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Cell. 2012 Jan 20;148(1-2):244-58. doi: 10.1016/j.cell.2011.12.017.

Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway.

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  • 1Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

Comment in

  • Oncogenic morphs of p53. [Nat Rev Cancer. 2012]
PMID:
22265415
[PubMed - indexed for MEDLINE]
PMCID:
PMC3511889
Free PMC Article

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