Etiology: Finding the Causes

There has already been intensive study into the contributions of behavior and lifestyle to breast cancer. Investigating the external physical causes of breast cancer means investigating things that women cannot, as individuals, control. The CBCRP’s goal is to understand how environmental exposure—to pesticides and other known or suspected cancer-causing substances in the air, food, water, or medications—may lead to biological changes that initiate breast cancer.

Research Conclusions

Five CBCRP grants studying the Etiology of breast cancer were completed in 2003.

Influence of Localized DDT Exposure on Breast Cancer.
The pesticide DDT can mimic or interfere with the action of hormones in humans and animals. Once inside the body, DDT remains stored in the fat surrounding breast tissue. In the body and in the environment, DDT gets broken down into hormone-like compounds, which may have the potential to influence breast cancer. Vicki L. Davis, Ph.D., at the Cedars-Sinai Medical Center, Los Angeles, tested two compounds that DDT breaks down into (metabolites) to see if they promoted mammary tumors in mice. One compound, pp DDE, inhibits male sex hormones and caused the highest number of tumors at the earliest ages. The other compound, o,p DDE, which acts like estrogen, only slightly promoted tumor growth. The two compounds appear to cancel out each other’s effects. This may explain why some previous studies have shown that DDT exposure increases breast cancer risk, and others have not. It also suggests that the ratio of the two compounds in the fat surrounding breast tissue may be important for how exposure to DDT influences the risk for breast cancer.

Breast Cancer Risk Factors: Lesbians and Heterosexual Women.
Some scientists have proposed that lesbians may be at two to three times the risk of breast cancer of heterosexual women. However, there have been no definitive population-based studies of this issue, and more information is needed. Suzanne L. Dibble, D.N.Sc., at the University of California, San Francisco, and Stephanie Roberts, M.D., at Lyon-Martin Women’s Health Services, San Francisco, investigated the distributions of standard risk factors among lesbians and heterosexual women. The research team surveyed 255 lesbians over age 40, and asked each to have both her sister closest in age and a heterosexual friend fill out the same survey. The estimated lifetime risk for developing breast cancer, based on known risk factors, was 11.1 out of every 100 lesbians and 10.6 out of every 100 heterosexual women. The lesbians in this study had more education than their friends or sisters, fewer live births, abortions, and miscarriages. Lesbians also weighed more in relation to their height than their sisters and friends. In addition, lesbians had more breast biopsies and mammograms than their sisters and were more likely to have been diagnosed with breast cancer than their friends. Based on this sample, lesbians have a higher risk profile for breast cancer than heterosexual women, but the difference is lower than previously surmised. Results of the study were published in the Journal of Gay and Lesbian Medical Association 1998 2(3):93-101.

Profiling of Tyrosine Phosphatases in Breast Cancer.
Many of the processes allowing cancer cells to multiply and spread are controlled through a type of reversible chemical reaction among cell proteins. The reaction either adds or subtracts a molecule of phosphorus to the protein, and these processes are also involved in breast cancer acquiring resistance to drug treatments like tamoxifen. Enzymes called tyrosine phosphatases remove a molecule of phosphorus from a protein and other enzymes called tyrosine kinases add one. The balance between the two determines the fate of the cell. Clifford Tepper, Ph.D., at the University of California, Davis, used a novel method to allow his team to examine all the tyrosine phosphatases in a cell and another technique that allowed them to examine 12,500 genes simultaneously. The team found five tyrosine phosphatases affected by levels of estrogen in cells. One of them, DUSP1, increased 3.5-fold when estrogen was withdrawn from cells. DUSP1 inhibits pre-programmed cell death, and DUSP1 was present at higher than normal levels in 4 out of 15 breast cancer tissue samples the team studied. The team generated a breast cancer cell line with high levels of DUSP1, and the cell line was highly resistant to treatment with tamoxifen, a treatment that kills cancer cells. Other parts of this research showed that a treatment to block the action of DUSP1 could be a beneficial addition to other breast cancer therapies.

