Aneuploidy and polyploidy associated with chromosomal instability are hallmarks of many breast cancers and have been implicated as some of the earliest steps in tumor formation. Recent evidence has established that aneuploidy/polyploidy can even predispose to breast cancer. While much is already known about the molecular mechanisms leading to aneuploidy/polyploidy, little is understood at the genetic and epidemiological level. We hypothesize that inherited variation in genes involved in regulating cell division contribute to the development of aneuploidy/polyploidy and subsequently to breast cancer. We propose a comprehensive multi stage approach to the study of genes involved in regulation of cell division using single variants and haplotypes. We will identify candidate variants and haplotypes associated with breast cancer risk in the Mayo Clinic Breast Cancer case-control Study and validate the associations in the Anglican Breast Cancer (ABC) Study. The genes containing the variants will be resequenced and haplotyped tagging variants representing small haplotype blocks will be selected and re-genotyped in an expanded Mayo Clinic Breast Cancer Study to identify the specific variants or haplotype blocks that account for the association with breast cancer risk. These variants and haplotypes will be validated in an expanded ABC study and the influence of these SNPs on gene expression and function will be characterized. Our specific aims are: Aim #1: To identify and confirm associations between Single Nucleotide Polymorphisms (SNPs) and haplotypes in genes that regulate cell division and breast cancer risk. Specific Aim #2: To characterize all genetic variation in the genes displaying association with breast cancer risk in the Mayo Clinic Breast Cancer Study population. Specific Aim #3: To identify the variants in these genes that account for the modified risk of cancer. Specific Aim #4: To characterize the functional significance of inherited variation in mitotic regulation genes that is associated with breast cancer risk. This study will address the contribution of the under-evaluated area of regulation of cell division to breast cancer etiology. The study will go beyond identification of risk markers to the characterization of the variants that actually cause the modification of breast cancer risk. The results will provide information for improved risk assessment and could provide targets for breast cancer prevention and therapeutic agents.