Genetic analysis of breast cancer progression

At the histological level, breast tumors display a variety of morphologic lesions which suggest the existence of an increasingly aberrant pathway of intermediate steps leading to the invasive primary tumor and its metastatic dissemination. In order to obtain direct evidence for this presumed progression, underlying genetic changes must be identified. Analyses of primary breast tumors have revealed a large number of dominant and recessive gene alterations encompassing several cellular attributes and activities. It is quite likely that some of these alterations are of a causal nature and thus enable the tumor to attain distinctive malignant phenotypes, such as, dysregulated proliferation, invasion, angiogenesis, and ability to metastasize. Considerable heterogeneity has been observed in the sequence of acquisition of these genetic changes, which is substantiated by recent comparative analyses between carefully microdissected preinvasive and invasive tumor. The data are evaluated here in the context of existing models of breast cancer progression. Implications and prospects for translational application to the clinic are also discussed.