.D., at the Northern California Cancer Center, Fremont, tested a battery of laboratory tests she developed to detect EBV on stored breast cancer tissues. Applying the tests to tumor tissue from non-Hispanic white and Latina breast cancer patients, Dr. Glaser and her team found very low levels of EBV in only a small number of patients, which indicated that EBV could have caused the tumors to develop. They also found that Latinas were more likely than non-Hispanic white women to have higher levels of the virus; that tumors with EBV tended to occur in women with more advanced and aggressive disease at diagnosis; and that there was no indication that EBV affected survival. These findings suggest that EBV may play some role in increasing breast cancer aggressiveness in a proportion of breast cancer patients.

HER-2/neu Gene Variations and Breast Cancer Risk
Women whose cancer cells make too much of the protein produced by the gene called HER- 2/neu tend to have more aggressive tumors. The HER-2/neu gene can be present in one of two "normal" forms (or polymorphisms). One of these polymorphisms has been found to be associated with a higher risk of breast cancer in Chinese women. The role of this polymorphism in African American and White women has not been determined. Michael Press, M.D., Ph.D., at the University of Southern California, Los Angeles, and colleagues studied normal forms of the HER-2/neu gene in blood cells taken from 1582 African American and White women. They investigated a single inherited polymorphism in Codon 655 (a codon is that part of DNA or RNA that codes for a single amino acid). To date, 1414 samples have been analyzed. When completed, this research could lead to a greater understanding of whether and to what extent an inherited HER-2/neu polymorphism increases breast cancer risk.

PBDEs in Tissues of Women With and Without Breast Cancer
Polybrominated diphenyl ethers (PBDEs) are a class of chemicals used as flame retardants in many commonly used consumer products, such as electronics and home furnishings. They persist in the environment and they accumulate in our fatty tissues. California women have the highest levels of PBDEs in the world, probably because of their extensive use to meet the State's fire safety standards. PBDEs disrupt thyroid function and impair development in animal studies. It is not yet known if there is any connection between PBDEs and breast cancer. Myrto Petreas, Ph.D., M.P.H., at the California Department of Health Services, Sacramento, and colleagues measured PBDEs in 152 samples of breast fat collected from women with and without breast cancer. Their preliminary analysis found no statistically significant differences in PBDE levels between the two groups. They also found no significant difference in dietary habits, reported residential proximity to potential sources of PBDEs and PCBs, or occupational exposures. The team plans to conduct further research into whether there were certain habits or characteristics common in the women who had the highest levels of PBDE exposures.

USC/NCCC Breast Cancer Research Training Program
The University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) is one of 41 federally designated comprehensive cancer centers nationwide. Michael Press, M.D., Ph.D., at the University of Southern California, Los Angeles, implemented a formal interdisciplinary graduate research training program led by epidemiologists and prevention scientists, behavioral scientists, tumor biologists, molecular geneticists, and radiation, surgical and medical oncologists. The training program matched 14 trainees to an appropriate faculty mentor with an active breast cancer research program. The trainees conducted research and also participated in an array of breast cancer programs at the USC/NCC, including Breast Center Rounds and Cancer Center Grand Rounds. Findings from the trainees’ research were published in Differentiation 27(2004)474, International Journal of Developmental Biology 48(2004)181, and Molecular and Cellular Biology 25(2005)5965.

Breast Cancer Risk Associated with High Mammographic Density
Mammographic density has been found to be one of the strongest predictors of breast cancer risk. Thea Tlsty, Ph.D., at the University of California, San Francisco, explored whether this increased risk could be due to biological processes that result in altered cell-cell and/or cellextracellular matrix interactions. These interactions, which are influenced by genetic, physiological, and environmental factors, are known to generate tissue with the same characteristics seen in mammographic density. Dr. Tlsty and her team identified molecular differences between low density and high density associated fibroblasts (the cells that give rise to connective tissue) that have the potential to link mammographic density to cancer risk. They demonstrated that a protein called Transforming Growth Factor-beta (TGFß) is increased in tissue with high mammographic density, and that TGFß appears to alter the expression of a receptor called CD36 in mammary fibroblasts. Dr. Tlsty believes this suggests that increased TGFß activity, working through a CD36 pathway, could lead to increased mammographic density and increased cancer risk. This work could lead to new methods of detecting breast cancer or decreasing mammographic density that could reduce breast cancer risk.

