Estrogen receptor beta decreases survival of p53-defective cancer cells after DNA damage by impairing G2/M checkpoint signaling

Estrogen receptor beta (ER beta) inhibits proliferation in different cellular systems by regulating components of the cell cycle machinery. Eukaryotic cells respond to DNA damage by arresting in G(1), S, or G(2) phases of the cell cycle to initiate DNA repair. Most tumor cells due to disruptions in the p53-dependent G(1) pathway are dependent on S-phase and G(2)/M checkpoints to maintain genomic integrity in response to DNA damage. We report that induction of ER beta expression causes abrogation of the S-phase, and the Chk1/Cdc25C-mediated G(2)/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 ER beta may be of predictive value for the successful response to chemotherapy.