Figure 8.

Origin of mammary tumors in BALB/c-Trp53^+/− mice. A: Expression of stem cell-related genes in tumor samples differing in keratins expressed. Expression of stem cell-related genes was examined in tumors expressing mixed keratins (V06 and V22) and tumors with luminal-only keratins (V07 and V14). The expression of each gene is expressed as a ratio compared with the levels in normal mammary epithelium obtained by enzymatic digestion. A set of 9 genes are differently expressed between the two groups (top panel). However, 69 genes showed similar patterns of expression between the groups (bottom panel). The genes are grouped according to functions or pathways: I, cell cycle regulators, chromosome modulators, and cell division-related genes; II, cytokines and growth factors; III, cell adhesion molecule; IV, embryonic stem cell-related genes; V, notch pathway-related genes; VI, Wnt pathway related genes; and VII, tissue-specific stem cell markers. B: Cellular origins of mammary tumors in BALB/c-Trp53^+/− mice. Mammary glands in BALB/c-Trp53^+/− mice display normal ductal and alveolar structures composed of luminal (green) and basal cells (red). Progenitor cells (orange) with a potential to differentiate into both epithelial lineages also reside in the normal structure. Loss of the wild-type allele of Trp53 in any of these cells would abolish the rate-limiting step in tumorigenesis, resulting in invasive mammary tumors. Because the majority of mammary tumors contain tumor cells expressing luminal and basal markers, a clonal origin within bipotent cells is suggested as the most common pathway. For tumors expressing only luminal or basal markers, there could be two possibilities. They may originate from bipotent progenitors and later partially differentiate into tumors with single lineage cells or they could originate within the lineage-restricted cells. The overall similarity of the stem cell gene expression pattern of tumors suggested the former path.