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Ciz1, a Novel DNA-Binding Coactivator of the Estrogen Receptor , Confers Hypersensitivity to Estrogen Action

¹ Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center; ² The University of Texas Graduate School of Biomedical Sciences at Houston; ³ Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and ⁴ Lister Institute of Preventive Medicine, University of York, York, United Kingdom

Requests for reprints: Rakesh Kumar, Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. E-mail: rkumar{at}mdanderson.org.

The transcriptional activity of the estrogen receptor (ER) is affected by regulatory cofactors, including chromatin-remodeling complexes, coactivators, and corepressors. Coregulators are recruited to target gene promoters through protein-protein interactions with ER and function as linker molecules between the DNA, DNA-binding proteins, and DNA-modifying enzymes. We recently showed that Cip-interacting zinc finger protein 1 (Ciz1) participates in the regulation of the cell cycle in estrogen-stimulated breast cancer cells. Despite the emerging significance of Ciz1 in the biology of breast cancer cells, regulation of endogenous Ciz1 in hormone-responsive cancer cells remains unknown. To shed light on the role of Ciz1 in breast tumorigenesis, we defined the regulation of Ciz1 by the ER pathway and found that Ciz1 is an estrogen-responsive gene. We also discovered that Ciz1 protein, a DNA-binding factor, coregulates ER by enhancing ER transactivation activity by promoting the recruitment of the ER complex to the target gene chromatin. In addition, we found that Ciz1 overexpression confers estrogen hypersensitivity to breast cancer cells and promotes the growth rate, anchorage independency, and tumorigenic properties of breast cancer cells. These findings revealed the inherent role of Ciz1, a novel DNA binding and ER coactivator, in amplifying estrogenic responses and promoting breast cancer tumorigenesis. (Cancer Res 2006; 66(22): 11021-9)