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The National Cancer Institute (NCI) is conducting and supporting a number of cutting-edge research studies to understand breast cancer risk factors in the environment. The studies aim to identify and assess risk factors, detect and quantify cancer-causing environmental exposures, explain mechanisms and pathways or processes that link exposures to cancer, and identify and evaluate genetic determinants of individual susceptibility to cancer. Investigators are also conducting research to develop or improve methods of surveillance, exposure measurements, and risk assessment that may be applicable in future epidemiologic studies of cancer.

This fact sheet describes selected studies and research programs in this area. It is not an exhaustive listing; more information on research related to the environment is available from the resources listed at the end of this document.

Most of NCI's research on breast cancer and the environment is supported by two components within the institute: the Division of Cancer Control and Population Sciences, which supports hundreds of grantees who conduct studies to estimate cancer risks from a broad range of possible causes and evaluate their contribution to the nation's overall cancer burden; and the Division of Cancer Epidemiology and Genetics, which conducts a national research program for population-based studies to identify environmental and genetic determinants of cancer.

1. Cancer Rates

Cancer Incidence and Survival: NCI's Surveillance, Epidemiology, and End Results (SEER) Program is an authoritative source of information on cancer incidence and survival in the United States. The SEER Program is the only comprehensive source of population-based information in the United States that includes stage of cancer at the time of diagnosis and survival rates within each stage. SEER and the National Program of Cancer Registries, run by the Centers for Disease Control and Prevention (CDC), are tracking breast cancer rates nationally and will provide increasingly complete data on breast cancer incidence and mortality for each state. SEER data are available at http://seer.cancer.gov/.

Cancer Mortality Atlas: NCI has published an updated Atlas of Cancer Mortality in the United States covering the years 1950-1994. The maps make it easy for researchers and state health departments to identify places where high or low rates occur, and to uncover patterns of cancer that would escape notice if larger areas, such as states, were mapped. The atlas will not tell researchers why death rates are higher in certain localities than in others, but it will provide important clues for further in-depth studies into the causes and control of cancer. The text, maps, rates, and data used to generate the cancer mortality atlas are accessible on an interactive Internet site at http://www3.cancer.gov/atlasplus/.

Regional Differences in Breast Cancer Rates: NCI, in collaboration with the National Institute of Environmental Health Sciences (NIEHS), is funding a group of epidemiologic studies that are pursuing factors that may account for regional differences in breast cancer rates in the United States. There has been a persistent pattern of elevated rates for breast cancer in the Mid-Atlantic and Northeast regions of the United States. Research has shown that established risk factors are largely responsible, but reasons for the remaining excess are unknown. Established risk factors include increasing age, having a family history of breast cancer, having a first child at a late age, never having given birth to a child, and having higher income.

2. Chemical and Physical Environmental Risk Factors

This section is divided into two parts:

1. The Long Island Breast Cancer Study Project (LIBCSP)
2. Other Chemical and Physical Environmental Risk Factor Studies


1. The Long Island Breast Cancer Study Project (LIBCSP)

The LIBSCP is an investigation of possible environmental causes of breast cancer in Suffolk, Nassau, and Schoharie counties in New York and in Tolland County, Conn. Sponsored by NCI and NIEHS, the project consists of more than 12 studies, including:

• Breast Cancer and the Environment on Long Island Study: This large, population-based case-control study of women in Nassau and Suffolk counties examined whether polycyclic aromatic hydrocarbons (PAHs), a pollutant caused by incomplete combustion of various chemicals including diesel fuel and cigarette smoke, and organochlorine compounds, which are chemicals found in many pesticides, are associated with increased risk for breast cancer among women on Long Island. The researchers found that organochlorine compounds are not associated with the elevated rates of breast cancer and that exposure to PAHs was associated with a modest increased risk. The investigators are continuing to look at whether breast cancer risk in some individuals may be associated with organochlorine exposures because of individual differences in metabolism and ability to repair DNA damage. In addition, other studies are under way using the population, data, or specimens from this study to elucidate possible environmental factors in breast cancer.

