Etiology: Finding the Causes

Over the past 50 years, scientists have identified a number of factors that increase cancer risk. They have used an epidemiologic approach, comparing a group of people with the disease to a cancer-free group for differences in environmental exposures, diet, and other lifestyle factors. However, using this approach, they have been able to identify only a portion of the factors affecting breast cancer risk, and haven't been able to explain the biological mechanisms that trigger the disease. Within the last decade, epidemiologic methods have been combined with genetics and molecular biology to gain a new understanding of events at the cellular level. Scientists are investigating the likely role of genes in determining how a cell responds to an environmental exposure, and whether this response begins the cell's journey toward cancer or not. Increasingly, the CBCRP funds research that uses this combined approach to apply the knowledge being gained in human genetics toward uncovering the precise causes of breast cancer.

Research Conclusions

Environment and Gene/ Environment Interactions: Nature vs. Nurture

Xenoestrogens and Breast Cancer in African American Women.

Organocholorine compounds are humanmade chemicals that include dioxins, furans, PCBs, and certain pesticides. They have been spread throughout our environment and can accumulate in human and animal tissues. The term “xenoestrogen” refers to these compounds' ability to take the place of the hormone estrogen in humans and animals. Xenoestrogens affect hormones and promote cancer in animals. Researchers suspect they also play a role in human breast cancer. Peggy Reynolds, of the Public Health Institute, Berkeley, originally planned to compare levels of xenoestrogens in the breast fat of African American women. However, when she couldn't recruit enough African American women, she included women of all races. In general, Dr. Reynolds found that women of color had higher levels of dioxins and furans in their breast fat than non-Hispanic white women, especially of the compounds PeCDD, DDE, HCB, and p-HCH. Since older women generally have higher levels of these chemicals in their breast tissue, Dr. Reynolds adjusted exposurespecific estimates of risk for age. Women of all ethnic groups who had higher levels of p-HCH also had a higher breast cancer risk. Women who had higher levels of the other compounds did not have a higher breast cancer risk. The sample size of 154 women was small, so these results are preliminary. However, the results offer pilot information on ethnic groups who have not been included in most previous studies of breast cancer risk and xenoestrogens.

The Insulin-Like Growth Factor (IGF) System and Breast Cancer. The insulin-like growth factor (IGF) system consists of several proteins produced by many cells in the body and circulating in the blood. They can work together to increase or decrease cell division. The IGF system may contribute to breast cancer by causing breast cells to divide, either directly or by working along with estrogens. A recent study found a strong association between high blood levels of one protein in the IGF system, IGF-1, and increased breast cancer risk in premenopausal white women. Brian E. Henderson, M.D., at University of Southern California, Los Angeles, investigated whether levels of IGF in the blood vary among post-menopausal African American, Japanese, Latina and white women. After controlling for age and weight, his team found differences among some ethnic groups in blood levels of four proteins from the IGF system. Latina women had the lowest levels of two of the proteins, IGF-1 and IGFBP-3. Post-menopausal Latina women also have the lowest rate of breast cancer. In addition, Dr. Henderson found that women with a repeat of a sequence [CA] in the structure of the gene that produces the IGF-1 protein had lower levels of IGF-1 in their blood than women with other IGF-1 genetic structures. However, the difference was not statistically significant. Identifying the gene structures that determine IGF system levels may provide greater understanding of individual variations in breast cancer risk, and potentially serve as indicators for women who would benefit most from screening or specific types of therapy.

Case Control Study

A case control study, also called a case comparison or retrospective study, compares a group of people with a disease ("cases") and a group of similar people without the disease ("controls"). Researchers gather information about both groups' past, such as exposure to a suspected cancer-causing agent, behaviors (such as smoking, drinking alcohol, occupation), or biological factors (such as history of the disease in the family, age of first menstruation). If the people with the disease have a higher rate of the factor in their past being investigated, then researchers infer that there is an association between the factor and the disease. If the association is very strong, and if it holds in other kinds of studies, the exposure, behavior, or biological factor is considered a possible cause or contributor to the disease. At this point, the investigation often shifts to the lab or clinic to uncover the biological mechanisms behind the association. As examples, case control studies have identified smoking as a cause of various cancers, determined the health risks associated with certain occupations, and pointed to sun exposure as a risk factor for skin cancer.

