The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis.
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.
Vaillant
François
F
VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Asselin-Labat
Marie-Liesse
ML
Shackleton
Mark
M
Forrest
Natasha C
NC
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2; D016158:Genes, p53; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000502:physiology
D014408:Biomarkers, Tumor; D019012:Integrin beta1; D039661:Integrin beta3; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse