| First Author | Chiche A | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 17 | Pages | 2355-2365 |
| PubMed ID | 27775073 | Mgi Jnum | J:241157 |
| Mgi Id | MGI:5897931 | Doi | 10.1038/onc.2016.396 |
| Citation | Chiche A, et al. (2017) p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors. Oncogene 36(17):2355-2365 |
| abstractText | 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 K5DeltaNbetacat mice displaying a constitutive activation of Wnt/beta-catenin signaling in basal cells. K5DeltaNbetacat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5DeltaNbetacat 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. |
