The natural history of cancer is still not clear. The clinical starting point has been identified in precancerous intraepithelial neoplasms. We currently think of neoplastic progression as a multi-step continuum involving multiple somatic mutations. Early detection programs have had enormous effects on mortality rates of some cancers. However, some patient populations seem to elude our best treatment efforts. Studies of epithelial precancers in animal models support the notion that the biological potential of the neoplastic cells is fully encoded in the precancer. This implies that the subsequent events are primarily epigenetic and that the code will be better understood by examining the precancers rather than the end-stage cancer. In this review and opinion we will focus primarily on breast cancer and some of the experimental models of breast cancer because they offer the richest data sets for answering the question posed in the title: Sequentially acquired or predetermined? In large measure, this is the result of three critical components: (1) Longstanding efforts to stratify breast cancer and precancer for prognosis and therapy response; (2) An array of genetically engineered mouse (GEM) models of breast cancer; and (3) Experimental model systems including mouse transplantation technologies. There is emerging data which is similar, however, in other organ sites, both epithelial (prostate, pancreas, intestine) and non-epithelial (glia, lymphoid), that may lead to related conclusions [1-5].
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