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Evasion of a Single-Step, Chemotherapy-Induced Senescence in Breast Cancer Cells: Implications for Treatment Response

Authors' Affiliations: Departments of ¹ Pathology, ² Pharmacology and Toxicology, and ³ Human Genetics and ⁴ Massey Cancer Center, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: David A. Gewirtz, Department of Medicine, Medical College of Virginia at Virginia Commonwealth University, P.O. Box 980230, Richmond, VA 23298-230. Phone: 804-828-9523; Fax: 804-828-8079; E-mail: gewirtz{at}mail2.vcu.edu.

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 ß-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 -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.

Key Words: senescence • breast cancer • drug resistance • Adriamycin • telomerase

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