Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells
Open accessAbstract
Aberrations of p53 occur in most, if not all, human cancers. In breast cancer, p53 mutation is the most common genetic defect related to a single gene. Immortalized human mammary epithelial cells resemble the earliest forms of aberrant breast tissue growth but do not express many malignancy-associated phenotypes. We created a model of human mammary epithelial tumorigenesis by infecting hTERT-HME1 immortalized human mammary epithelial cells expressing wild-type p53 with four different mutant p53 constructs to determine the role of p53 mutation on the evolution of tumor phenotypes. We demonstrate that different mutant/wild-type p53 heterozygous models generate loss of function, dominant negative activity, and a spectrum of gain of function activities that induce varying degrees of invasive potential. We suggest that this model can be used to elucidate changes that occur in early stages of human mammary epithelial tumorigenesis. These changes may constitute novel biomarkers or reveal novel treatment modalities that could inhibit progression from primary to metastatic breast disease.
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The MDA-MB-231, TMD231, and MDA-MB-468 cell lines used in this study all have missense mutations in the p53 DNA binding domain.
“The MDA-MB-231 (mtp53 R280K), the MDA-MB-231 derivative TMD231 (mtp53 R280K) and the MDA-MB-468 (mtp53 R273H) cells used in our study all have missense mutations within the DNA binding domain of p53 (33).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [33]
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- Authors
- Junk, D. J., Vrba, L., Watts, G. S., Oshiro, M. M., Martinez, J. D., & Futscher, B. W.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Futscher, Bernard W.
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 10
- Issue
- 5
- Pages
- 450-461
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC2373910
- OpenAlex
- W1898075343
- Cited by
- 74
- References
- 45
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 2
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (0114420)
- University of Arizona Cancer Center
- Frances McClelland Institute for Children, Youth, and Families
- University of Arizona
- National Institutes of Health (CA 23074, ES 06694)
- National Cancer Institute (R29CA065662, CA 23074, T32CA009213, CA09213, CA65662, R01CA065662, P30CA023074)
- National Institute of Environmental Health Sciences (ES 06694, P30ES006694)
- Division of Graduate Education (0114420)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- TP53 mutation, breast cancer, mammary epithelial cells, tumor invasion, gain-of-function p53, p53 deficiency, dominant-negative p53, metastasis
- MeSH terms
- Adenoviridae, Breast Neoplasms, Cell Movement, Cell Transformation, Neoplastic, Cells, Cultured, DNA, Flow Cytometry, Genes, Dominant, Humans, Mutation, Neoplasm Invasiveness, Phenotype, Promoter Regions, Genetic, RNA, Messenger, Subcellular Fractions, Tumor Stem Cell Assay, Blotting, Western, Tumor Suppressor Protein p53, Disease Progression, Telomerase, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Chromatin Immunoprecipitation, Immunoprecipitation, Cell Proliferation
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