Identification of Early Epigenetic Changes in African-American Progenitor Cells and Their Role in Breast Cancer Initiation
Abstract
Among all ethnicities, women of African American (AA) origin have continued to have the highest breast cancer mortality rates. This is observed even in places where the standard of care is the same. This suggests that the tumors that arise in AA are different from European American (EA) tumors. This proposal addresses two challenges: "to identify what makes the breast susceptible to cancer development" and "to prevent breast cancer" in this minority population. We believe that AA women are exposed to different hormonal and environmental carcinogens, for example, cigarette smoke and carcinogens present in barbecued, charred meats. These lifetime exposures leave their imprint on long-lasting "stem cells" in the breast in the form of changed gene expression or marks on DNA called methylation. In this proposal, first, we would like to discover what these changes are in the breast stem cells by looking at the entire genome of the breast cells. We will do this by looking at normal breast tissue from 50 women who are undergoing mastectomy for their breast cancer. Tissue will be collected from the opposite "normal" breast (lower risk), from normal looking breast tissue close to the tumor (higher risk), and some tumor tissue as well for validating (testing to see if they continue to be present in the tumor cells) the genes discovered in the normal high risk breast tissue. We will look at the gene expression pattern and DNA methylation pattern of the whole genome to search for changes between the low and high risk normal looking breast tissue. We will make a list of these markers and compare the list with the list of markers present in the Caucasian woman s breast to find out which are the genes that may lend aggressive properties to the AA tumors. If these changes or "risk markers/genes" can be reversed with known drugs or natural compounds present in plants, we can eliminate the changed breast cells when they are still harmless-thus we could like to prevent breast cancer. Thus, we hypothesize that differences in breast cancer incidence and mortality between AA and EA women can be explained in part by molecular AA-specific events that take place in the progenitor or stem cells of normal breast tissue that is responding to environmental signals, such as carcinogen exposure, that are important for tumors to begin. Also, these environment-induced alterations can be reversed by pathway specific drugs or natural chemopreventives. The proposed studies will help us understand breast cancer in AA women better, how it begins, and how it can be treated. In the long run, it will reduce disparity. How is this study different from other studies? This study proposes to combine the strengths of a unique research environment in Johns Hopkins breast program where the researchers work hand in hand with the clinicians making this possible; expertise in genomic analysis; and bioinformatics with preclinical testing. We emphasize the need not to consider breast cancer in AA and EA as the same disease, and to recognize that these changes take place over a lifetime, and are already present in the outwardly normal looking tissue. The study addresses identification of "risk" markers, so that we may reverse the bad molecular changes using drugs or natural chemopreventives at an early stage. We have to recognize and attack the changed cells early, before it presents itself as a cancer. Prevention is the only way we will be able to eradicate cancer, and studies of this type will be the first steps.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510017
Entities
People
- Saraswati Sukumar
Organizations
- Johns Hopkins University
- United States Army