Etiology: Finding the Caues

The ultimate goal of eradicating breast cancer can only come about through prevention of the disease. Understanding the causes of the disease is one approach to reaching this goal.

It is now widely recognized that breast cancer does not arise through a single event, but emerges via multiple paths comprised of complex interacting factors. These factors include hereditary genetic characteristics, dynamic states of susceptibility, environmental insults and random genetic events. Dissecting and deciphering these multiple factors will help us to identify populations and individuals who are at higher risk than others for developing breast cancer and to find ways to prevent or interrupt the evolution of breast cancer.

In the current funding cycle, the BCRP awarded six grants that explore the causes of breast cancer in different ways. One of these is a Training Program Award (Ronald Ross), designed to train graduate students in a multidisciplinary environment that will encourage innovative thinking about breast cancer problems.

Two of the awards are Community-Initiated Research Collaboration (CIRC) Awards. In a Pilot Award, a team (Mary Gould of Marin Breast Cancer Watch and Margaret Wrensch of University of California, San Francisco) will explore methods to collect information about adolescent years from older women, with a long-term goal of identifying factors in adolescence that might lead to breast cancer later in life. In a CIRC Full Research Award, Stephanie Roberts of Lyon-Martin Women’s Health Services and Suzanne Dibble of the University of California, San Francisco are working together to explore a commonly believed but unproven hypothesis that lesbians have higher frequencies of some known breast cancer risk factors, leading to a higher risk of breast cancer in this population.

An IDEA was awarded to Lisa Shames to explore the role of exercise in breast cancer recurrence. Several studies have suggested that exercise may reduce the risk of breast cancer, but whether it can also help in preventing recurrences of breast cancer has not yet been established.

It is well recognized that life-long exposure to hormones contributes to the development of breast cancer, but individual differences in hormone levels and the risk associated with these are not understood. New hypotheses have been generated by the finding in earlier BCRP-funded research that variations in genes involved in the production of estrogen may explain individual variations. This has led to a new study by Heather Feigelson, exploring variations in two genes and their association with circulating blood levels of estrogen, as well as known risk factors for breast cancer. Understanding the biological basis for epidemiologic findings opens the door to risk identification, prevention and treatment tailored to individuals. These and other risks factors are also being explored in a hypothesis-generating study by Deirdre Hill, who will be receiving postdoctoral training in breast cancer research.

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Community Research Collaboration – Pilot Awards


Marin County Breast Cancer Study of Adolescent Risk Factors

Mary Gould
Marin Breast Cancer Watch

Margaret Wrensch, Ph.D.
University of California, San Francisco- Department of Epidemiology and Biostatistics

Marin Breast Cancer Watch (MBCW) is a grass-roots, nonprofit, tax-exempt organization of approximately 350 members, established in 1995 because of community concern regarding the high incidence of breast cancer in Marin County, California.

The long range goal of the MBCW project is to evaluate the hypothesis that, in addition to risk factors that are already well known, there are others, as yet unidentified that may be at play during adolescence and contribute to the high incidence of breast cancer later in life. If found, identification of these other risk factors ultimately may lead to a reduction in the risk of breast cancer. To develop this proposal, MBCW initiated a collaboration with established breast cancer researchers at the University of California, San Francisco to provide scientific input. Guided by the results of the pilot study, and in concert with our UCSF epidemiologic colleagues, we plan to conduct a population based case-control study in Marin County of breast cancer risk factors in adolescence including, but not limited to: physical development, physical activity; diet and nutrition; medical history; prescription, non-prescription, or recreational drug use, alcohol use and smoking, radiation and other potentially carcinogenic environmental exposures, residential history, and sexual activity. The goal of this CIRC Pilot Project is to develop a research approach that will best address the potential relationships among breast cancer risk, established breast cancer risk factors (such as reproductive and menstrual histories and socioeconomic status) and novel adolescent and pre-adolescent factors. The preliminary data necessary to prepare a full-scale research proposal on this topic will be collected in this pilot effort.

Few modifiable risk factors for breast cancer have yet been defined, despite population migration studies showing that breast cancer risk is modifiable over a single lifetime. In exploring the problem of high breast cancer rates among women in Marin County through a study of modifiable adolescent and pre-adolescent risk factors, we will address two priority areas of breast cancer research. These are breast cancer etiology, through greater attention to relatively unexplored adolescent and pre-adolescent factors, and prevention, through inclusion in the planned full-scale study of a large number of potentially modifiable factors.

In this Pilot study, we will: (1) complete comprehensive literature reviews on the role of pre-adolescent and adolescent factors in breast cancer development and on methods to enhance women’s memory and minimize the effect that having breast cancer has on what women remember; (2) conduct three focus groups to review MBCW’s overall hypotheses and help develop methods for enhancing memory of pre-adolescent and adolescent experiences and exposures that can be used in population-based research; (3) refine study hypotheses; (4) develop the study questionnaire, orientation video, and other necessary study materials; (5) conduct informal and formal pilot testing of study materials and methods; and (6) prepare a comprehensive CIRC Full Research Award proposal.

