Breast cancer takes center stage.

Breast cancer is the second leading cause of cancer deaths in American women today, claiming more than 40,000 lives annually. Accumulating evidence suggests that interactions between genetic and environmental factors may be at the center of its causation. Understanding exactly which such factors are involved in breast cancer and their mechanisms of action is a subject of great interest among patient advocates and scientists. To help build the underpinnings of this understanding, the NIEHS and the National Cancer Institute (NCI) have jointly funded the development of four new Breast Cancer and the Environment Research Centers.

The idea for the centers arose in part from debate at a one-day brainstorming session held in April 2002, where patient advocates, breast cancer specialists, and scientists from other disciplines discussed with NIEHS staff gaps in knowledge, roadblocks to progress, and opportunities for future research regarding breast cancer and the environment. NIEHS staff used these recommendations in planning a new multidisciplinary research program.

In October 2003 came the announcement that $35 million (over seven years) had been allocated for the new centers. The four centers are located at Fox Chase Cancer Center in Philadelphia, Pennsylvania; Michigan State University in East Lansing; the University of Cincinnati in Ohio; and the University of California, San Francisco (the "Bay Area Center").

The spirit of collaboration and responsiveness to public health concerns has been fundamental in the creation of the centers. Kenneth Olden, director of the NIEHS, remarked at a November 2003 kickoff and planning meeting that "the community of breast cancer advocates were there from the inception of this idea, and we have worked [together] to make it a reality."

The research to be conducted by the centers will revolve around the hypothesis that there are periods of vulnerability in the development of the mammary gland when exposures to environmental agents may impact the breast in ways that can influence breast cancer risk in adulthood. The new centers will address this scenario by functioning as a consortium, working in close collaboration to pursue two specific approaches to this hypothesis. One approach will use basic science techniques in laboratory animals and cell cultures, and the other will use epidemiologic studies in human populations. "The four centers will work in close cooperation, so that we can do more than what could be achieved by the individual laboratories," says Gwen Collman, chief of the NIEHS Susceptibility and Population Health Branch and program administrator for the centers.

One unusual feature of the program is that the awards will be made for seven years, compared to the usual five years for center grants. This will allow for prospective studies of developmental landmarks in populations of girls, and integration of laboratory and epidemiologic research.

Research on Mammary Gland Development

The goal of the laboratory research project is to conduct collaborative experiments using animal and cell culture models to characterize the molecular basis of the mammary gland over the life span, and to determine how this development may be affected by exposure to environmental agents. Each of the four centers bring to the table unique capabilities with regard to studying a variety of animal and cell culture models to look at histologic, pathologic, cellular, and subcellular end points that may be caused by environmental exposures.

The Fox Chase Cancer Center researchers will examine the effects of exposures to hormonally active xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A, butyl benzyl phthalate, genistein, and diethylstilbestrol on the mammary gland in rats at certain periods of development. Serum from exposed rats will be analyzed to identify biomarkers of exposure to these chemicals that could possibly be used for exposure assessment in human populations. In addition, the Fox Chase team will explore how timing of exposure to these xenobiotics alters susceptibility to 7,12-dimethylbenz[a]anthracene, a mammary cancer inducer.

The University of Cincinnati team will use the rat as a model to study how factors related to obesity and dietary factors may interact to promote breast cancer. They will explore the effects of dietary fatty acids (such as mono- and polyunsaturated fatty acids) and phytoestrogens (such as those found in soy products) on hormonal balance, mammary gland morphology, gene expression, and susceptibility to carcinogenesis. In addition to these in vivo experiments, the Cincinnati team will use rat mammary epithelial organoids in culture to study mechanisms of DNA damage.

The Bay Area Center investigators will use mouse models to study the molecular basis of mammary gland development. They will expose both normal mice and those that are genetically susceptible to developing tumors to prototypical carcinogens such as ionizing radiation at different developmental points in order to define the morphologic and functional alterations that occur in the mammary gland. These experiments will be complemented with in vitro studies to search for cellular mechanisms of action.

The Michigan State University team will use mouse models to study progesterone receptor function and activity in the development of the breast, and how that function is altered with exposure to environmental agents. Their experiments will center around the hypothesis that increased lifetime exposure to progesterone and estrogen underlies the increased risk of breast cancer associated with early onset of menarche, late age at menopause, and hormone replacement therapy.

The centers will also participate in a coordinated epidemiologic study of the environmental and genetic determinants of puberty. This research will be conducted by prospectively following several cohorts of prepubescent girls at different stages in development to determine bow hormonal changes, obesity, diet, family history, psychosocial stressors, environmental exposures, and genetic polymorphisms, among other factors, may interact to control mammary gland development and other landmarks of puberty. As a result of information provided from the animal studies, relevent human genetic polymorphisms will be selected. Then interactions between environmental agents and the genes that affect their susceptibility will be explored.

