Aberrant DNA methylation patterns of miRNAs and breast cancer racial disparities

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DESCRIPTION (provided by applicant): Background: Breast cancer incidence is higher in women of European ancestry (EA) than in women of African ancestry (AA) overall, yet AA women are more likely to be diagnosed with estrogen receptor negative, high histological grade tumors that are associated with an overall more aggressive clinical course and poor prognosis. The reasons for these disparities in breast cancer remain unknown; however, environmental and lifestyle risk factors clearly contribute to an increased susceptibility for biologically aggressive types of the disease in AA women. Importantly, recent progress in breast cancer research has indicated that the biological mechanisms behind the association may lie in the ability of these risk factors to modulate DNA methylation, thus potentially altering the gene expression and contributing to cancer racial differences. Further, aberrant DNA methylation of microRNAs (miRNAs) may have a much broader effect than altering the methylation level in protein-coding genes, because a single miRNA can regulate expression of multiple target genes. However, to our knowledge, no study has examined the impact of aberrant DNA methylation of miRNAs on breast cancer disparities and whether and how environmental and lifestyle risk factors play a role in this relationship. Research and Training Plan: We propose to study aberrant DNA methylation in miRNAs, an understudied area, and its association with dietary and lifestyle factors, in relation to breast cancer racial disparities. This proposed study utilizes the data generated from a genome-wide methylation analysis in breast tumor tissue from AA and EA women using the Illumina Infinity 450K array platform and from a large case-control study, the Women's Circle of Health Study (WCHS), with biospecimens and extensive questionnaire data from AA and EA women with breast cancer. In Aim 1, we first propose to select miRNA that are differentially methylated by race and ER status from the genome-wide array, and verify these by an independent, high-throughput sequencing-based methylation analysis method; we will also assess miRNA expression levels. In Aim 2, we will further examine the differentially methylated loci in depth in tumors from 500 AA and 500 EA patients participating in WCHS. Lastly in Aim 3, we will examine associations between miRNA methylation patterns and various dietary and lifestyle factors, and their role in relation to breas cancer racial differences between AA and EA women. While my previous experience and training in medicine, nutrition, and cancer epidemiology provides a solid foundation for me to pursue the proposed research interests, I have limited knowledge and expertise in molecular epidemiology, particularly in epigenetics, and analysis of complex data, and their applications to human populations. This career development award will provide me the opportunity to gain training and mentoring in several targeted areas, including knowledge in breast cancer biology, molecular carcinogenesis and the role of miRNAs, advanced methods and techniques in genetic/epigenetics, skills in biostatistics and bioinformatics, and general training in the ethica conduct of scientific research, grant writing and development. New knowledge and skills in these areas will be obtained through mentorship (Drs. Christine Ambrosone, Michael Higgins, Song Liu, and Steven Belinsky),formal courses, practical laboratory training, seminars, workshops, and conferences. The experience and knowledge gained from this award will ultimately prepare me to develop and submit a R01 application for funding that is necessary to establish myself as an independent researcher. Objective: The main objective of this career development award is to gain training and mentoring in above mentioned targeted areas in order to develop and expand my career as a cancer epidemiologist with a deeper and comprehensive knowledge of DNA methylation and miRNAs and their roles in carcinogenesis and cancer prevention. My long-term goal is to develop expertise and be able to integrate the most current epigenetic, molecular and statistical methods into population-based studies, especially to study the contribution of epigenetic alterations and their associations with environmental, dietary and lifestyle factors in relation to cancer risk. I am particularly interestd in breast cancer and racial disparities, but also would like to apply the knowledge and skills gained through this training to other cancers. In summary, this career development award will provide me invaluable experience for a successful transition into scientific independence in molecular cancer epidemiology with a focus on epigenetics and its role of cancer prevention. Cancer Relevance: The proposed work addresses an understudied area of breast cancer and will contribute to the limited literature for a better understanding of the epigenetic role, in particular aberrant methylation on miRNAs, in breast cancer racial disparities. We will also be able to evaluate modifiable factors that are associated with aberrant methylation patterns. Findings could provide important information for the discovery of novel biomarkers and the development of targeted preventive and therapeutic strategies.