• Electromagnetic Fields (EMFs) and Breast Cancer: This population-based case-control study on Long Island investigated whether electromagnetic fields (EMFs) are associated with increased risk for breast cancer. The researchers did not find an association between EMFs and breast cancer risk, including specifically the use of electric blankets.

• Epidemiology of Breast Cancer on Long Island: This hospital-based case-control study investigated breast cancer risk in relation to levels of organochlorine pesticide compounds in Nassau and Suffolk counties (Long Island) and in Schoharie County, N.Y. The researchers found that increased risk for breast cancer did not appear to be associated with past exposure to organochlorine compounds. There was no association between breast cancer risk and levels of total pesticides or total polychlorinated biphenyls (PCBs). PCBs are organochlorine compounds used in transformers, capacitators, and other electrical equipment. They are no longer used in new equipment, but are still present in the environment.

• Organochlorines and Risk of Breast Cancer: This pilot hospital-based case-control study investigated the relationship between exposure to organochlorine compounds and risk for breast cancer in Tolland County, Conn. Data on the Tolland County study population were included in a larger hospital-based case-control study of women from Connecticut, which did not find an association between organochlorine compounds and increased risk for breast cancer.

• PAHs and Risk of Breast Cancer: In a follow-up analysis to the Breast Cancer and the Environment on Long Island Study, NCI grantees are using a different assay than was used in the initial study to measure the level of binding of PAHs to DNA -- forming what is called PAH-DNA adducts -- and to analyze the role of these adducts in the etiology of breast cancer. The aim of the study is to correlate DNA damage in the lymphocytes in the blood with breast tissue damage in order to validate the use of blood as a surrogate for tissue in future studies. They also are testing the hypothesis that women with dietary and lifestyle exposures to PAHs have higher levels of PAH-DNA adducts in breast tissue and in blood.

• Estimating Exposure to PAHs: An NCI-funded researcher is conducting a feasibility study on estimating historical exposures of women in the study to PAHs using geographic modeling techniques. The methodology provides estimates of an individual's exposure to PAHs over a 30-35 year period, including childhood exposures, and thus complements estimates based on biomarkers of short-term exposure to PAHs, such as PAH-DNA adducts.

• Metropolitan New York Registry of Breast Cancer Families: The registry is recruiting families who have a history of breast and/or ovarian cancer. Participants are asked to contribute information, blood, and urine samples that can be used for studies on the causes of these diseases. The registry is one of six international registry sites funded by NCI to provide researchers a source of information and specimens to speed their investigations into the causes of breast cancer.

• Environmental Exposures and Breast Cancer on Long Island: This investigation is being conducted to determine whether prior land use (for example, farm land), exposure to various chemicals in drinking water, or length of residence in close proximity to hazardous waste sites, industrial sites, or toxic release inventory sites may increase risk for breast cancer on Long Island. Findings are expected to be reported in 2003 or 2004.

• Estrogen Metabolites as Biomarkers for Breast Cancer Risk: In this study, investigators examined whether differences in the way women's bodies process the natural hormone estrogen may be related to breast cancer risk. Estrogen is metabolized by two main, competing pathways, either to 2-hydroxyestrone or to 16-alpha-hydroxyestrone. Some research has suggested that the balance between the estrogen metabolite 16-alpha-hydroxyestrone, which has been associated with breast cancer, and 2-hydroxyestrone, which has not, may affect risk for the disease. The researchers found that postmenopausal women with very low levels of the "good" metabolite relative to the "bad" metabolite had a greatly increased risk of breast cancer, compared to women with high levels of the "good" metabolite. Because of the small number of study participants, further study is needed to confirm the findings.

• Regulation of Scatter Factor Expression in Breast Cancer: This research evaluated how a growth factor called scatter factor may regulate growth of breast cancer. Using tissue samples from Long Island women, the scientists found that levels of scatter factor are higher in invasive breast cancers than in non-invasive cancers. It also induces breast cells to produce an enzyme that degrades tissue, thus facilitating tumor invasion, and stimulates formation of new blood vessels, which is essential for tumor growth and spread.

