Critical Role for Aberrant CpG Island Methylation in the Evolution and Progression of Breast Cancer: Characterization of Known Genes and Identification of Novel Genes

摘要

CpG island methylation is an epigenetic modification of DNA associated with the silencing of gene transcription. The hypothesis of this proposal is that breast cancers develop along different pathways, some involving aberrant CpG island methylation for gene inactivation. Some of the genes or CpG islands identified in the methylation-dependent pathways will also be inactivated early in breast cancer evolution and/or will be associated with prognosis. These hypotheses will be tested in innovative studies that will identify novel CpG islands methylated in stage I or III breast cancers using the new technique of methylation specific representation differential analysis. The frequency and timing for methylation of these novel CpG islands will be defined in a case control study of ductal cell carcinoma in situ, stage I, and stage III ductal cell carcinomas. This study is collecting data on other risk factors (e. g., hormone profiles, alcohol intake) for breast cancer. In addition, cellular and genetic endpoints that are potentially prognostic for this disease: cell proliferation index (Ki-67), HER2/neu, progesterone receptor and estrogen receptor expression are being determined in this ongoing study. The novel technique of methylation-specific polymersae chain reaction will be used to detect methylated alleles in DNA from fixed tissue. Together, these results will identify novel CpG islands in breast cancer, define their timing for inactivation, identify pathways that may lead to breast cancer through gene inactivation by methylation, and identify markers of prognosis.