Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway

William A. Freed-Pastor, Hideaki Mizuno, Xi Zhao, Anita Langerød, Sung Hwan Moon, Ruth Rodriguez-Barrueco, Anthony Barsotti, Agustin Chicas, Wencheng Li, Alla Polotskaia, Mina J. Bissell, Timothy F. Osborne, Bin Tian, Scott W. Lowe, Jose M. Silva, Anne Lise Børresen-Dale, Arnold J. Levine, Jill Bargonetti, Carol Prives

Research output: Contribution to journalArticlepeer-review

695 Scopus citations


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.

Original languageEnglish
Pages (from-to)244-258
Number of pages15
Issue number1-2
StatePublished - 20 Jan 2012
Externally publishedYes


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