• Representational Difference Analysis of Breast Cancer: The study examined genetic changes in breast tumor tissue from patients on Long Island using a technique called representational difference analysis. Certain alterations in genes may be linked to environmental exposures, and certain mutations may be characteristic of specific exposures.

• Home Pesticide Use: An NCI grantee is conducting an analysis of pesticide use in the home based on questionnaire data.

Information is also available on: NCI Web Site Digest Page-Long Island Breast Cancer Study Project: http://www.nci.nih.gov/cancerinfo/LIBCSP, and The Long Island Breast Cancer Study Project Web site: http://epi.grants.cancer.gov/LIBCSP/index.html

2. Other Chemical and Physical Environmental Risk Factors

Breast Cancer and the Environment Centers: NCI is collaborating with NIEHS to fund four Breast Cancer and the Environment Centers. These centers will study the impact of prenatal-to-adult environmental exposures that may predispose a woman to breast cancer. Both laboratory and human population studies are included. In laboratory animals, the researchers will study development of mammary tissue and the effects of specific environmental agents. They also will enroll different ethnic groups of young girls and study their exposures to a wide variety of environmental agents as they mature through puberty.

Breast Cancer and the Environment: Two collaborative studies are attempting to clarify the effects of environmental factors on breast cancer risk among women who carry alternations in breast cancer susceptibility genes such as those involved in DNA repair, or hormone or carcinogen metabolism. DNA samples from buccal cells (cells from the inside of the cheek) have been collected from over 4,000 cases and 4,000 controls participating in a population-based U.S. case-control study conducted by the University of Wisconsin, Harvard University and Dartmouth-Hitchcock Medical Center. In addition, high-quality exposure assessment, and blood, tissue and urine samples have been collected in a second population-based study of 2,500 cases and 2,500 controls in Poland (described below). The large sample size in both of these studies will provide the necessary statistical power to evaluate gene-environment interactions in breast cancer etiology.

The Polish Breast Cancer Study: In a collaborative effort with Polish investigators, NCI scientists are assessing the influence of occupational and environmental factors in the development of breast cancer, as well as lifestyle factors such as diet, nutrition, body size, and physical activity. The study has special components to assess the relationship between breast cancer risk and occupational exposures (given that a large proportion of Polish women work outside their homes, often in industrialized settings) and to physical activity (women are being asked to wear accelerometers to provide more objective evidence of their recreational, occupational and household levels of physical activity). This study, which includes state-of-the art exposure assessment techniques (detailed questionnaire, physical activity monitors, and other measurements), as well as collection of biological materials (blood, buccal cells, urine, and tissue samples), will provide an opportunity to evaluate the role of genetic and hormonal alterations, biomarkers of exposure and early biologic effect on breast cancer risk.

The Agricultural Health Study: A number of studies have shown that farmers and other agricultural workers are at elevated risk of several cancers, in spite of their lower overall risk of cancer mortality. Pesticides, sunlight, viruses, mycotoxins (toxic substances produced by fungi), well water contaminants, and a variety of other occupational exposures are suspected to play a role in this increased risk. In an effort to identify the agents responsible for the excess risks, NCI and NIEHS, in collaboration with the National Institute for Occupational Health and Safety and the Environmental Protection Agency, are supporting the Agricultural Health Study, an ongoing prospective cohort study of about 90,000 people, including farmers, their spouses and children, licensed private pesticide applicators, and commercial pesticide applicators. The study is being expanded to include the collection of buccal cells from 30,000 women to evaluate genetic susceptibility to breast and other cancers in relation to environmental factors, including pesticide exposures. Markers of genetic susceptibility also will be assessed in the context of a series of nested case-control studies. Disease risks among spouses of farmers will also be examined, providing an opportunity to evaluate breast cancer risk factors. The Agricultural Health Study Web Site is: http://www.aghealth.org/.

