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Evasion of a single-step, chemotherapy-induced senescence in breast cancer cells: implications for treatment response.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2005 Apr 01; Vol. 11 (7), pp. 2637-43. - Publication Year :
- 2005
-
Abstract
- 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.<br />Experimental Design: MCF-7 cells were treated with a single, clinically relevant dose (0.75-1.0 micromol/L) of Adriamycin. Two weeks following induction of senescence, clonal outgrowths were expanded and characterized in terms of senescence-associated beta-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.<br />Results: A senescence-resistant (SR) clone (clone 2) was identified that was largely refractory to both Adriamycin-induced and gamma-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.<br />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.
- Subjects :
- Blotting, Western
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Breast Neoplasms radiotherapy
Camptothecin pharmacology
Cell Cycle Proteins genetics
Cell Line, Tumor
Cell Proliferation drug effects
Cell Proliferation radiation effects
Cellular Senescence radiation effects
Clone Cells drug effects
Clone Cells metabolism
Clone Cells radiation effects
Cyclin-Dependent Kinase Inhibitor p21
Drug Resistance, Neoplasm
Gamma Rays
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Gene Expression Regulation, Neoplastic radiation effects
Genes, Tumor Suppressor
Humans
Immediate-Early Proteins genetics
Nuclear Proteins genetics
Oligonucleotide Array Sequence Analysis methods
Paclitaxel pharmacology
Proto-Oncogene Proteins c-bcl-2 genetics
Telomerase metabolism
Teniposide pharmacology
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins
bcl-2-Associated X Protein
Antibiotics, Antineoplastic pharmacology
Cellular Senescence drug effects
Doxorubicin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 15814644
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-04-1462