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Oncogene. 2017 Apr 27;36(17):2355-2365. doi: 10.1038/onc.2016.396. Epub 2016 Oct 24.

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

Author information

1
Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
2
Institut de Cancérologie de l'Ouest, Bvd Jacques Monod, Saint Herblain, France.
3
GenoSplice Technology, iPEPS - ICM, Hôpital Pitié Salpêtrière, Paris, France.
4
Division of Molecular Pathology and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
5
Institut national de la santé et de la recherché médicale, Paris, France.

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.

PMID:
27775073
DOI:
10.1038/onc.2016.396
[Indexed for MEDLINE]

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