Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway

Freed-Pastor, W. A., Mizuno, H., Zhao, X., Langerød, A., Moon, S. H., Rodriguez-Barrueco, R., Barsotti, A., Chicas, A., Li, W., Polotskaia, A., Bissell, M. J., Osborne, T. F., Tian, B., Lowe, S. W., Silva, J. M., Børresen-Dale, A. L., Levine, A. J., Bargonetti, J., Prives, C. (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell, 148 (1-2). pp. 244-258. ISSN 00928674 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22265415
DOI: 10.1016/j.cell.2011.12.017

Abstract

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. © 2012 Elsevier Inc.

Item Type: Paper
Uncontrolled Keywords: actin mevalonic acid mutant protein protein p53 sterol regulatory element binding protein article breast cancer breast carcinogenesis cancer cell controlled study gene expression gene mutation genome analysis human human cell morphology nucleotide sequence phenotype priority journal promoter region spheroid cell sterol synthesis upregulation
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
organs, tissues, organelles, cell types and functions > organs types and functions > breast
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organs, tissues, organelles, cell types and functions > organs types and functions
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Microarray Service
CSHL labs > Lowe lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: Matt Covey
Date Deposited: 30 Jan 2013 21:33
Last Modified: 30 Oct 2015 16:21
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26942

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