A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells

Oncogene. 2007 Jul 12;26(32):4656-67. doi: 10.1038/sj.onc.1210269. Epub 2007 Feb 12.


The zinc-finger protein A20/TNFAIP3, an inhibitor of nuclear factor-kappaB (NF-kappaB) activation, has been shown to protect MCF-7 breast carcinoma cells from TNFalpha-induced apoptosis. As estrogen receptor (ER) status is an important parameter in the development and progression of breast cancer, we analysed the effect of 17beta-estradiol (E2) treatment on the expression of A20. We found that A20 is a new E2-regulated gene, whose expression correlates with ER expression in both cell lines and tumor samples. With the aim of investigating the impact of A20 expression on MCF-7 cells in response to ER ligands, we established stably transfected-MCF-7 cells overexpressing A20 (MCF-7-A20). These cells exhibited a phenotype of resistance to the 4-hydroxy-tamoxifen cytostatic and pro-apoptotic actions and of hyper-response to E2. Dysregulations in bax, bcl2, bak, phospho-bad, cyclin D1, cyclin E2, cyclin D2 and cyclin A2 proteins expression were shown to be related to the resistant phenotype developed by the MCF-7-A20 cells. Interestingly, we found that A20 was also overexpressed in MVLN and VP tamoxifen-resistant cell lines. Furthermore, high A20 expression levels were observed in more aggressive breast tumors (ER-negative, progesterone receptor-negative and high histological grade). These overall findings strongly suggest that A20 is a key protein involved in tamoxifen resistance, and thus represents both a new breast cancer marker and a promising target for developing new strategies to prevent the emergence of acquired mechanisms of drug resistance in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cyclins / metabolism
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm / genetics
  • Estradiol / pharmacology*
  • Estrogen Antagonists / therapeutic use*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Tumor Necrosis Factor alpha-Induced Protein 3


  • Antineoplastic Agents, Hormonal
  • Apoptosis Regulatory Proteins
  • Cyclins
  • DNA-Binding Proteins
  • Estrogen Antagonists
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Tamoxifen
  • afimoxifene
  • Estradiol
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3