p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène p53 et l'activation de la signalisation de la bêta-caténine favorisent le développement d'un cancer du sein triplement négatif
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/[beta]-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/[beta]-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5[Delta]N[beta]cat mice displaying a constitutive activation of Wnt/[beta]-catenin signaling in basal cells. K5[Delta]N[beta]cat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5[Delta]N[beta]cat 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 [beta]-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.