Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway

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• 作者：William  ; A. Freed-Pastor¹ ; Hideaki Mizuno² ; ³ ; Xi Zhao⁴ ; ⁵ ; Anita Langerø ; d⁴ ; Sung-Hwan Moon¹ ; Ruth Rodriguez-Barrueco⁷ ; Anthony Barsotti¹ ; Agustin Chicas⁸ ; Wencheng Li⁹ ; Alla Polotskaia¹⁰ ; Mina  ; J. Bissell¹¹ ; Timothy  ; F. Osborne¹² ; Bin Tian⁹ ; Scott  ; W. Lowe⁸ ; Jose  ; M. Silva⁶ ; ⁷ ; Anne-Lise Bø ; rresen-Dale⁴ ; ⁵ ; Arnold  ; J. Levine² ; Jill Bargonetti⁹ ; Carol Prives¹ ; ^{clp3@columbia.edu}
• 刊名：Cell
• 出版年：2012
• 出版时间：20 January 2012
• 年：2012
• 卷：148
• 期：1-2
• 页码：244-258
• 全文大小：2092 K

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Summary

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.