Mevalonate pathway upregulated by mutant p53; pathway sufficient for phenotypic effects of p53
FRIDAY, Jan. 20 (HealthDay News) -- Mutant p53 disrupts breast architecture, possibly via upregulation of the mevalonate pathway, according to a study published in the Jan. 20 issue of Cell.
William A. Freed-Pastor, from Columbia University in New York City, and colleagues used a three-dimensional culture model of breast cancer to determine which cellular signaling pathways were affected by mutant p53.
The researchers found that nonmalignant breast epithelial cells had an acinar morphology, and breast cancer cells had a disorganized morphology. Depletion of mutant p53 in breast cancer cells induced a phenotypic reversion to a more acinar-like morphology. Genome-wide expression profiling showed upregulation of the mevalonate pathway by mutant p53. Use of statins and sterol biosynthesis intermediates showed that the mevalonate pathway was necessary and sufficient for the p53-induced phenotypic effects on breast tissue architecture. In human breast tumors, p53 mutation correlated with highly expressed sterol biosynthesis genes.
"Our results demonstrate that mutant p53 can disrupt mammary acinar morphology and that downregulation of mutant p53 from malignant cells is sufficient to phenotypically revert these cells," the authors write. "We hypothesize that tumors bearing p53 mutations evolve to become highly reliant on metabolic flux through the mevalonate pathway, making them particularly sensitive to inhibition of this pathway."
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