A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.
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.
Vendrell
J A
JA
CNRS UMR 5160, Centre de Pharmacologie et Biotechnologie pour la Santé, Faculté de Pharmacie, Montpellier, France.
Ghayad
S
S
Ben-Larbi
S
S
Dumontet
C
C
Mechti
N
N
Cohen
P A
PA
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3