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p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors

Oncogene volume 36, pages 2355–2365 (2017)Cite this article

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Abstract

Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/β-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/β-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5ΔNβcat mice displaying a constitutive activation of Wnt/β-catenin signaling in basal cells. K5ΔNβcat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5ΔNβcat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53-deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and β-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies.

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Acknowledgements

We are particularly grateful to A Di Cicco, D Gentien, A Rapinat and B Albaud for expert technical assistance, to Dr I Grandjean, S Jannet and the personnel of the animal facilities at Institut Curie for taking care of the mice and to Z Maciorowski, A Viguier and S Grondin for excellent assistance with flow cytometry. We also thank Dr JL Jorcano for providing mouse strains and Dr D Medina for valuable discussions. The work was supported by grants from La Ligue Nationale Contre le Cancer (Equipe Labelisée 2013), Canceropôle Ile de France (2014-1-SEIN-01-ICR-1) to MAG. and a grant from La Ligue Nationale Contre le Cancer Comités d’Ile de France to MMF. MM and AC received funding from Association pour la Recherche sur le Cancer; AC, from Institut Curie and Servier Laboratories; MAG. is Directeur de Recherche, MMF, MAD and AG are Chargé de Recherche at the Institut National de la Santé et de la Recherche Médicale (INSERM).

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Authors and Affiliations

  1. Institut Curie, PSL Research University, CNRS, UMR144, Paris, France

    A Chiche, M Moumen, M Romagnoli, V Petit, M-A Deugnier, M A Glukhova & M M Faraldo

  2. Institut de Cancérologie de l’Ouest, Bvd Jacques Monod, Saint Herblain, France

    H Lasla & P Jézéquel

  3. GenoSplice Technology, iPEPS – ICM, Hôpital Pitié Salpêtrière, Paris, France

    P de la Grange

  4. Division of Molecular Pathology and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J Jonkers

  5. Institut national de la santé et de la recherché médicale, Paris, France

    M-A Deugnier, M A Glukhova & M M Faraldo

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  1. A Chiche
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Chiche, A., Moumen, M., Romagnoli, M. et al. p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors. Oncogene 36, 2355–2365 (2017). https://doi.org/10.1038/onc.2016.396

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