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: Hao Zhang, Xiangyang Xie, Xudong Zhu, Jianhua Zhu, Chunfang Hao, Qiujun Lu, Lihua Ding, Yufei Liu, Lei Zhou, Yaling Liu, Cuifen Huang, Chungen Wen, Qinong Ye
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 52 Pg. 43188-97 (Dec 30 2005) ISSN: 0021-9258 [Print] United States
• PMID: 16219765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens
• Ligands
• NFATC Transcription Factors
• RNA, Small Interfering
• Transcription Factors
• RNA
• DNA
• Luciferases
• Glutathione Transferase
• Cathepsin D

Topics

• Binding Sites
• Blotting, Western
• Breast Neoplasms (metabolism)
• Cathepsin D (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Chromatin Immunoprecipitation
• DNA (metabolism)
• Disease Progression
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (metabolism)
• Estrogens (metabolism)
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Glutathione Transferase (metabolism)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Ligands
• Luciferases (metabolism)
• NFATC Transcription Factors (metabolism)
• Plasmids (metabolism)
• Promoter Regions, Genetic
• Protein Binding
• Protein Structure, Tertiary
• RNA (metabolism)
• RNA, Small Interfering (metabolism)
• Response Elements
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Time Factors
• Transcription Factors (metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Transfection
• Two-Hybrid System Techniques
• Up-Regulation