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, applying knowledge being gained in human genetics to uncover the precise causes of breast cancer.
Research Conclusions
Oral Contraceptives, Hormonal Risk Factors, and BRCA1.
A large number of women who get breast cancer at an early age may have mutations in 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, investigated whether oral contraceptive use has any effect on rates of breast cancer among women with mutations in their BRCA1 genes. Dr. Ursin looked 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 compared 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 used the new ABI 3700 sequencer to sequence the women's BRCA1 genes. To date, the research team has conducted 1,361 interviews and collected mammograms on 641 women. This research will be completed with funding from another agency, with results available within a year.
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 July 1, 1997, and June 30, 1999, and comparing them with women who have not had breast cancer. The team is 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, smoking, alcohol use, standard breast cancer risk factors, and age-adjusted lifetime years of residence in Marin County. The team has completed in-person interviews with 301 women with breast cancer and 305 women without the disease. Although CBCRP funding for this research has ended, the team will continue to analyze the data and publish results when they have them. A recent published finding (Breast Cancer Res. 2003;5(4):R88- R102) from this study suggested that alcohol consumption was a factor in the higher rates of breast cancer for Main County: women who had at least two drinks a day were more than twice as likely to be diagnosed with breast cancer as women who drank less, according to the study. Thus, this finding supports demographics and lifestyle as opposed to geographical (i.e., environmental) risk factors as explanatory factors in Marin County's high rates of breast cancer.
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, tested the hypothesis that a variation of 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. This gene codes for an enzyme that helps regulate estrogen levels. Three versions of the gene are possible: A1/A1, A2/A2, and A1/A2. Some studies have shown that women with at least one A2 (A2/A2 or A1/ A2) have higher levels of estrogen and higher risk of breast cancer. If identical twins who both had breast cancer had higher rates of the A2/A2 or A1/A2 gene, this would provide evidence of the CYP17 gene being associated with breast cancer. However, in this study, identical twins with only one of the pair having had breast cancer had the highest rate of A2/A2 or A1/A2 (76%) followed by identical twins who both had breast cancer (69%) and identical twins who had not had the disease (53%). The researchers are unable to draw final conclusions about the relationship, if any, between the CYP17 gene and breast cancer.
Unique Genes Expressed in Cancer Cells.
Craig V. Byus, Ph.D., of the University of California, Riverside, identified genes that are turned off or on by the enzyme ornithine decarboxylase (ODC) in cells. It appears that a high level of ODC turns on or off certain genes, and this allows a cell to become more like cancer. Dr. Byus encountered difficulties with the first lab technique he used, so he tried another approach, which succeeded. The research team found 12 genes that become more active in the presence of high levels of ODC. The team also found that these same 12 genes are abnormally active in several types of cancer cells. The genes include jun-d, jun-c, jun-b and cfos. The research team now believes that high levels of ODC lead to high levels of a series of chemical reactions within cells known as the MAP kinase cascade. Funding from the CBCRP allowed this research team to accumulate enough data to receive a five-year grant from the National Institutes of Health to continue these studies in breast cancer cells and prostate cells.
Environment and Gene/Environment Interactions: Nature vs. Nurture
Hormones and Nutrition: Understanding the Modern Woman's
Postmenopausal Breast Cancer: Obesity & 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 Keck School of Medicine, University of Southern California, Los Angeles, investigated 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 investigated the levels of leptin and variations in the leptin receptor gene in 38 healthy obese women age 40 or over and past menopause. The team found a strong association of total percent body fat and the leptin gene variation Lys109Arg, and a similar, though less precise, association between this gene variation and a high body-mass index. Another leptin receptor gene variation they tested, Gln223Arg, showed no significant associations. Understanding the relationship of genes and obesity could help shed light on the causes of postmenopausal breast cancer.
Tamoxifen-Induced Endometrial Cell Transformation.
