Cited by 865Cancer, Lipids, and MetabolismCancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancer

Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway

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Freed-Pastor, William A., Mizuno, Hideaki, Zhao, Xi, Langerød, Anita, Moon, Sung-Hwan, Rodriguez-Barrueco, Ruth, Barsotti, Anthony, Chicas, Agustin +11 more·2012·Cell

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.

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Crossref · 10.1016/j.cell.2011.12.017

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  • GOF mut-p53 induces an anomalous, carcinogenic metabolism (i.e., lipid metabolism and Warburg effect) and disturbed tissue architecture.

    “In addition, GOF mut-p53 induces an anomalous, carcinogenic metabolism (i.e., lipid metabolism and Warburg effect) and disturbed tissue architecture [70,71].”

    From The p53 Pathway in Glioblastoma (2018) · cites this paper as [70]

    The Discussion (page unavailable) reports that certain mutant p53 proteins disrupt mammary acinar morphology in 3D culture and increase expression of mevalonate-pathway genes, supporting the tissue-architecture and lipid-related metabolism portions of the claim. The paper does not report that mutant p53 induces the Warburg effect; that portion is not supported by this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • De novo cholesterol biosynthesis from malonyl-CoA plays a role in tumorigenesis.

    “In addition to fatty acid production, the de novo biosynthesis of cholesterol from malonyl-CoA plays a role in tumorigenesis as well.”

    From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Freed-Pastor et al., 2012

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Authors
Freed-Pastor, W. A., Mizuno, H., Zhao, X., Langerød, A., Moon, S.-H., Rodriguez-Barrueco, R., Barsotti, A., Chicas, A., Li, W., Polotskaia, A., Bissell, M. J., Osborne, T. F., Tian, B., Lowe, S. W., Silva, J. M., Børresen-Dale, A.-L., Levine, A. J., Bargonetti, J., & Prives, C.
Affiliations
  • Columbia University (US)
  • Institute for Advanced Study (US)
  • Oslo University Hospital (NO)
  • Cold Spring Harbor Laboratory (US)
  • Rutgers New Jersey Medical School (US)
  • The Graduate Center, CUNY (US)
  • Lawrence Berkeley National Laboratory (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author
Prives, Carol
Venue
Cell
Publisher
Elsevier BV
Published
2012-01
Volume
148
Issue
1-2
Pages
244-258
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2150144117
Cited by
865
References
85
Citations by year
2026: 25 · 2025: 44 · 2024: 53 · 2023: 58 · 2022: 69 · 2021: 72 · 2020: 82 · 2019: 74 · 2018: 64 · 2017: 57 · 2016: 69 · 2015: 62 · 2014: 60 · 2013: 47 · 2012: 28
FWCI
20.86
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
Funders
  • Breast Cancer Research Foundation
  • National Cancer Institute (CA-87497, P01CA087497, R37CA064786, R01CA077742, CA77742, P30CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
mutant p53, mevalonate pathway, breast cancer, sterol biosynthesis, statins, therapeutic target
MeSH terms
Breast Neoplasms, Female, Humans, Mevalonic Acid, Mutation, Promoter Regions, Genetic, Tumor Suppressor Protein p53, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Cell Line, Tumor, Sterol Regulatory Element Binding Proteins, Metabolic Networks and Pathways, Prenylation

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