Causal Changes in DNA Methylation and Breast Cancer Development

Aberrant DNA methylation plays an important role in breast cancer initiation and progression via inactivation of tumor suppressor genes and activation of oncogenes. Identifying causal epigenetic changes that drive breast cancer development remains a major challenge in the field. Conventional approaches comparing DNA methylation profiles in tumor and adjacent non-tumorous tissue have shown that changes in DNA methylation contribute to deregulation of gene expression in breast cancer. However, such approaches are unable to distinguish causal DNA methylation alterations, which drive tumorigenesis, from reactive ones that are influenced by the tumor. In addition, important cancer-related methylation changes may have been missed when a suboptimal baseline control (adjacent non-tumorous tissue) was used in previous studies. We hypothesize that an individual’s genetic susceptibility and environmental risk factors contribute to causal alterations in DNA methylation for breast cancer and that such causal changes have already taken place in normal breast tissue before tumor occurrence. In order to test this hypothesis, normal breast tissue from healthy women is required and must be used. We have access to unique normal breast tissue through the Susan G. Komen Tissue Bank at Indiana University Simon Cancer Center (IUSCC). This resource represents the only biorepository in the world for large numbers of epidemiologically annotated, optimally prepared normal breast tissue specimens (>3200) from healthy women encompassing a wide range of ages and environmental exposures. We have built long-term collaborative relationships with this biobank and have already generated interesting preliminary data using normal breast tissue samples from healthy women. Therefore, we are uniquely positioned to test this hypothesis.