Restoration of Radiation-Responsiveness of Estrogen-Receptor Negative Breast Cancer Cells

Abstract

Abstract : ER-negative human breast cancers are radioresistant due to hypermethylation and hypoacetylation of the ER gene and restoration of ER expression in ER-negative cells by treatment with the demethylating agent (5-Aza-dC) and HDAC inhibitors restores sensitivity to radiation therapy. We used two human ER-negative breast cancer cell lines (MDA-MB-231 and Hs578t) and one ER-positive cell line (MCF-7 cells, positive control) to test the effect of these inhibitors. In addition, MDA-MB-231 cells transfected with either control vector or wild-type human ER-alpha were used as appropriate controls. Cells were pretreated with HDAC inhibitors or Zebularine and our preliminary data demonstrates that both the drugs can independently restore radiosensitivity to these cells. Both agents reactivated ER-alpha which could be detected by Western blot. Though preliminary, our data suggests that a combination of both DNA methyl transferase inhibitors and HDAC inhibitors can activate ER protein and sensitize cells to ionizing radiation.