title: Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells.
abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F+RT). This study was conducted to assess the effects of fulvestrant alone vs. F+RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F+RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F+RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F+RT was 0.885±0.013 vs. 0.622±0.029 @2 Gy, 0.599±0.045 vs. 0.475±0.054 @4 Gy, and 0.472±0.021 vs. 0.380±0.018 @6 Gy RT (p=0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F+RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p<0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F+RT compared with irradiation alone. F+RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F+RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.
authors: Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province, PR China. wangstella5@163.com
authors: Jing
authors: J
authors: Wang
authors: Qifeng
authors: Q
authors: Yang
authors: Bruce G
authors: BG
authors: Haffty
authors: Xiaoyan
authors: X
authors: Li
authors: Meena S
authors: MS
authors: Moran
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D051135:Rad51 Recombinase