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Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway
- Source :
- Cell. (1-2):244-258
- Publisher :
- Elsevier Inc.
-
Abstract
- Summaryp53 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.
- Subjects :
- Simvastatin
Mutant
Mevalonic Acid
Breast Neoplasms
Mevalonic acid
Biology
medicine.disease_cause
Article
General Biochemistry, Genetics and Molecular Biology
chemistry.chemical_compound
Cell Line, Tumor
medicine
Humans
Promoter Regions, Genetic
Transcription factor
Prenylation
Sterol Regulatory Element Binding Proteins
Mutation
Biochemistry, Genetics and Molecular Biology(all)
Molecular biology
Cell biology
Sterol regulatory element-binding protein
chemistry
Cell culture
Female
Mevalonate pathway
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Tumor Suppressor Protein p53
Carcinogenesis
Metabolic Networks and Pathways
Subjects
Details
- Language :
- English
- ISSN :
- 00928674
- Issue :
- 1-2
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....39769ea68f525d84e077b59ac4b8c7cd
- Full Text :
- https://doi.org/10.1016/j.cell.2011.12.017