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Differential Regulation of Elafin in Normal and Tumor-Derived Mammary Epithelial Cells Is Mediated by CCAAT/Enhancer Binding Protein β

Departments of ¹ Experimental of Radiation Oncology and ² Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Khandan Keyomarsi, Department of Experimental of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095. Phone: 713-792-4845; Fax: 713-794-5369; E-mail: kkeyomar{at}mdanderson.org.

CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor implicated in the control of development, differentiation, and proliferation of mammary epithelial cells. However, it remains unclear how C/EBPβ is involved in tumor suppression through its interaction with specific downstream genes in breast cancer. Tumor cells overexpress serine proteases, which play crucial roles in tumor invasion and metastasis. Elafin is an endogenous serine protease inhibitor and is transcriptionally down-regulated in most tumor cell lines. In this study, we show that C/EBPβ is differentially expressed in normal versus tumor cell lines and normal adjacent versus tumor tissues obtained from breast cancer patients. We identified elafin as a downstream effector of C/EBPβ and show that elafin is also differentially regulated between normal and tumor cells. The mechanism by which C/EBPβ regulates elafin expression is through its direct interaction with the elafin promoter. There are three C/EBPβ binding sites involved in the elafin promoter activity, and the overexpression of C/EBPβ transactivates the elafin gene through these sites in tumor cells. RNA interference studies in normal cells further evidenced the requirement of the C/EBPβ for the elafin expression and negative feedback loop between C/EBPβ and elafin. We suggest that elafin is a novel substrate of C/EBPβ, and alterations in C/EBPβ isoforms result in their differential binding to the elafin promoter, leading to the altered expression of the elafin between normal and tumor cells. [Cancer Res 2007;67(23):11272–83]