title: p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors.
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.
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
authors: A
authors: A
authors: Chiche
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
authors: M
authors: M
authors: Moumen
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
authors: M
authors: M
authors: Romagnoli
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
authors: V
authors: V
authors: Petit
authors: Institut de Cancérologie de l'Ouest, Bvd Jacques Monod, Saint Herblain, France.
authors: H
authors: H
authors: Lasla
authors: Institut de Cancérologie de l'Ouest, Bvd Jacques Monod, Saint Herblain, France.
authors: P
authors: P
authors: Jézéquel
authors: GenoSplice Technology, iPEPS - ICM, Hôpital Pitié Salpêtrière, Paris, France.
authors: P
authors: P
authors: de la Grange
authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: J
authors: J
authors: Jonkers
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.|Institut national de la santé et de la recherché médicale, Paris, France.
authors: M-A
authors: MA
authors: Deugnier
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.|Institut national de la santé et de la recherché médicale, Paris, France.
authors: M A
authors: MA
authors: Glukhova
authors: Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.|Institut national de la santé et de la recherché médicale, Paris, France.
authors: M M
authors: MM
authors: Faraldo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019859:Proto-Oncogene Proteins c-met