Breast Cancer Chemoprevention with Dietary Herbal Estrogens
It is widely recognized that exposure to estrogens increases the risk of developing breast cancer. Estrogens enter breast cells from the blood and then bind to proteins, called estrogen receptors (ER), that are in the cell nucleus. Once estrogen binds to the ER, it increases the production of several proteins that can cause breast cells to grow and form tumors. It was initially thought that there was only one ER. Then, in 1996 a second receptor, ERß was discovered. Dale Leitman, M.D., Ph.D., at the University of California, San Francisco, is investigating the role of Erß in breast cancer. For this project, Dr. Leitman and his team began by studying cells that only contained ERalpha. They found that estradiol, the estrogen that is made in the body, stimulated the proliferation of these cells and produced tumors in mice. They then took the cells that made only ERalpha and infected them with a virus that produces ERß. They found that estradiol inhibited growth and tumor formation in these cells, which suggested that estrogens that interact only with ERß could be used to prevent breast cancer. The team then studied the effects of an herbal formula, MF101, which contains 22 different herbs that are often used in Traditional Chinese Medicine to prevent breast cancer and menopausal symptoms in women with breast cancer. They found that MF101 prevented the breast cancer cells from growing and forming tumors in mice. This suggests that further research into herbal estrogens could lead to the development of new drugs to prevent breast cancer.

Estrogen Receptor Beta Agonists to Prevent Breast Cancer
The drug tamoxifen is able to block the production of all types of breast cancer when given early in life to rodents. However, tamoxifen cannot be given to young women as a chemopreventive because it puts them into menopause. Tamoxifen targets both the alpha and beta estrogen receptors (ER). New drugs that target only the ERß receptor block the ability of estrogen to drive cancer-causing cell proliferation without causing menopause. Peter Kushner, Ph.D., at the University of California, San Francisco, found that some ERß ligands (a hormone is the ligand for its specific protein receptor) could inhibit estrogen-stimulated growth in human breast cancer cells. Dr. Kushner and his team also discovered that ERß increases the efficacy of anti-estrogens, like tamoxifen, because it affects programmed cell death (apoptosis) and cell cycling. This work could lead to new ways to diagnose and treat breast cancer. Findings from this research appeared in Breast Cancer Research and Treatment 2007 July 19[Epub ahead of print].

Breast Cancer Prevention with Estrogen
A full term pregnancy at an early age is the only natural physiological condition that drastically reduces breast cancer risk. Satyabrata Nandi, Ph.D., at the University of California, Berkeley, investigated the biological basis of the protective effect of pregnancy by mimicking its effect in rats that had never given birth. Dr. Nandi and his team found that there was a decreased ability for cancer cells to grow in the rats that had been given the estrogen treatment that mimicked a pregnancy; that the treatment induced changes in the protein levels of the genes that regulate growth of the mammary glands; and that the rats that received estrogen had a decreased secretion of hormones from the pituitary gland, which provided protection against mammary cancer. They also found that the protective hormonal treatment had no harmful effects on the health or reproductive physiology of the rats. This research raises the possibility that correctly timed simulated pregnancy can be preventive for breast cancer. The findings from this research were published in Proceedings of the 4th International Symposium on Hormonal Carcinogenesis (2003), and Proceedings of the 94th Annual Meeting of American Association for Cancer Research (2003).

The IGF Pathway & Breast Cancer Risk in African Americans
Studies have found that African American women are more likely than White women to be diagnosed with aggressive breast cancer, to be diagnosed at a younger age, and to die from their disease. Susan Neuhausen, Ph.D., at the University of California, Irvine, studied genes in the insulin-like growth factor (IGF) pathway in African American and Nigerian women with and without breast cancer to investigate whether genetic changes might be one reason for these differences. Dr. Neuhausen and her team specifically looked for inherited variations in a single site in the DNA. This is called a Single Nucleotide Polymorphisms or SNP. The team found statistically significant associations between two sets of inherited variants, called IGFBP2 and IGFBP5, and breast cancer risk. This work provides evidence that genetic variation in the IGF signaling pathway plays a role in breast cancer risk in two independent populations of African descent. This finding could lead to new ways of preventing and treating breast cancer in African American women.

Grants in Progress: 2007

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 Metastasis: a Heritable Trait?
Alice Whittemore
Stanford University

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

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

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

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

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

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 2007

Breast Cancer Risks in California Nail Salon Workers
Peggy Reynolds and Linda Okahara
Northern California Cancer Center and Asian Health Services

Circuit Training to Lower Breast Cancer Risk in Latina Teens
Jaimie Davis
University of Southern California