The long-term objective of the proposed study is to understand the molecular mechanisms underlying the carcinogenic process of breast cancer. The hypothesis to be tested is that the high morphological heterogeneity associated with breast cancer development is a reflection of different molecular pathways involved in the carcinogenic process. To test this hypothesis, a systematic study of genome-scale analysis is required. For this purpose, 600 genetic markers covering the entire human genome will be identified. The markers will be incorporated into a multiplex genotyping system with which 2,880 genotypes per day will be easily determined by one investigator using the materials from microdissection. This system will be used to examine the loss of heterozygosity (LOH) at all marker loci in all common forms of invasive breast carcinomas and to examine tumor suppressor genes (TSGs) involved in different pathways. Different pathways will be compared to determine the TSGs that are commonly involved in the carcinogenic process and those that are responsible for the morphological features. All common breast lesions that have been considered as precursors of breast cancer will also be included in the study so that the involvement of TSGs at different stages of the corresponding pathways can be examined. The resulting data will also be used to locate the chromosomal regions where chromosomal breakage and/or somatic recombination occur frequently, to identify reliable prognostic markers, and to provide molecular information for curing the disease.
