Mutant p53 Disrupts Mammary Acinar Morphogenesis via the Mevalonate Pathway
By William A. Freed-Pastor, Hideaki Mizuno, Xi Zhao, A. Langerød, S. Moon, R. Rodríguez-Barrueco, A. Barsotti, A. Chicas, Wencheng Li, A. Polotskaia and 9 more. Cell, 2012
810 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/f3072697a43b337ab22b614f61d430ac867070c1
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In Cancer Research
In Oncology
- William A. Freed-Pastor
- Carol Prives
- F. Mantovani
- Licio Collavin
- Huafeng Zhang
- Zhaoyong Li
- G. Del Sal
- Vladimir N Uversky
Citations in the corpus
- Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “Recently, it was reported that mutant p53 interact with SREBPs and is recruited to the promoters of multiple genes encoding mevalonate pathway enzymes, including HMG-CoA reductase, in a SREBPdependent way [104].”
- Mutant p53: one name, many proteins. (2012, background): “DNA contact (or class I) mutants, exemplified by p53-R273H, are missense mutations in the amino acid residues that normally make direct contact with target DNA sequences.”
- Statin use and reduced cancer-related mortality. (2012, neutral): “Small 6,032 (32) 36,509 (13) 4,842 (32) 13,629 (30)”
- Mutant p53 as a guardian of the cancer cell (2018, positive): “A similar reasoning can be applied to the MVP, whose induction both mediates tumorigenic activities of mutp53 and supports its accumulation in cancer cells [19, 44].”
- Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development (2013, background): “The same study that demonstrated that mutant p53 proteins activate the mevalonate pathway by binding to SREBP (described above), also showed that inhibition of different enzymes within this pathway blocks the invasive morphology of breast cancer cells grown in 3D, potentially by interfering with ger”