Cancer in Women-Occupational and Environmental Risk Factors: Little is known about occupational cancer risks among women. Limited studies have suggested that women are susceptible to the same carcinogens as men, but risks may vary due to hormonal, metabolic, genetic, or other differences. To pursue this issue, NCI scientists are collaborating with investigators at Vanderbilt University and the Shanghai Cancer Institute to conduct a cohort study of 75,000 women in Shanghai, China, to evaluate a number of risk factors for a variety of cancers, including breast cancer, with special attention to the role of occupational and environmental exposures. Blood and urine specimens collected at baseline will be used to measure levels of environmental carcinogens and metabolites, as well as biomarkers of susceptibility in relation to subsequent risk of cancer. Over time, this study will become an invaluable data source for identifying environmental risk factors and gene-environment interactions for cancer in women.

Textile Workers Study: This project will test the hypothesis that EMFs and night shift work are risk factors for breast cancer among female textile workers in Shanghai, China. This case-control study will derive cases from a very large cohort of female textile workers (270,000) who were part of an intervention study on breast cancer screening. The levels of EMFs will be determined by direct measurement and historical records, and the investigators will evaluate whether the risks associated with EMFs and night shift work are modified by other factors including age, reproductive history, and occupational exposure to solvents.

Breast Cancer among a DDT-Exposed Population in Triana, Ala.: NCI is conducting a study of the possible relationship between exposure to the pesticide DDT and risk for breast cancer, benign (non-cancerous) breast conditions, and other outcomes among women from Triana, Ala. Environmental contamination from a manufacturing site resulted in body burdens of DDT 10 times higher than in the general U.S. population among residents of the surrounding area. Researchers are evaluating levels of DDT, DDE (a metabolite of DDT), PCBs, and other chemicals in the blood of women who have developed breast cancer, benign breast conditions, or dense breast tissue, as compared with women in the community without these conditions. The study will attempt to determine whether women with higher body burdens of this pesticide and its metabolite are at increased risk for developing breast cancer or benign breast disease.

Residential Environment and Genetics: An NCI grantee is conducting a case-control study to investigate the role of residential distance from steel mills, chemical factories, toxic waste sites and other industrial sites as risk factors for breast cancer among women in Erie and Niagara counties, N.Y. The researchers will estimate exposures to benzene and PAHs based on residential proximity to these industries and evaluate breast cancer risk by the levels of estimated exposures. They will also determine whether genetic variability in a number of metabolizing enzymes (N101, GSTM1-1, GST P1-1, and CYP1A1) influence the risk, if any, due to the environmental factors.

PCBs, CYP1A1 Polymorphisms, and Breast Cancer in Connecticut: A previously conducted case-control study of breast cancer in Connecticut has been expanded to include an assessment of genetic factors. This research focuses on the risk associated with environmental PCBs and variations in the sequence of a particular metabolizing gene called CYP1A1. The CYP1A1 gene is involved in activating certain types of chemicals into their carcinogenic or cancer-producing form and is also involved in hormone metabolism. By comparing the body burdens of PCBs in women with and without breast cancer, the study will evaluate whether women with an elevated body burden of PCBs and with specific genetic variations in the CYP1A1 gene are at an increased risk of breast cancer.

Hormone-Related Gene Variants and Environmental Factors in Breast and Prostate Cancer: In this first study of the NCI Consortium of Cohorts, questionnaire data and biospecimens from 10 large study populations are being pooled to conduct studies of hormone-related gene variants and environmental factors involved in the development of breast and prostate cancer. Data are being analyzed from 6,160 patients with breast cancer and 8,850 patients with prostate cancer. Risks of these tumors will be examined in relation to inherited gene variants, endogenous hormones and growth factors, as well as lifestyle and other factors.

Measuring Environmental Exposures: NCI, NIEHS, and the CDC are conducting, funding, and coordinating efforts to develop new tools to measure environmental exposures. There is a pressing need for such tools, since few chemical agents are known to leave markers of past exposure in the body.

