Abstract
The cells of origin and mechanisms that underpin tumor heterogeneity in breast cancer are poorly understood. Here, we have examined three mouse models of mammary tumorigenesis (MMTV-wnt-1, MMTV-neu, and p53(+/-)) for changes in their epithelial cell hierarchy during the preneoplastic and neoplastic stages of tumor progression. In preneoplastic tissue, only MMTV-wnt-1 mice showed a perturbation in their epithelial subpopulations. In addition to an expanded mammary stem cell pool, repopulating cells capable of yielding extensive mammary outgrowths in vivo were revealed in the committed luminal progenitor population. These findings indicate that wnt-1 activation induces the appearance of aberrant progenitor cells, and suggest that both mammary stem and progenitor cells can serve as the cellular targets of wnt-1-induced tumorigenesis. In tumors arising in MMTV-wnt-1 tumors, the luminal epithelial progenitor marker CD61/beta3 integrin identified a cancer stem cell (CSC) population that was highly enriched for tumorigenic capability relative to the CD61(-) subset. CD61 expression also defined a CSC subset in 50% of p53(+/-)-derived tumors. No CSCs, however, could be identified in the more homogeneous MMTV-neu/erbB2 model, suggesting an alternative model of tumorigenesis. Overall, our findings show the utility of the progenitor marker CD61 in the identification of CSCs that sustain specific mammary tumors.
Highlights
Mouse models of mammary tumorigenesis have been used extensively to investigate the genetic pathways that lead to mammary tumorigenesis [1]
In the case of established mammary tumors, we report that the luminal progenitor marker CD61/h3 integrin identifies a cancer stem cell (CSC) population in MMTV-wnt-1 and p53+/À tumors that is markedly enriched for tumor-forming capacity
As previously noted [2], the LinÀCD29hiCD24+ population was expanded in preneoplastic tissue from MMTVwnt-1 mammary glands at 8 weeks of age compared with agematched control glands (Fig. 1A), despite an age-related increase in the mammary stem cells (MaSCs)-enriched population
Summary
Mouse models of mammary tumorigenesis have been used extensively to investigate the genetic pathways that lead to mammary tumorigenesis [1]. In the normal mouse mammary gland, mammary stem cells (MaSCs) with a phenotype of CD29hiCD49f hiCD24mod/+ have been identified [2,3,4] and shown to regenerate a complete functional mammary gland at the single-cell level. This population, comprises mature myoepithelial cells and presumptive basal progenitor cells. Luminal progenitor cells have been defined based on expression of either CD61 [5] or CD133/prominin-1 [6], where the. Shacklelon: Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan
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