title: Stimulatory cross-talk between NFAT3 and estrogen receptor in breast cancer cells.
abstract: Estrogen receptors (ERalpha and ERbeta) are ligand-regulated transcription factors that play critical roles in the development and progression of breast cancer by regulating target genes involved in cellular proliferation. The transcriptional activity of ERalpha and ERbeta is known to be modulated by cofactor proteins. We used a yeast two-hybrid system and identified NFAT3 as a novel ERbeta-binding protein. NFAT3 interacted with ERalpha and ERbeta both in vitro and in mammalian cells in a ligand-independent fashion. NFAT3 bound specifically to the ERbeta region containing the activation function-1 domain, a ligand-independent transactivation domain. Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta. NFAT3 increased binding of ERalpha to the estrogen-responsive element and was recruited to endogenous estrogen-responsive promoters. NFAT3 was expressed differentially in many breast cancer cell lines and overexpressed in a subset of breast cancer patients. Knockdown of endogenous NFAT3 reduced the growth of human breast cancer ZR75-1 cells in a ligand-independent manner. Taken together, these results suggest that NFAT3 may play important roles in ER signaling and represent a novel target for breast cancer therapy.
authors.affiliation: Department of Molecular Oncology, Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Xie
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Chunfang
authors.initials: C
authors.lastname: Hao
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Lu
authors.forename: Lihua
authors.initials: L
authors.lastname: Ding
authors.forename: Yufei
authors.initials: Y
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Yaling
authors.initials: Y
authors.lastname: Liu
authors.forename: Cuifen
authors.initials: C
authors.lastname: Huang
authors.forename: Chungen
authors.initials: C
authors.lastname: Wen
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D012313:RNA; D004247:DNA; D008156:Luciferases; D005982:Glutathione Transferase; D002402:Cathepsin D