3. Environmental Radiation Risk

Atomic Bomb Survivors: The Life Span Study of 120,000 atomic bomb survivors in Japan is the primary source of data to quantify radiation risks in humans. In collaboration with the Radiation Effects Research Foundation, NCI scientists are studying the effects of radiation on the incidence of various cancers, including breast cancer. Of particular interest are biomarkers of radiation-related effects and possible modifiers of radiation-related risk, such as lifestyle variables, exposure to other carcinogens, and predisposing host factors like age, sex, and susceptibility genes.

A report of extremely high, dose-specific relative risks for early-onset breast cancer in women prior to age 35 suggests increased sensitivity to radiation among a genetically predisposed population subgroup. NCI scientists are addressing this hypothesis through compilation of family history data for early-onset and later-onset cases of breast cancer, and exploring the potential for molecular assays of archival tumor tissue for biomarkers of susceptibility.

Breast and Other Cancers Following X-Rays for Scoliosis: NCI researchers worked with orthopedic medical centers and M.D. Anderson Cancer Center in Houston, Texas to determine whether female scoliosis patients, who typically undergo routine X-rays of the spine throughout their adolescent growth spurt to monitor spine curvature changes, are at an increased risk of dying of breast cancer. The 5,466 women in the study, who received an average of 24.7 X-rays, were found to have a 70 percent higher risk of breast cancer than women in the general population. The risk of dying from breast cancer increased significantly with the number of X-rays. Patients who had 50 or more exams had nearly four times the risk of dying from breast cancer as women in the general population. Similarly, the risk of dying of breast cancer increased with increasing estimated cumulative radiation dose to the breast. Analyses of breast cancer incidence in this cohort, which take into account other breast cancer risk factors, are underway.

Breast and Other Cancers Among Patients and Their Relatives with Ataxia Telangiectasia (A-T): Studies have suggested a link between the ATM (ataxia telangiectasia, mutated) gene and increased breast cancer risk, but findings have been inconsistent. NCI is currently conducting a large, international study to further examine the risk of cancer in A-T families. A-T is a rare, genetic disease of childhood. Patients usually have immune system abnormalities, are very sensitive to the effects of radiation treatments, and are at high risk of developing and dying of cancer, particularly leukemias and lymphomas. Blood relatives of patients with A-T appear to be at marginally increased risk of cancer compared to the general population, based on a population-based, record linkage study conducted by NCI in Denmark, Sweden, Finland and Norway. Female relatives had a small excess of breast cancer, which was statistically significant only for mothers of the A-T patients. The findings of this study suggest that mutations in the ATM gene may play some role in breast cancer, but other factors may modify these effects.

Radiologic Technologists: In collaboration with the University of Minnesota, NCI researchers are conducting a study of 146,000 radiation technologists (73 percent female) certified for two or more years during 1926-1982. This unique occupational cohort offers a rare opportunity to evaluate and quantify carcinogenic risks of protracted, low-dose radiation exposures. Mortality analyses revealed a significantly increasing risk of breast cancer with number of years certified among women who were first certified before 1940, when radiation exposures were likely to be high. These results are being evaluated in detailed incidence analyses to quantify risks according to work history, procedures, practices, and protective measures. Health physicists and dosimetry experts are leading an effort to estimate annual and cumulative radiation doses for individual radiologic technologists using film badge records, work history information obtained from questionnaires, and biomarkers of exposure. In addition, new initiatives are under way to evaluate interactions with susceptibility genes in DNA repair, hormonal levels, and other potential etiologic pathways.

4. Related Topics

CRISP (Computer Retrieval of Information on Scientific Projects), a searchable database of federally funded biomedical research projects: http://crisp.cit.nih.gov.

5. NCI Resources

NCI's Cancer Research Portfolio, a compilation of NCI research organized by type of cancer and type of cancer research: http://researchportfolio.cancer.gov.

For more information about cancer, visit NCI's Web site at http://www.cancer.gov/

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