Genomic Instability in Breast Cancer Sigurdur Ingvarsson Institute for Experimental Pathology, University of Iceland at Keldur, Iceland; E-mail: siguring@hi.is The presence of numerical and structural chromosome aberrations is a common characteristic of tumor cells. Accumulation of these aberrations leads to dramatic changes within the genome. These changes have tumor type and stage specific pattern of segmental losses and gains, resulting in gene losses and gene copy number imbalances. Tumor development and progression is driven by sequential acquisition of specific gene alterations, and chromosome aberrations contribute to these processes. Genomic instability in tumors can be classified as chromosome instability (CIN) and microsatellite instability (MIN). MIN is in general less frequent in tumors than CIN, but is rather frequent in some tumors of the digestive tract. This is mainly due to germline mutations in mismatch repair genes associated with the HNPCC cancer syndrome, but can also be due to somatic mutations and epigenetic mechanism. While MIN is rare in breast tumors, CIN is demonstrated in the majority of breast tumors (about 70%) by aneuploidy, deletions, amplifications and rearrangements. Although the reasons for CIN in breast tumors are not well understood, explanations can partly be obtained from deficient control of genes controlling cell proliferation, apoptosis, DNA repair or chromosome segregation. Among these genes are TP53, MYC, AURKA, BRCA1 and BRCA2. TP53 is relatively well studied and is believed to be a guardian of genome integrity. Myc seems to affect tumor pathogenesis in several ways, including increased proliferation and immortalization of the cancer cells and induction of CIN. The STK15 gene encodes the aurora A kinase, which has been shown to bind to centrosomes and is important in controlling their number and the segregation of correct chromosomes to the daughter cells during mitosis. Genomic instability is high in some hereditary breast cancer, particularly in tumors of BRCA1 and BRCA2 mutation carriers, a finding which is in line with the role of the gene products in DNA repair. Some recent developments in drug therapy are based on molecular and genomic findings about breast cancer pathogenesis. Defects in checkpoint control generate CIN and are believed to facilitate tumorigenesis, but additional disabling of checkpoint signaling is a possible anticancer strategy.