Community Outreach and Translation

The work of the centers will be enhanced and their discoveries transmitted to the public through the Community Outreach and Translation Core (COTC) in each center. The COTCs will provide an essential link between the scientists and the communities that are likely to benefit from the information being generated by the research.

The COTCs will focus their efforts on working with area breast cancer advocacy groups and other local organizations to reach the communities that will eventually participate in the studies. The centers will work closely with their community partners to translate the findings, as they are uncovered, into useful, pertinent health messages that can engage potential participants in the studies in such a way that they become invested in the progress of the studies, and retention is thus enhanced. This will be especially important given the expected length of the studies.

In addition, the Department of Communication at Michigan State University will create public health message materials that can be used in the mass media nationwide. Communication of health messages will be a crucial part of the studies; it must strike a balance between the awareness of potential risk factors and health-promoting messages. Says Maria Carolina Hinestrosa, cofounder and executive director of the patient advocacy organization Nueva Vida, "We must avoid promoting fear of the breast, where girls and young women see their breasts as a threat."

Mechanisms for Collaboration

The centers program was created through a cooperative agreement that will support the work to be conducted both within and across centers. A steering committee will govern the network, and will comprise the center directors, a COTC member from each center, two NIEHS representatives, and one NCI representative. The steering committee will establish specific research tasks and milestones for each project. The committee will also oversee subcommittees for each of the two projects.

The progress and activities of the centers will be reviewed by a council working group, which will advise the NIEHS director on that progress and make recommendations for complementing this work. The working group has been established as a subcommittee of the National Advisory Environmental Health Sciences Council (which advises the U.S. Department of Health and Human Services, the NIH, and the NIEHS on research issues, programmatic content, and related factors in the environment that affect human health). It is composed of two of that council's members, one member of the NCI National Cancer Advisory Board, and six ad hoc members representing breast cancer advocates and other breast cancer researchers. The working group will help produce messages to be shared with the breast cancer community.

Collaborators in the centers hope that the findings that arise from their efforts will translate into applications that increase awareness of the causes of breast cancer and their implications for public health. In the words of NCI epidemiologists Sandra Melnick and Deborah Winn, speaking at the November 2003 kickoff meeting, these centers will allow scientists to ask the "right questions with the right technology, and provide answers [on the causes of breast cancer] to the public."

Breast Cancer and the Environment
Research Centers

Center           Collaborators               Community Partners

University of    Marin Breast Cancer Watch   Marin Breast Cancer Watch
California,      Lawrence Berkeley           Bayview Hunters Point
San Francisco      National Laboratory         Health & Environmental
San Francisco,   University of Michigan        Assessment Task Force
California       Kaiser Permanente of        Breast Cancer Fund1
                   Northern California       Bay Area Breast Cancer
                 Roswell Park Cancer           SPORE Advocacy Core
                   Center                    Community Health Academy
                 California Department of
                   Health Services
                 Marin County Department
                   of Health and Human
                   Services

Fox Chase        The University of Alabama   The Renaissance
Cancer Center    Mount Sinai School of         University for
Philadelphia,      Medicine                    Community Education of
Pennsylvania                                   the Harlem Children's
                                               Zone Project
                                             Girls, Inc.
                                             New York City Parks
                                               Foundation
                                             Community Science
                                               Specialists
                                             Share

University of    Cincinnati Children's       Breast Cancer Alliance of
Cincinnati         Hospital Medical Center     Greater Cincinnati
Cincinnati,                                  Patterns, Inc.
Ohio                                         Pink Ribbon Girls
                                             Susan G. Komen Breast
                                               Cancer Foundation,
                                               Greater Cincinnati
                                               Affiliate
                                             American Cancer Society,
                                               Cincinnati Area Office
                                             Breast and Cervical
                                               Cancer Screening
                                               Project
                                             Greater Cincinnati
                                               Occupational Health
                                               Center
                                             Lower Price Hill Women's
                                               Wellness Group
                                             National Breast Cancer
                                               Coalition
                                             The Wellness Community
                                             YWCA Breast & Cervical
                                               Health Network

Michigan State   n/a                         Faith Access to Community
University                                     Economic Development
East Lansing,                                Susan G. Komen Breast
Michigan                                       Cancer Foundation
                                             Michigan Environmental
                                               Council
                                             American Cancer Society,
                                               Great Lakes Division