Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes
Open accessAbstract
Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.
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Spontaneous loss of p16 by DNA methylation in HMECs does not completely bypass senescence but is associated with polyploid cell accumulation (Romanov et al., 2001).
“and spontaneous loss of p16 due to DNA methylation in HMECs does not completely bypass senescence but is associated with the accumulation of polyploidy cells (Romanov et al., 2001).”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Romanov et al., 2001
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- Tlsty, T. D. et al. Potentiation of genomic instability in normal human mammary epithelial cells by an epigenetic event. J. Mammary Gland Biol. Neoplasia (in the press).
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- Authors
- Romanov, S. R., Kozakiewicz, B. K., Holst, C. R., Stampfer, M. R., Haupt, L. M., & Tlsty, T. D.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Tlsty, Thea D.
- Venue
- Nature
- Published
- 2001-02
- Volume
- 409
- Issue
- 6820
- Pages
- 633-637
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1565166977
- Cited by
- 560
- References
- 27
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 13 · 2022: 4 · 2021: 12 · 2020: 8 · 2019: 11 · 2018: 13 · 2017: 9 · 2016: 15 · 2015: 12 · 2014: 15 · 2013: 22 · 2012: 20
- FWCI
- 25.11
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Griffith Research Online (submittedVersion)
- Funders
- National Aeronautics and Space Administration
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cellular senescence, human mammary epithelial cells, telomere shortening, telomere crisis, genomic instability, chromosomal abnormalities, mammary carcinogenesis, oncogenic transformation, fibroblasts
- MeSH terms
- Adolescent, Adult, Breast, Cell Division, Cell Transformation, Neoplastic, Cells, Cultured, Chromosome Aberrations, Epithelial Cells, Female, Fibroblasts, Humans, Karyotyping, Tumor Suppressor Protein p53, Telomere, Cellular Senescence
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