Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise.
In a previous work, we reported that young transgenic (Tg) mice expressing the intracellular domain of Notch1 (N1(IC)) showed expansion of lin(-) CD24(+) CD29(high) mammary cells enriched for stem cells and later developed mammary tumors. Mammary tumor formation was abolished or greatly reduced in cyclin D1(-/-) or cyclin D1(+/-) N1(IC) Tg mice, respectively. Here, we studied the epithelial cell subsets present in N1(IC)-induced tumors. CD24(-) CD29(int) and CD24(+) CD29(high) cells were found to be present at low numbers in tumors. The latter had the same properties as those expanded in young Tg females, and neither cell population showed tumor-initiating potential nor were they required for maintenance of tumors after transplantation. CD24(int) CD29(int) cells were identified as tumor-initiating and mammosphere-forming cells and represent a large percentage tumor cells in this model. Their number was significantly lower in tumors from cyclin D1(+/-) N1(IC) Tg mice. Using cyclin D1 shRNA knockdown, we also show that N1(IC)-induced tumor cells remain addicted to cyclin D1 for growth and survival. Interestingly, at lower levels of cyclin D1 or after transplantation in the presence of normal mammary cells, these N1(IC)-expressing tumor cells reverted to a state of low malignancy and differentiate into duct-like structures. They seem to adopt the fate of bi-potential stem/progenitor cells similar to that of the expanded CD24(+) CD29(high) stem/progenitor cells from which they are likely to be derived. Our data indicate that decreasing cyclin D1 levels would be an efficient treatment for tumors induced by N1 signaling.
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montréal, Québec, Canada.
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D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D019012:Integrin beta1 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D019012:Integrin beta1; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D019938:Cyclin D1