Cheryl L. Thompson, Ph.D. - US grants

DESCRIPTION (provided by applicant): This career development award will provide the necessary training and resources for Dr. Cheryl L. Thompson, junior faculty in the department of Family Medicine at Case Western Reserve University, to transition into an independent investigator. Training in the area of structural equation modeling, molecular genetics and breast cancer, through coursework, seminars, conference attendance and project involvement, as directed by her mentors, will allow Dr. Thompson to become a strong breast cancer genetic epidemiologist. High mammographic breast density (MD) is emerging as one of the strongest risk factors, as well as a potential intermediate marker, for breast cancer. Genetic influence clearly plays an important role in breast cancer and is an important determinant of MD. Results from multiple trials showing an unexpected significantly elevated risk of breast cancer among women taking combined hormone replacement therapy (HRT) highlights the important, but under-appreciated, role of progesterone as well as estrogen in the etiology of breast cancer. Perturbation of phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) signaling has also been implicated as an important oncogenic pathway in breast cancer development. Furthermore, mechanistic studies indicate that cross-talks occur between the estrogen receptor (ER) and progesterone receptor (PR) and PI3K/AKT in breast tissue. Genetic variations in ER/PR and the PI3K/AKT signaling pathway are likely to affect MD, its changes over time, and subsequently, the risk of breast cancer. An ongoing case-control study is recruiting women with a history of breast cancer as well as healthy screened controls. Multiple (^3) screening films prior to the diagnosis of cancer (cases), or prior to recruitment (controls), from 1500 breast cancer cases and 1500 controls are being retrieved to examine the relationship of longitudinal changes in MD and risk of breast cancer. The current proposal expands on this ongoing study to collect genetic samples and examine inherited variants in the ER/PR and PI3K/AKT signaling pathways in relation to both MD and longitudinal changes in MD as they relate to breast cancer risk. An understanding of the effect of inherited polymorphisms in these genes on MD and breast cancer risk will give us important new insight into breast cancer tumorigenesis. Knowledge of these variations as they relate to risk of breast cancer may have significant implication for better risk stratification and prediction and tailored strategies for breast cancer prevention and intervention. This study will provide the platform for the Pi's career development with a focus on breast cancer genetic epidemiology and pathway-based analysis. It will set the stage for the Pi's transition into an independent investigator and for seeking additional national funding based on this project to expand the study population to give sufficient power to tackle the complex gene- gene and gene-environment interactive and joint effects within these pathways on the trajectories of MD and risk of breast cancer.

TECHNICAL ABSTRACT Cancer is the second leading cause of death in the United States, and breast cancer (BrCa) is the most diagnosed malignancy among women, and the second highest cause of cancer deaths. Despite lower overall incidence, African American (AA) women experience an earlier age of onset of BrCa and have significantly higher mortality rates compared to white women diagnosed with BrCa. Although screening, access and treatment may contribute to some of this disparity, it is clear that there are additional mechanisms underlying these disparities. New research suggests that racial differences in epigenetic profiles may be crucial for explaining inequalities of BrCa. Epidemiological studies have identified numerous factors associated with risk of developing BrCa. Hormonal factors, such as parity, age at first birth, age at menarche and oral contraceptive use, all have well established associations with BrCa risk. A number of other factors are also associated with BrCa risk, including body mass index (BMI), physical activity, family history, and specific genetic risk variants. However, additional research is needed to determine the underlying biological pathways of these well-established risk factors with BrCa risk. Interestingly, data in the literature suggests that effects of these risk factors differ by race, having smaller or larger effects on BrCa risk in AA populations compared to white populations. Epigenetic variants, including DNA methylation, are modifications to DNA that are both heritable and variable based on environmental variation. Epigenetic mechanisms thus may represent a link between genetic and environmental risk factors that underlie the development of BrCa, and also may explain racial differences in effect of risk factors for breast cancer. Two independent groups have recently identified that DNA methylation based on a handful of markers throughout the genome robustly predicts an individual?s chronological age and thus captures the ?epigenetic clock? for biological aging. It has been shown that ?epigenetic age acceleration? ? the difference between methylation-predicted age and chronological age ? is consistently associated with overall mortality and many age-related diseases including cancer. It has been further shown that epigenetic aging rates are significantly associated with race, sex, and with known cancer risk factors such as smoking and obesity, providing the first human evidence suggesting aging-related epigenetic processes are potential molecular underpinnings for racial health disparities. In this project, we will conduct a pilot project that will examine the impact of epigenetic age on the effect of known environmental and lifestyle risk factors for BrCa as it relates to breast cancer risk and then test to see if they differ by race. We will measure epigenetic age through methylation profiling of breast tissue and blood to evaluate (1) ability of blood epigenetic age to correlate with breast tissue epigenetic age; (2) assess differences by race and (3) to provide preliminary data on the correlation of breast epigenetic age with breast cancer risk factors. This proposal will provide the important preliminary data to expand this line of inquiry understanding environmental, genetic and epigenetic factors in BrCa carcinogenesis and BrCa disparities. The samples included in this project are from a large BrCa case-control study, and includes a socioeconomic status and racially diverse group of patients recruited from the Case CCC catchment area. This proposal will facilitate the generation of necessary pilot data for a larger R01 level grant to more fully study this important line of inquiry.