The genetics of sporadic breast cancer.

Breast cancer is a complex disease in which numerous genetic aberrations occur. It is unclear which, if any, of these abnormalities are causative of breast tumorigenesis. However, on the basis of the currently accepted view of breast cancer as a multistep process, it is possible that specific abnormalities may be required in the progression from a normal breast epithelial cell to an invasive tumor cell. Figure 3 shows a schematic putative model of breast cancer progression based primarily on epidemiological and histopathological studies (Page and DuPont, 1992). Advances in methodology have allowed us to more precisely determine the approximate chronology of some of these aberrations and the possible roles each plays in the formation of malignancy. Simplistically, one could speculate that it is the early loss of cell cycle control in the presence of a mitogenic stimulus that allows a cell to divide unchecked. Such uncontrolled proliferation in the absence of wild type p53 would yield a high level of genomic instability. As proliferation continues, numerous additional chromosomal abnormalities occur, and increased tumor heterogeneity would be observed as distinct subpopulations emerge in the evolution toward a progressively more aggressive phenotype. However, much still remains to be learned to gain a full understanding of the key players behind the genetic evolution of breast cancer. Only by analyzing preinvasive and putative early stages of breast cancer will we be able to characterize the most probable sequence of genomic abnormalities.