We expect that by increasing knowledge of breast cancer etiology, our studies ultimately will enhance possibilities for breast cancer prevention. Bringing together community members and scientists interested in breast cancer research in a successful initial collaborative endeavor will create enthusiasm for future studies. Most importantly, information obtained may suggest learning tools and lifestyle changes in adolescence that can be incorporated into the lives of our daughters to prevent breast cancer.

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Community Research Collaboration – Full Research Awards


Breast Cancer Risk Factors: Lesbian and Heterosexual Women

Stephanie Roberts, M.D.
Lyon-Martin Women's Health Services

Suzanne Dibble, D.N.Sc.
University of California, San Francisco- School of Nursing

Some scientists have looked at the risk factors for breast cancer and the little that is known about lesbians and speculated that the risk for developing breast cancer may be two to three times higher for lesbians than for heterosexual women. But no scientific studies have been published on this issue. We have just finished a small study comparing information contained in the medical records of lesbian and heterosexual women and have found some differences in the distribution of some breast cancer risk factors. We need to do a larger study because some of the established risk factors for developing breast cancer are not collected in medical records. Also, the women whose records we studied attended a clinic that mostly serves young, urban, poor women. Therefore, we would like to compare a larger group of women from throughout California who are of different sexual orientations, living situations, and incomes to explore the distribution of risk factors for breast cancer.

The research question that we would like to answer is: Are the distributions of the standard risk factors for developing breast cancer different for women who call themselves lesbians in contrast with their heterosexual sisters or heterosexual female friends? We will ask lesbians throughout California to complete an anonymous survey. The lesbians will be asked to give the same survey to a sister (if she has one) and a heterosexual female friend. Then we will compare the differences between them. Lesbians will be recruited through articles, flyers, advertisements, a toll-free telephone number, clinics like Lyon-Martin Women's Health Services that specialize in serving lesbians, and through doctors who are members of the Gay and Lesbian Medical Association. We will use special techniques to be sure that we get a variety of women who represent the mix of lesbians living in California, and that help reach women who are not public about being lesbian.

If we find in this larger study that the lesbians have a different distribution of risk factors for developing breast cancer than their heterosexual sisters and friends, then lesbians and their health care providers need to know this. More studies can then be done to see if these risk factors can be modified or if lesbians need to have more frequent breast exams, mammograms, or biopsies than do heterosexual women.

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Innovative, Exploratory and Developmental Awards – Type II


Exercise and the Prevention of Breast Cancer Recurrence

Lisa Shames, Ph.D.
University of Southern California- Department of Preventive Medicine

Of those women who have received a diagnosis of invasive breast cancer, on average, 30% will develop a recurrence within five years. There is substantial evidence to suggest that exercise protects women against the development of an initial breast cancer. Why breast cancer survivors sometimes relapse however, is poorly understood. This innovative study will attempt for the first time to examine whether the protective effect of physical exercise activity observed among healthy women can be extended to include breast cancer survivors.

The specific aims of this study are: 1) to determine the feasibility of conducting a large-scale intervention study and 2) to preliminarily evaluate the hypothesis that physical exercise activity patterns after a primary diagnosis are associated with a reduced likelihood of a relapse. The specific aims of this study will be assessed by obtaining demographic information, medical history, body weight, diet, and physical exercise activity patterns (including recreational, occupational, and activities associated with daily living) via telephone interview. We will conduct our study on a population of approximately 3,500 women diagnosed with a primary breast cancer. From this population, we will identify patients who have relapsed (cases) and compare their responses to a group of women who have not relapsed (controls).

One of the unfortunate consequences of relapse is that many women die as a result of their disease. We plan to examine whether women who die from a relapse are different (with respect to physical exercise activity habits) from women who are surviving. This task will be accomplished by selecting a subset of patients who have relapsed but are still living and comparing their responses to those of a close family member. Once the validity of this measure has been established, we can design future studies that will include critical information about all women who have been diagnosed with breast cancer.

This study will contribute significantly to our understanding of the relationship between physical exercise activity and risk of breast cancer recurrence. By establishing this relationship, we hope to provide practical advice to women who have already been diagnosed with breast cancer on how they may reduce their risk of developing a recurrence through physical exercise activities. Our research has a direct impact on the missions and goals of the Breast Cancer Research Program by providing a means to reduce morbidity and mortality among women who have already been afflicted with this disease.

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New Investigator Award


Multi-Ethnic Study of Genetic Control of Plasma Hormones

Heather Feigelson, Ph.D.
USC/Norris Comprehensive Cancer Center- Department of Preventive Medicine

A large and compelling body of scientific evidence indicates that estrogens play a major role in causing breast cancer. We have been investigating three genes that are involved in the production of estrogens in the body and have found that one gene, called CYP17, is associated with a 2.5 times increased risk of advanced breast cancer. We have also found that CYP17 may, in part, be responsible for the genetic control of hormone levels occurring naturally in the body.