Hormones and Nutrition: Understanding the Modern Woman's Lifestyle

Mammography Density and Sex Steroid Genes. Women with a larger percentage of dense areas in the mammogram image of their breasts have a higher risk of breast cancer. Hormones influence breast density. Menstruating women have more dense areas than post-menopausal women. Women who take hormone replacement therapy after menopause may also have more dense areas. Sue Ingles, Ph.D., at the University of Southern California, Los Angeles, tested the hypothesis that genes involved in the production of female sex hormones are associated with breast density. Her team analyzed the genes of 453 white and African American women with breast cancer. The team looked at four genes: cytochrome p450c 17 (CYP 17), 17(hydroxy steroid dehydrogenase 1 (HSD17B1), 3b- HSD II, and the progestin receptor (PR) gene. On each gene, the team looked for variations called single nucleotide polymorphisms (SNPs). They turned up some evidence that dense breasts are associated with a variation called the A2 allele on the CYP17 gene. If these genes are associated with dense breasts, it could help researchers better understand the role natural hormones in the body play in breast cancer. It could also help predict which women are at a high risk for breast cancer if they use hormone replacement therapy.

Gene-Diet Tobacco Interactions in Breast Cancer in Asians. Anna H. Wu, at the University of Southern California, Los Angeles, investigated several enzymes, smoking, and soy foods in relation to the risk for breast cancer. The enzymes she studied are all involved in the activation and detoxification of a large number of compounds commonly found in our diet and in tobacco smoke. The amount of these enzymes in cells is governed by genes, and Dr. Wu investigated whether variations in these genes can make women more susceptible to breast cancer. Analyzing the blood samples of 372 Asian women who had breast cancer and 354 who did not, Dr. Wu found no association between rates of breast cancer and variations in the genes that produce four enzymes- CYP1A1, GSTM1, GSTT1, and GSTP1. However women who smoke and who also have genes that produce less or no GSTM1 and GSTP1 appear to have a greater risk for breast cancer. Dr. Wu also investigated the same group of Asian women's intake of soy foods. Those who ate the most soy foods during adult life had a 30% lower risk of breast cancer than those who ate the least soy foods. In addition, women who ate tofu at least 4 times a week during adolescence had a 35% lower risk than women who ate tofu once a month or not at all as teenagers.

Research in Progress

Environment and Gene/Environment Interactions: Nature vs. Nurture

Breast Cancer Susceptibility Genes in Very High Risk Women. A woman with relatives who have had breast cancer is at a higher risk for the disease than a woman whose relatives haven't had it. A woman whose identical twin has had breast cancer is at an even higher risk. Ann S. Hamilton, Ph.D., at the University of Southern California, Los Angeles, is testing the hypothesis that a structure on the CYP17 gene may occur more often in twins where one or both of the women have had breast cancer than in women who haven't had the disease. She is completing laboratory work on tissue that was preserved when the cancer was first diagnosed in 92 twins and recruiting more study subjects.

Marin County Breast Cancer Study of Adolescent Risk Factors. Margaret Wrensch, Ph.D., of the University of California, San Francisco, and Georgiana Farren, M.D., of Marin Breast Cancer Watch, Marin County, are studying women in Marin County, a community with high rates of breast cancer. The research team is looking at a group of women diagnosed with breast cancer between 7/1/97 and 6/30/99, and comparing them with women who have not had breast cancer. They are looking for differences in the age at which the women had their first menstrual period, the age at which the women's breasts developed, major life events before age 21, adolescent and adult socioeconomic status, age-adjusted lifetime years of residence in Marin County, and other events during adolescence which may have affected the women's lifetime risk. The team has completed in-person interviews with 235 out of a projected 300 women with breast cancer and 181 out of a projected 300 women without the disease.

Oral Contraceptives, Hormonal Risk Factors, and BRCA1. A large number of women who get breast cancer at an early age may have mutations on the gene BRCA1. Recent evidence suggests, however, that not all women with one of these mutations will develop breast cancer. Giske Ursin, M.D., Ph.D., at the University of Southern California, Los Angeles, is investigating whether oral contraceptive use has any effect on rates of breast cancer among women with mutations on their BRCA1 genes. Dr. Ursin will look at oral contraceptive dose, length of time the women used oral contraceptives, age at first use, and how recently the women used oral contraceptives. She will compare the risk of breast cancer associated with oral contraceptive use by women with mutated BRCA1 with data from previous studies for rates of breast cancer associated with oral contraceptive use by women in the general population. Working with tissue samples, she is using the new ABI 3700 sequencer to sequence the women's BRCA1 genes. To date, the research team has conducted 756 interviews, collected mammograms on 235 women, and completed sequencing of the genes of 92 women. They are in the process of sequencing the genes of 192 more women. Over the next year, they will analyze the data.