USC/NCCC Breast Cancer Research Training Program.
The CBCRP encourages and supports training in breast cancer research for new research scientists. Ronald K. Ross, M.D., and Michael Press, M.D., Ph.D., maintain the multifaceted Breast Cancer Research Training Program at the University of Southern California/Norris Comprehensive Cancer Center, Los Angeles. Five trainees are supported each year in areas such as pathology, molecular biology, cell biology, and cancer control. The trainees work under a multidisciplinary faculty. Over the years, 30 scientists have received training. Several have gone on to win grants to pursue breast cancer research on their own, and the majority of the trainees have developed a long-term commitment to breast cancer research.

Exercise and Risk of Breast Cancer Recurrence.
Strenuous lifetime exercise lowers women’s chances of getting breast cancer. Malcolm C. Pike, Ph.D., and Lisa Shames, Ph.D., at the Keck School of Medicine, University of Southern California, Los Angeles, investigated whether exercise can prevent a recurrence of breast cancer. The team contacted women treated for breast cancer at Norris Hospital between 1987 and 1997 and interviewed them about their exercise habits since their diagnosis and treatment. Women whose breast cancer had recurred, or who developed a new breast tumor, were matched with women whose cancer had not recurred, and who had the same stage of tumor at diagnosis, age at diagnosis, and year of diagnosis. Results suggested that women who exercised were only half as likely to have their breast cancer recur as those who exercised little or not at all. However, the number of women studied was so low that the results are not statistically significant. Still, this research suggests that exercise is associated with a much-reduced rate of breast cancer recurrence and is worthy of further research in a larger study population.

Research in Progress

A number of ongoing CBCRP grants in the topic of Etiology reported progress in 2003.

Pesticides and Breast Cancer in Hispanic Women in California.
Paul K. Mills, Ph.D., at the Public Health Institute, Berkeley, is attempting to determine if the risk of breast cancer in Hispanic California women is increased due to their exposure to two classes of commonly-used pesticides, the organochlorines and the triazines. The research team investigated exposure to pesticides among female members of the United Farm Workers (UFW) of America, the state’s largest agricultural labor union, comparing the pesticide exposure of 90 UFW members with breast cancer, and 450 UFW members without. Women who had breast cancer were 54 percent more likely to have the highest exposure to all the agricultural chemicals covered in this study. Women with breast cancer were more than twice as likely to have the highest exposure to the pesticide chlordane, four times as likely to have the highest exposure to the pesticide Dicofol, and 82 percent more likely to have the highest exposure to the herbicide simazine. However, these results were not statistically significant. The research team is analyzing the data further. The results of the study could further public understanding of the impact of agricultural chemicals and expand justification for integrated pest management and workforce protection from toxic chemicals.

Androgen Receptor Gene and PSA Gene in Breast Cancer Risk.
Androgens are hormones; although they are usually thought of as male hormones, they play important roles in the female body and may protect against breast cancer. Wei Wang, M.D., at the University of Southern California, Los Angeles, is analyzing DNA samples from 504 African American women, half of whom have breast cancer and half of whom do not. The team is looking for genetically-determined differences in the PSA pathway, which is a series of chemical interactions within breast cells that are affected by androgen. So far, the team has analyzed genetic variations among the women for the first of two genes they are studying, the PSA gene, and they are in the process of doing the same for the second, the androgen receptor gene.

The Androgen Receptor and Mammographic Density.
Women with breasts that appear denser on a mammogram have an increased risk of breast cancer. Elizabeth Lillie, M.S., of the Keck School of Medicine, University of Southern California, Los Angeles, is investigating the androgen receptor gene, which produces a protein that allows breast tissue to be affected by the hormone androgen. Some studies have suggested that women with a version of the androgen receptor gene that produces less active androgen receptor protein have a higher breast cancer risk. She has found that post-menopausal women who have ever used estrogen and progestin therapy, and who also have the version of the androgen receptor gene that produces less active protein, have denser breasts. This means that the androgen receptor gene may play a role in determining whether estrogen and progestin therapy (often called hormone replacement therapy) causes breast cancer. Research results have been published in Breast Cancer Research 5 (2003):164-173.

