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Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise

Oncogene volume 32, pages 3410–3419 (2013)Cite this article

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Abstract

In a previous work, we reported that young transgenic (Tg) mice expressing the intracellular domain of Notch1 (N1IC) showed expansion of lin− CD24+ CD29high 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+/− N1IC Tg mice, respectively. Here, we studied the epithelial cell subsets present in N1IC-induced tumors. CD24− CD29int and CD24+ CD29high 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. CD24int CD29int 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+/− N1IC Tg mice. Using cyclin D1 shRNA knockdown, we also show that N1IC-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 N1IC-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+ CD29high 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.

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Acknowledgements

This work was supported by grant to PJ from the Canadian Institute of Health Research (CIHR). PJ is a recipient of a Canada Research Chair. We thank Jean-René Sylvestre for excellent animal care. We are grateful to Annie Lavallée as well as to Éric Massicotte and Julie Lord for their excellent assistance with tissue sections and flow cytometry, respectively.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montréal, Québec, Canada

    H Ling & P Jolicoeur

  2. Division of Experimental Medicine, McGill University, Montréal, Québec, Canada

    P Jolicoeur

  3. Department of Microbiology and Immunology, Université de Montréal, Montréal, Québec, Canada

    P Jolicoeur

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Correspondence to P Jolicoeur.

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Ling, H., Jolicoeur, P. Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise. Oncogene 32, 3410–3419 (2013). https://doi.org/10.1038/onc.2012.341

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