Influence of Localized DDT Exposure on Breast Cancer. The pesticide DDT can mimic or interfere with the action of hormones in humans and animals, and once it enters our bodies, it is stored in our fat. So DDT has tremendous potential to influence the development of breast cancer. In the body and in the environment, DDT is broken down into compounds that either act like the female hormone estrogen, or inhibit male sex hormones. Vicki L. Davis, Ph.D., at the Cedars-Sinai Medical Center, Los Angeles, is examining how the individual compounds into which DDT breaks down in the body influence the development of mammary tumors in mice. Mouse mammary tumors provide a good model to investigate cellular and genetic changes which lead to breast cancer in women. The research team has treated the mammary tissue of mice with one of the following: a DDT compound that mimics estrogen, a DDT compound that inhibits male hormones, an estrogen naturally produced in women, and an inhibitor of male hormones that is used to treat prostate cancer. The treatments are designed to affect only the mammary gland and not the entire body, to determine if DDT in breast fat influences cancer formation. The team will compare the number of mice that develop tumors, how early they develop them, and the tumor growth rates for the four groups.

Hormones and Nutrition: Understanding the Modern Woman's Lifestyle

Physical Activity and Diet in Adolescents with Disabilities. A number of studies suggest that physical activity and diet may be associated with a risk for breast cancer, but none of these studies have targeted women with disabilities. Carol Koprowski, Ph.D., R.D., and K. Sarah Hall, Ph.D., both at California State University, Northridge, are developing appropriate assessment tools to measure physical activity and diet in adolescent females with disabilities. They have recruited adolescent women with disabilities, along with their families, from three southern California school districts. The research team is conducting focus groups where participants discuss their views on whether current recommendations about diet and exercise are appropriate for adolescents with disabilities. They are also interviewing the young women about their own diets and exercise habits.

Postmenopausal Breast Cancer: Obesity and the Leptin Receptor. Obese women and women who gain weight during adulthood have an increased risk for breast cancer after menopause. Leslie Bernstein, Ph.D., at the University of Southern California, Los Angeles, is investigating the relationship between body composition, hormones, and a candidate gene for obesity, the leptin receptor gene. Leptin is a recently-discovered hormone produced by human fat cells. It plays a role in fat storage and metabolism, and may be involved in breast cancer. The leptin receptor gene produces a protein that allows cells to take in leptin. Dr. Bernstein is investigating the levels of leptin and variations in the leptin receptor gene in healthy obese women. The research team has recruited and collected data on 21 women. They are continuing to recruit more women. Results from this study could shed light on the causes of breast cancer after menopause.

Genes Determining Estrogen Susceptibility in Breast Cancer. Many breast tumors depend on the hormone estrogen for growth and survival and can be treated with anti-estrogen drugs like tamoxifen. However, some tumors eventually progress to an estrogen-independent form and become drug resistant. Wensheng Wei, Ph.D., at the Stanford University School of Medicine, Palo Alto, is attempting to identify, isolate, and map the structure of estrogen susceptibility genes that are required for breast cells to respond to estrogen stimulation. Dr. Wei is using a technique called Random homozygous knock-out (RHKO), removing genes from cells and observing the cells for changes in behavior. During the first year, Dr. Wei has solved technical problems with the RHKO technique and constructed the target cell line. Eventually, Dr. Wei hopes to identify changes in estrogen susceptibility genes that lead to tumors becoming estrogen independent.

Other Searches for the Causes

Breast Cancer Risk Factors: Lesbians and Heterosexual Women. Only a small amount of information is known about lesbians and breast cancer, but scientists believe lesbians' risk of getting the disease may be two to three times higher than that of heterosexual women. Suzanne L. Dibble, D.N.Sc., of the University of California, San Francisco, and Stephanie Roberts, M.D., of Lyon-Martin Women's Health Services, San Francisco, are investigating whether lesbians indeed have a higher risk. They distributed surveys to lesbians age 40 and older throughout the state of California, and asked each lesbian to have one heterosexual female friend who lives in California and a sister (if she has one) to fill out an identical survey. To date, 543 lesbians, 543 heterosexual friends, and 359 sisters have completed surveys. The research team is analyzing the data. If lesbians do turn out to have a greater risk for breast cancer, it may be possible to lower some of this risk through culturally-specific interventions.

Breast Cancer in California Teachers-Regional Variations. Rates of breast cancer in the San Francisco Bay Area are higher than in other parts of the nation. Scientists have known for a long time 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. During the first year, she identified cases of breast cancer among the women in the survey, and coded 96% of the women who took part in the survey for geographic location. She will examine risk factors for breast cancer that include reproductive history, family history, physical activity, exposure to hormones, diet, and other lifestyle factors. She will consider both current and historic place of residence, along with environmental exposures and social patterns in the women's neighborhoods. An initial assessment of the data indicates that breast cancer in teachers tends to mirror statewide patterns, with the San Francisco Bay Area having higher rates than other areas of the state. The initial assessment also indicates that teachers living in the San Francisco Bay Area may be at higher risk for breast cancer for reasons other than geographic location.

Research Initiated in 2001

Environment and Gene/Environment Interactions: Nature vs. Nurture

Hormones and Nutrition: Understanding the Modern Woman's Lifestyle

Other Searches for the Causes