Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway
Menée sur un modèle tri-dimensionnel de culture cellulaire, cette étude identifie un mécanisme par lequel une forme mutée du gène p53, en activant la voie de signalisation mévalonate, perturbe l'architecture des tissus mammaires
p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53. º Depletion of mutant p53 phenotypically reverts breast cancer cells in 3D culture º Mutant p53 upregulates mevalonate pathway genes via SREBP transcription factors º HMG-CoA reductase inhibitors mimic the phenotypic effects of mutant p53 depletion º TP53 mutation correlates with elevation of mevalonate pathway genes in human tumors Metastasis-associated p53 mutations disrupt breast tissue organization by upregulating transcription of sterol biosynthesis genes, highlighting p53 status as a predictive marker for responsiveness to statin therapy in cancer.