Fig. 9

Schematic model of neoplastic progression in 129:Stat1 ^−/− tumorigenesis. On the basis of data presented here, a model of neoplastic progression can be proposed. 129:Stat1 ^−/− renders (1) a subpopulation of Forkhead box A1-committed progenitor cells (large oval pale [LOP] cells) susceptible to oncogenesis. On the basis of limited distribution of LOP cells within the ductal tree, this tumor progression occurs after the beginning of ductal morphogenesis. The LOP cells have a selective advantage in the 129:Stat1 ^−/− cytokine-poor environment. (2) With the onset of adulthood and aging, continued proliferation of a subset of LOP cells gains further selective advantage, forming abortive (aberrant) side buds in some contexts and (3) focal dysplastic proliferation with loss of cell polarity, identified as a mammary intraepithelial neoplasia (MIN). The earliest MIN do not induce a significant host response, exhibit nontruncating prolactin receptor (PRLR) mutations, and generally have a morphologically identifiable basement membrane and myoepithelial layer. (4) However, with further adaptive changes, the MIN LOP cells attract a pronounced protumor host response of macrophages, T lymphocytes, and granulocytes, including mast cells and fibrotic extracellular matrices (microenvironmental elements). (5) The basement membrane and myoepithelial cells become disorganized and disintegrate, with progression of MIN to invasive ductal carcinoma with truncated PRLR mutations