Abstract CN04-02: Breast cancer, early development and the environment: A transdisciplinary approach

The search for the causes of breast cancer remains among the top priorities in cancer research. Even though recent trends suggest a turn downward in both incidence and mortality, breast cancer remains the most common female cancer in the industrialized world. Furthermore, marked disparities have long been observed between race/ethnic and socioeconomically defined groups in incidence, survival and mortality that are ill understood. Unlike most cancers, breast cancer incidence in the United States is higher among white and higher socioeconomic groups, except in early onset pre-menopausal breast cancer where African American women have the highest incidence. Likewise, the overall higher incidence in whites compared to blacks is reversed for survival and mortality. To combat the impact of this common cancer among women and the disparities observed, intense efforts have been directed towards the development of new approaches to early detection, chemotherapeutics, surgical and radiation treatments with promising results. However, very little can be offered to women in the area of true primary prevention, short of chemoprevention and the causes of observed disparities remain ill understood. Environmental factors stemming from both lifestyle practices and industrial toxins remain an area of intense public and scientific concern, even though few environmental factors, beyond ionizing radiation, alcohol consumption and hormone replacement therapy, are of proven etiologic significance. Efforts to unravel the complex causal web leading to breast cancer through epidemiologic and clinical approaches have focused primarily on proximate causes by studying adult women with, or at risk of, breast cancer. Basic science has focused on fundamental mechanisms of genetic susceptibility, stem cell origins, molecular signaling, and epithelial-stromal interactions among other factors. In a shift in focus over recent decades, there is now wide recognition that the origins of breast cancer probably occur early in development, especially during the times of rapid breast development including the pubertal transition. New multidisciplinary, multi-level approaches are needed to understand this period of development and the many pathways through which environmental factors may have an impact on breast cancer in adult life. The Breast Cancer and the Environment Research Centers (BCERC), sponsored by the National Institute for Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI) were developed after a period of focused and thoughtful advocacy integrated with scientific consultation. In 2003, BCERCs were awarded to The Fox Chase Comprehensive Cancer Center in Philadelphia, Michigan State University in East Lansing, Michigan, the University of Cincinnati, and the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. The goal of these Centers is to better understand the role of environmental factors in pubertal development as a window on breast cancer etiology and to generate the knowledge needed for the primary prevention. A multiethnic cohort of prepubertal girls has been recruited in order to study the impact of environmental exposure on the onset of pubertal breast development and other pubertal endpoints. At baseline, 1222 girls have been entered into the cohort with mean ages of 7.13 years in Cincinnati, 7.34 years in New York City, and 7.38 years in the San Francisco Bay Area. A parent or guardian identified 34.4% as White, non-Hispanic, 25.3% as Black, non-Hispanic, 4.3% as Black Hispanic, 29.9% as Hispanic, 4.5% as Asian, and 1.7% in some other category. The socioeconomic status of these girls also varies widely from those living in neighborhoods in East Harlem in New York City to Marin County in California. Previous studies have documented substantial differences by race and ethnicity in the onset of puberty, an observation that BCERC investigators will be able to confirm and understand more fully as it might reflect on disparities in adult breast cancer. Integrated with the human studies BCERC investigators are examining the impact of environmental exposures on mammary development and mammary carcinogenesis in animal models during puberty and across the lifespan. The multicenter BCERC initiative is extremely interactive across the multidisciplinary composition of the investigator team, both in its approach to defined research questions, and in the integrated nature of the science with community and advocacy participation. Investigators are invested in making our approach truly “transdisciplinary”. To be specific, transdisciplinary science occurs when scientists from multiple disciplines work interactively on a common problem with a common conceptual model (or framework) and, as a result, develop novel cross-disciplinary methods, insights, and research approaches that would not have occurred with a traditional uni-disciplinary investigation. BCERC scientists have agreed on a common conceptual framework that permits multiple investigators to locate their particular hypotheses within it, taking into account our best understanding of pubertal development and the environment from both a social ecologic and lifespan perspective. Our conceptual framework acknowledges the complexity of breast cancer etiologic factors along a continuum from pre-natal in utero exposures through the postmenopausal years, although we are focusing on the years of pubertal development. At each stage of the lifespan, the model recognizes possible influences at multiple levels from genes to cells, tissues and the organism, through individual behavior, to family, neighborhood and other “upstream” social factors. While the focus in our study of humans is limited to the pre-pubertal and pubertal stages of the lifespan, our animal models allow us to consider the mechanistic basis for the effects of environmental exposures and other influences on the mammary gland across the lifespan. This in turn will provide a bridge for the development and testing of mechanism-based prevention strategies in humans. From this integrated transdisciplinary approach it is anticipated that information about relevant exposures generated from the human studies can be applied to the animal studies and, in turn, the animal studies will provide a mechanistic understanding of how environmental exposures may impact pubertal breast development and adversely influence breast cancer risk in adult life. BCERC research addresses aspects of the timing of puberty and the biology of the developing the mammary gland that create a period of vulnerability. We explore whether exposures to environmental factors (e.g., phenols, phthlates, phytoestrogens, genistein, dietary fat, ionizing radiation, psychosocial factors) prior to and during puberty may influence breast cancer risk in adulthood. Multiple hypotheses are being tested by developing and interrogating rodent models and rodent and human cell culture systems to characterize the molecular basis of mammary gland development over the lifespan. We seek to determine how environmental agents may affect this development, and to better understand the process of breast carcinogenesis. In the simultaneously conducted epidemiologic cohort studies, conceptually integrated with the studies in animal and human tissue models, additional hypotheses posit roles for the environmental, psychological, behavioral, metabolic and genetic factors as determinants of puberty. With this approach, we seek to elucidate how genetic polymorphisms, cell biology, hormonal changes, obesity, diet, environmental exposures, family history, psychosocial stressors, social factors and other determinants interact to influence mammary gland development and other landmarks of puberty. The BCERC studies will permit in-depth study of disparities in pubertal onset by both race/ethnicity and socioeconomic status and relate observed differences back to etiologic factors from the genetic to the social level. In published studies African American girls have been observed to experience menarche an average of three months earlier than white girls. The earlier age of menarche persisted even after adjustment for weight, height, and other characteristic, suggesting that the effects of other factors on puberty, such as environmental exposures or lifestyle factors, may be most pronounced among those whose genetic or other biologic characteristics make them most susceptible to mediating pathways. Interestingly, as mentioned above, breast cancer incidence is higher in African-American women before age 40 than in white women, although the reverse is true after that age. Although this may be related to earlier onset at age of menarche, other lifestyle considerations, as well as genetic considerations, also may play a role. The presentation will include new results from both animal model studies and the cohort of girls that help elucidate the determinants of pubertal onset and disparities in this outcome by race/ethnicity and socioeconomic status. BCERC is taking a transdisciplinary approach to answering this important and complex question of environmental influences on puberty. Although the strongest hypothesis explaining the decline in the age of puberty stems from the effects of nutritional factors and increased caloric intake, the elucidation of the potential role of genetic susceptibility, endocrine disrupting chemicals in the environment, various forms of psychosocial stress and adverse aspects of the social and built environment, require expertise from multiple disciplines working on this scientific challenge together.