In this study, we propose to expand this work by examining the association between CYP17 and a second gene, HSD17B1, and plasma levels of several steroid hormones in healthy, postmenopausal women. We will also examine the relationships between these genes and important known risk factors for breast cancer including body weight, age at menarche, age at first birth, number of children the woman has borne, age at menopause, and the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) among healthy postmenopausal women.

The study will include 170 randomly selected women from each of four racial-ethnic groups: African-American, Japanese, Latina and White, resulting in a total sample size of 680. These women are part of a larger on-going study of cancer.

This study could have several important consequences. In the field of cancer prevention, there is likely to be substantial interest in the interaction between these genes and exogenous estrogen use, i.e., OCs and HRT. As a genetic marker of risk, these genotypes may provide new tools for identifying high risk groups of women for prevention and treatment protocols. Finally, understanding the genetic control of steroid hormone biosynthesis can provide new insights into reproductive biology and endocrinology.

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Postdoctoral Fellowship Award


Radiation, Reproductive & Menstrual Factors & Breast Cancer

Deirdre A. Hill, Ph.D.
University of Southern California- School of Medicine

Women under age 40 may get breast cancer for different reasons than women who are older. Breast cancer risk in younger women may be greatly affected by events and exposures that occur during childhood or adolescence. We would like to look at reasons why women get breast cancer at young ages (< 40yrs.). We have talked with 744 young women who developed breast cancer in Los Angeles County from 1983-89 and 744 similar women who did not develop breast cancer. The women were asked about things such as past illnesses that might be related to breast cancer. We would like to find out if the women who got radiation for an illness while they were a child or a teenager have a higher risk of breast cancer. This includes diagnostic X rays for an illness or injury, or radiation given to treat an illness. Women who get X rays at today's levels probably do not have a higher risk of breast cancer. We do not know if women who got X rays as children when dose levels were higher have an increased risk. We would also like to find out if women who got X rays at the time of a pregnancy or when they first menstruated have a higher risk of breast cancer because the breasts may be more sensitive at that time.

In our second project, we would like to find out more information about how a woman's pregnancies and her menstrual cycles affect her risk of breast cancer. We want to see if having a miscarriage or choosing to end a pregnancy changes the risk of breast cancer in these women. A pregnancy that ends early (before 20 weeks) may only affect breast cancer risk in women who are age 40 or younger or who have never had a child. Because there are relatively few women like this, some studies have not been able to interview many, but in this study we talked with many such women. Women who have menstrual cycles that occur more or less often than 28 days may have a different risk of breast cancer than women whose cycles come every 28 days. We want to find out if the number of days in a menstrual cycle affects breast cancer risk. We would also like to see if women who have cycles that are very different in the number of days between them each month have a different risk of breast cancer. Women who have ever been told by a doctor that they have certain illnesses of the female organs such as endometriosis, uterine fibroids, or ovarian cysts may have a risk of breast cancer that is higher or lower than women who have not. Women who have been told that they cannot have a child also may have a risk of breast cancer that is different from other women. Breast cancer risk in these women can be looked at as well. Pregnancies, menstrual cycles, and certain illnesses of female organs may be related to the level of a woman's hormones, and if we can understand them better, we may be able to understand more about breast cancer risk.

Events during childhood and the teenage years may greatly influence breast cancer risk; research studies are now asking women many questions about that time period. For some women, 40 or 50 years have gone by since adolescence. In our third project, we would like to look at how well women can remember those years. We have information such as height, weight, and age at first menstruation from young women who were followed through their teen years. Five to nine years later, we asked them to remember and write down this information. We can compare their actual report of height, weight, and age at menstruation to their later memory. Research studies may be able to find out more about how breast cancer risk is related to the teenage years if we know how well women can remember this information.

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Training Program Award


USC/Norris Breast Cancer Research Program

Ronald K. Ross, M.D.
University of Southern California- Department of Preventive Medicine

This application is to renew a Training Program for graduate students in breast cancer research in conjunction with the Breast Cancer Research Program of the University of Southern California/Norris Comprehensive Cancer Center (NCCC). The goals of the training program are to recruit the most capable graduate students possible; to help make these students future outstanding breast cancer scientists through a comprehensive approach to training established in the previous BCRP grant; and to facilitate these goals by offering students outstanding mentors and resources for conducting breast cancer research.

In its first three years the training program has been highly successful. Five trainees have been supported annually from among approximately 10 highly qualified applicants each year after careful review and scoring by senior scientists at the NCCC. Trainees are highly interdisciplinary in their interests, which include pathology, molecular biology, cell biology and cancer control. Trainees have been matched to an appropriate faculty mentor with an active breast cancer research program. They have participated in a variety of specialized activities at the NCCC related to breast cancer, including weekly NCCC Breast Cancer rounds, monthly breast cancer seminars, and an annual BCRP off-campus retreat. Although it is too early to assess the long-term success of this program in expanding the pool of full-time high-quality breast cancer research scientists in California, all trainees are being directed towards a long-term commitment to breast cancer research.

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