Abstract
Abstract Breast cancer is one of the most common cancers to afflict women in the world. Anthracycline-based regimens, including doxorubicin and epirubicin (epidoxorubicin), are common therapies for patients with breast cancer. Doxorubicin and epirubicin are inhibitors of topoisomerase II, which cause double strand DNA breaks. Following anthracycline-induced damage, DNA damage response pathways are activated in order to initiate cell cycle arrest, DNA repair, and/or cell death. The recent introduction of PARP inhibitors highlights the clinical relevance of targeting DNA repair pathways in treating this disease. Recently, two histone deacetylase (HDAC) inhibitors have been approved by the Federal Drug Administration for the treatment of cutaneous T-cell lymphoma: vorinostat and romidepsin. HDAC inhibitors reduce the repair of DNA, and are being used in combination with DNA damaging chemotherapeutic agents. The mechanisms regulating the HDAC inhibitor-mediated reduction of DNA repair in breast cancer cells are not well established. Understanding these mechanisms will identify key therapeutic targets for reducing DNA repair, define the role of HDACs in DNA repair, and allow for the enrichment of patients most susceptible to HDAC inhibitor-chemotherapy combined treatment. Previously, our group has demonstrated an increase in DNA decondensation which permits greater access of anthracyclines to DNA after therapeutic inhibition of HDACs. New results demonstrate that phosphorylation of p53 at Serine 15 is decreased in the presence of epirubicin after pre-treatment with vorinostat in a time- and concentration-dependent manner. Total p53 protein levels are also decreased, while mRNA levels remain unchanged after combined treatment. Treatment of breast cancer cells with valproic acid or entinostat also attenuates phosphorylation of p53 after epirubicin treatment, suggesting the involvement of Class I HDACs in the activation of p53. Phosphorylation of DNA repair kinase ATM is also decreased following DNA damage in the presence of clinically relevant concentrations of vorinostat, and corresponds with a decrease in activation of downstream factors including CHK1, CHK2, and BRCA1. These results demonstrate that inhibition of Class I HDACs in breast cancer cells delays DNA damaging response signaling through p53 modification after anthracycline administration; suggesting a possible mechanism for synergy between HDAC inhibitors and DNA damaging agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2614. doi:10.1158/1538-7445.AM2011-2614
Published Version
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