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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Female
  • Gene Deletion
  • Mice
  • Neoplastic Stem Cells / pathology*
  • Proto-Oncogene Proteins c-met / metabolism
  • Signal Transduction
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology*
  • Tumor Suppressor Protein p53 / deficiency*
  • Tumor Suppressor Protein p53 / genetics
  • beta Catenin / metabolism


  • Tumor Suppressor Protein p53
  • beta Catenin
  • Proto-Oncogene Proteins c-met