Tamoxifen is a medication for treating and preventing breast cancer, but it also increases a woman's risk for cancer of the endometrium, which is the inner lining of the uterus. Tamoxifen inhibits the activity of a group of enzymes called protein kinase C (PKC). There are more than 11 kinds of PKC; one, a type of PKCä, can suppress tumor growth. Zhimin Lu, Ph.D., of the Salk Institute for Biological Studies, La Jolla, investigated whether tamoxifen causes endometrial cancer by inhibiting the action of PKCä. The team found that cells that had already gone through some early steps toward becoming cancerous went much further along the process when exposed to tamoxifen. Tamoxifen pushed these cells further toward becoming cancerous by activating a series of chemical reactions in the cell called ERK1/2, inhibiting PKCä, and increasing the activity within the cell of an enzyme called phospholipase D. This research provides important insights into the side effects of tamoxifen and may point toward more effective treatment and prevention for breast cancer.
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. All women with advanced breast cancer eventually progress to the state where their tumors resist drug treatment. Wensheng Wei, Ph.D., at the Stanford University School of Medicine, attempted to identify, isolate, and map the structure of estrogen susceptibility genes that are required for breast cells to respond to estrogen stimulation. Dr. Wei used a new technique, random homozygous knock-out (RHKO), removing genes from cells and observing the cells for changes in behavior. Dr. Wei solved some technical problems with the RHKO technique and began screening genes in human breast cancer cells. With this research, Dr. Wei made progress toward the goal of identifying changes in estrogen susceptibility genes that lead to tumors becoming estrogen independent.
Research in Progress
Environment and Gene/Environment Interactions: Nature vs. Nurture
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 is stored in body 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. Mammary tumors are the mouse equivalent of breast tumors. So far, the team has found that two compounds into which DDT breaks down accelerate the development of tumors, although it is unclear if these compounds make tumors more likely to form. One of these compounds inhibits male sex hormones and accelerates tumor development the most, the other acts like estrogen and accelerates tumor development to a lesser extent.
Pesticides and Breast Cancer in Hispanic Women in California.
Paul 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 has compared breast cancer rates among Hispanic women and amounts of the pesticides applied in each of 58 California counties. There was no elevated risk in the first time period they studied, 1988-1993. But for 1994-1999, a higher risk of breast cancer was found among Hispanic women in the counties with the highest use of several pesticides, including DDT and toxaphene. The research team will also compare the pesticide exposure of women farm workers who have breast cancer with those who do not.
Hormones and Nutrition: Understanding the Modern Woman's Lifestyle
Dietary Fat, Fat Metabolizing Genes, and Breast Cancer Risk.
A diet high in certain types of fat may promote breast cancer. 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 these fats. So far, her team has identified many previously-undiscovered genetic differences in dietary fat metabolism. They have tested the genes from 814 women with breast cancer and 910 women without the disease from three ethnic groups: white, Hispanic, and African American. If a high-fat diet is found to increase breast cancer risk for women with certain genes, then diet changes could be recommended to these women. If certain fat metabolizing genes raise a woman's risk for breast cancer, then drugs to inhibit the enzymes these genes produce could be used for prevention or treatment.
Other Searches for the Causes
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 secondand 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 exposure to chemicals formed when meats and fish are cooked at high temperatures or infection with Epstein Barr virus increase breast cancer risk. To date, they have completed interviews with 189 Hispanic women with breast cancer and 37 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 225 DNA samples that will be stored for future molecular studies.
Breast Cancer in California Teachers—Regional Variations.
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. She found that breast cancer rates are 20% higher for teachers in the San Francisco Bay Area and 17% higher for teachers in the Los Angeles-Orange County-San Diego area than for teachers in the rest of the state. These numbers are consistent with the rates for women as a whole in California. The researchers are considering characteristics of the geographic area, such as living near traffic or pesticide use, as well as personal characteristics of the teachers, such as family history and diet. So far, no characteristics of the geographic areas or the women themselves fully explain the higher risk for teachers in some parts of the state.
Research Initiated in 2002
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. She is trying to determine whether varying versions of this gene are related to breast density. There are conflicting studies in cells, animals, and humans about whether the variations in the androgen receptor gene are associated with breast cancer risk.
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 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 is affected by androgen.
USC/NCCC Breast Cancer Research Training Program.
The CBCRP encourages and supports training in breast cancer for new research scientists. Ronald K. Ross, M.D., maintains the multifaceted Breast Cancer Research Training Program at the University of Southern California, 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 multi-disciplinary faculty from USC and the Norris Comprehensive Cancer Center.
