Estrogen receptor beta decreases survival of p53-defective cancer cells after DNA damage by impairing G₂/M checkpoint signaling.
Estrogen receptor beta (ERβ) inhibits proliferation in different cellular systems by regulating components of the cell cycle machinery. Eukaryotic cells respond to DNA damage by arresting in G₁, S, or G₂ phases of the cell cycle to initiate DNA repair. Most tumor cells due to disruptions in the p53-dependent G₁ pathway are dependent on S-phase and G₂/M checkpoints to maintain genomic integrity in response to DNA damage. We report that induction of ERβ expression causes abrogation of the S-phase, and the Chk1/Cdc25C-mediated G₂/M checkpoints after cisplatin and doxorubicin exposure in p53-defective breast cancer cells but not in p53 wild-type mammary cells. This impairment of DNA damage response that involves BRCA1 downregulation and caspase-2 activation results in mitotic catastrophe and decreased cancer cell survival. These results indicate that in cancers where p53 is defective, assessment of the presence of ERβ may be of predictive value for the successful response to chemotherapy.
Thomas
Christoforos G
CG
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA. chthomas@uh.edu
Strom
Anders
A
Lindberg
Karolina
K
Gustafsson
Jan-Ake
JA
D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D047629:Estrogen Receptor beta; D008024:Ligands; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin