Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway
2012
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 pathwayas significantly upregulated by mutant p53. Statins and
sterol biosynthesisintermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with
sterolgene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed
sterol biosynthesisgenes in human breast tumors. These findings implicate the
mevalonate pathwayas a therapeutic target for tumors bearing mutations in p53.
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