Evasion of a Single-Step, Chemotherapy-Induced Senescence in Breast Cancer Cells: Implications for Treatment Response
Open accessAbstract
Purpose: The purpose of this study is to define the mechanistic basis for recovery of proliferative capacity in breast tumor cells after chemotherapy. Here, we test the hypothesis that evasion of senescence confers resistance to chemotherapeutic drugs and ionizing radiation. Experimental Design: MCF-7 cells were treated with a single, clinically relevant dose (0.75-1.0 μmol/L) of Adriamycin. Two weeks following induction of senescence, clonal outgrowths were expanded and characterized in terms of senescence-associated β-galactosidase activity, gene expression profiles (Affymetrix U95 probe sets, Affymetrix, Santa Clara, CA) with confirmatory Western analyses, and telomerase activity following a second drug treatment. Levels of intracellular Adriamycin, as well as cross-resistance to other therapeutic agents, were also determined to define the resistance phenotype. Results: A senescence-resistant (SR) clone (clone 2) was identified that was largely refractory to both Adriamycin-induced and γ-irradiation–induced senescence. Clone 2 continued to proliferate and maintain high levels of telomerase activity following a second drug treatment, when treated parental cells expressed very low levels of telomerase and many positive cell cycle regulators. SR clone 2 also expressed substantially more cdc-2 than parental cells and undetectable levels of MDR1, showed an intact p53 checkpoint and only a modestly lower level of intracellular drug accumulation, while exhibiting cross-resistance to other topoisomerase inhibitors. Conclusions: SR clone 2 is intrinsically resistant to DNA damage–induced senescence perhaps through an ability to prevent down-regulation of cdc-2. Telomerase is a marker of proliferative recovery for breast cancer cells after chemotherapy exposure. Evasion or escape from a single-step, drug-induced senescence may represent a unique and previously unrecognized drug-resistance phenotype.
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Doxorubicin-induced senescent MCF7 breast cancer cells retaining wild-type TP53 but harbouring a PIK3CA E545K mutation were able to form colonies upon drug removal.
“Doxorubicin- induced senescent MCF7 breast cancer cells retaining wild- type TP53 but harbouring a PIK3CA E545K mutation were able to form colonies upon drug removal 182 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [182]
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Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Tumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy.
Saleh, T., Tyutyunyk-Massey, L., & Gewirtz, D. A. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3437 · Cited by 259 · see citing works
Self-citationCellular senescence and cancer treatment
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Senolytics for Cancer Therapy: Is All that Glitters Really Gold?
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Self-citationNon-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
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Self-citationDynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells
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- Authors
- Elmore, L. W., Di, X., Dumur, C., Holt, S. E., & Gewirtz, D. A.
- Affiliations
- Departments of 1Pathology,
- 2Pharmacology and Toxicology, and
- Virginia Commonwealth University (US)
- Venue
- Clinical Cancer Research
- Published
- 2005-04-01
- Volume
- 11
- Issue
- 7
- Pages
- 2637-2643
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2138277729
- Cited by
- 151
- References
- 2
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 18 · 2020: 6 · 2019: 9 · 2018: 6 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 13 · 2013: 6 · 2012: 5
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Virginia Commonwealth University
- Medical Research and Materiel Command
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- senescence escape, chemotherapy-induced senescence, drug resistance, breast cancer, doxorubicin, telomerase activity, MDR1, gamma irradiation, topoisomerase inhibitors, cross-resistance, MCF-7 cells, senescence-associated β-galactosidase
- MeSH terms
- GADD45 Proteins, Antibiotics, Antineoplastic, Breast Neoplasms, Camptothecin, Clone Cells, Doxorubicin, Gamma Rays, Humans, Nuclear Proteins, Teniposide, Blotting, Western, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Cellular Senescence, Paclitaxel, Immediate-Early Proteins, Cell Cycle Proteins, Drug Resistance, Neoplasm, Telomerase, Proto-Oncogene Proteins c-bcl-2, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Tumor Suppressor Proteins, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, bcl-2-Associated X Protein
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