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Down-Regulation and Growth Inhibitory Role of C/EBP in Breast Cancer

Authors' Affiliations: ¹ Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine and ² Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California

Requests for reprints: Sigal Gery, Cedars-Sinai Medical Center, Davis Building 5066, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-4609; Fax: 310-423-0225; E-mail: gerys{at}cshs.org.

Purpose: CCAAT/enhancer binding proteins (C/EBP) are a family of transcription factors that regulate proliferation and differentiation in a variety of tissues. The purpose of this study was to explore the possibility that C/EBP is involved in breast cancer.

Experimental Design: We quantified C/EBP mRNA expression levels in 24 primary breast tumors, 16 normal breast samples, and 8 breast cancer cell lines using quantitative real-time reverse transcription-PCR assay. C/EBP protein levels were further determined by immunohistochemical analysis. To examine the consequence of C/EPB expression in breast cancer, we stably transfected an inducible C/EPB expression vector into three breast cancer cell lines.

Results: Low expression of C/EBP mRNA was found in 83% of primary breast cancer samples. Immunohistochemical study further showed either a markedly reduced or undetectable expression of C/EBP protein in 30% of breast cancer specimens. The other 70% of breast cancers had C/EBP expression in both the cytoplasm and nucleus; in control, C/EBP was localized to the nucleus in the normal ductal cells. C/EBP expression was associated with estrogen- and progesterone receptor–negative status. Induction of C/EBP expression in these cell lines resulted in growth inhibition accompanied by G₀-G₁ cell cycle arrest and reduced anchorage-independent cell growth. C/EBP expression was associated with down-regulation of c-myc and up-regulation of p21, PPAR, and the breast epithelial differentiation marker, maspin.

Conclusions: These results suggest that reduced expression of C/EBP may play a role in the development and/or progression of breast cancer.

Key Words: C/EBP • antiproliferative • breast cancer

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