Dietary Fat, Fat Metabolizing Genes, and Breast Cancer Risk.
A diet high in omega-6 fats, which are found in many vegetable oils—including corn, canola, and safflower—may cause breast cancer. Other fats may be harmless or even protective. Sue Ann Ingles, Ph.D., of the University of Southern California, Los Angeles, is investigating whether genetic differences in fat metabolism make some women more prone to breast cancer if their diets are high in omega-6 fats. Her team tested the genes from 814 women with breast cancer and 910 women without the disease from three ethnic groups: white, Hispanic, and African American. So far, the team has found that African American women who do not have the most common version of one fat metabolizing gene, 12-LOX, are 1.5 times more likely to get breast cancer than African American women with the most common version. If those women whose 12-LOX gene puts them at higher risk also eat a higher than average amount of omega-6 fats, then they are 2.3 times as likely to get breast cancer.

Migration and Breast Cancer Risk in Hispanics.
Foreign-born Hispanic women living in the San Francisco Bay Area have a lower risk of breast cancer than second- and third-generation migrants. Women who migrated after age 40 have a lower risk than women who migrated at a young age. Esther John, Ph.D., of the Northern California Cancer Center in Union City, is investigating breast cancer risk and migration-related lifestyle changes in Hispanic women. The lifestyle changes include menstrual and reproductive events, physical activity, diet, body size, weight change, hormone use, smoking, and alcohol consumption. In addition, her team will see if infection with Epstein Barr virus or exposure to chemicals formed when meats and fish are cooked at high temperatures increase breast cancer risk. To date, they have completed interviews with 408 Hispanic women with breast cancer and 435 who do not have the disease. The team plans to interview a total of 1,050 women and merge their data with a previous study of over 2,500 Hispanic women. The team has also collected 826 DNA samples that will be stored for future molecular studies. They hope to identify lifestyle factors that can be changed to prevent breast cancer.

Breast Cancer in California Teachers—Regional Variations.
Scientists have long known that breast cancer rates vary widely by geographic area, but they don’t know why. Peggy Reynolds, Ph.D., at the Public Health Institute, Berkeley, is attempting to discover if women face a higher risk of breast cancer because they live in certain geographic areas, or if more women at high risk of getting the disease for other reasons happen to live in those geographic areas. She is using personal information available on 133,000 active and retired school employees participating in the California Teachers Study. She found that teachers in the San Francisco Bay Area have a rate of breast cancer 22 percent higher, and teachers in the Los Angeles- Orange County-San Diego area have a rate 16 percent higher, than teachers in the rest of the state. These numbers are consistent with the rates for women as a whole in California. Teachers in the Bay Area and three south counties were slightly older, represented a more racially diverse population, and were more likely to live in urban and affluent neighborhoods. While older age and affluence are associated with a higher breast cancer risk, these characteristics of the teachers do not fully explain the excess risk in the Bay Area and the three southern California coastal counties. Results from this study were published in Epidemiology 2004 15(1):6-12.

Research Initiated in 2003

Four grants studying external influences on breast cancer began in 2003.

The Hygiene Hypothesis and Breast Cancer Risk.
Recent research shows that children who get exposed to more germs develop a healthier immune system. Children raised in a sanitized, disease-free environment get more allergies and autoimmune diseases. Christina Clarke, Ph.D., at the Northern California Cancer Center, Union City, is investigating whether women with less exposure to germs during childhood later have an increased risk for breast cancer.

Epstein-Barr Virus in Breast Cancer Tissues.
By adulthood, almost everyone is chronically infected with Epstein-Barr virus. Most infections are harmless; a small minority cause stomach cancer, lymphoma, or nasal cancer. This virus may also play a role in some cases of breast cancer. Sally Glaser, Ph.D., at the Northern California Cancer Center, Union City, will use sensitive new laboratory techniques to test 100 tumor samples for the virus and identify characteristics of women whose tumors contain the virus.

Genetics, Obesity, and Breast Cancer Risk.
Catherine Carpenter, Ph.D., at the University of California, Irvine, will investigate whether various forms of several genes make women more likely to be obese and also more likely to get breast cancer.

Prolactin and Breast Cancer Risk in a Multiethnic Cohort.
The hormone prolactin is important to milk production and to breast development during puberty and pregnancy. Women with higher levels of prolactin in their blood may have a higher risk for breast cancer. Brian Henderson, M.D., at the Keck School of Medicine, University of Southern California, Los Angeles, is investigating whether genes control the levels of prolactin in the blood, and if some versions of these genes are more common among women who have had breast cancer than among women who haven’t had the disease.