title: Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway.
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.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Freed-Pastor
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Moon
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.forename: Anthony
authors.initials: A
authors.lastname: Barsotti
authors.forename: Agustin
authors.initials: A
authors.lastname: Chicas
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.forename: Alla
authors.initials: A
authors.lastname: Polotskaia
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Jill
authors.initials: J
authors.lastname: Bargonetti
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism*; D009154:Mutation; D054876:Prenylation; D011401:Promoter Regions, Genetic; D019821:Simvastatin / Q000494:pharmacology; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051779:Sterol Regulatory Element Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019821:Simvastatin; D008798:Mevalonic Acid