title: TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells.
abstract: OBJECTIVE
  Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells.
  
  
  METHODS
  Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay.
  
  
  RESULTS
  TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU.
  
  
  CONCLUSIONS
  TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Meng-Yao
authors.initials: MY
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Zhi
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Bian
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Meng-Dan
authors.initials: MD
authors.lastname: Xu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Fei-Ran
authors.initials: FR
authors.lastname: Gong
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.|Department of Oncology, the People's Hospital of Jingjiang, Jingjiang, 214500 China.
authors.forename: Juan
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.|PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, 215021 China.|Jiangsu Institute of Clinical Immunology, Suzhou, 215006 China.|Institute of Medical Biotechnology, Soochow University, Suzhou, 215021 China.
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.|Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, 310006 China.
authors.forename: Liu-Mei
authors.initials: LM
authors.lastname: Shou
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.
authors.forename: Meng
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China.|PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, 215021 China.|Jiangsu Institute of Clinical Immunology, Suzhou, 215006 China.|Center for Systems Biology, Soochow University, Suzhou, 215006 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
keywords: Breast cancer; Chemotherapy sensitization; Radiotherapy sensitization; TNF-α