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Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors

Oncogene volume 29, pages 4543–4554 (2010)Cite this article

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Abstract

Members of the Notch family are involved in the development of breast cancer in animal models and in humans. In young transgenic mice, expressing intracellular activated Notch1 (N1IC) in mammary cells, we found that CD24+ CD29high progenitor cells had enhanced survival, and were expanded through a cyclin D1-dependent pathway. This expansion positively correlated with the later cyclin D1-dependent formation of basal-like ductal tumors. This expanded population exhibited abnormal differentiation skewed toward the basal cells, showed signs of pre-malignancy (low PTEN/p53 and high c-myc) and contained stem cells with impaired self-renewal in vivo, and more numerous multipotent, ductal-restricted progenitors. Our data suggest that N1IC can favor transformation of progenitor cells early in life through a cyclin D1-dependent pathway.

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Acknowledgements

This work was supported by grant to PJ from the Canadian Institute of Heath Research (CIHR). PJ is a recipient of a Canada Research Chair and HL of a Postdoctoral Fellowship from CIHR Training grant in cancer. We are grateful to Annie Lavallée as well as to Eric Massicotte and Martine Dupuis for excellent assistance with tissue sections and flow cytometry, respectively, and to Dominic Filion for image analysis.

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Authors and Affiliations

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

    H Ling, J-R Sylvestre & 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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  1. H Ling
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Correspondence to P Jolicoeur.

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Ling, H., Sylvestre, JR. & Jolicoeur, P. Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene 29, 4543–4554 (2010). https://doi.org/10.1038/onc.2010.186

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