A role for CCAAT/enhancer binding protein beta-liver-enriched inhibitory protein in mammary epithelial cell proliferation

The transcription factor, CCAAT/enhancer binding protein beta (C/EBP beta), regulates the expression of genes involved in proliferation and terminal d ifferentiation. Dimerization of the dominant-negative C/EBP beta -liver-enr iched inhibitory protein (LIP) isoform with the C/EBP beta -liver-enriched activating protein (LAP) isoform inhibits the transcriptional activation of genes involved in differentiation. Consequently, an increase in LIP levels may inhibit terminal differentiation and lead to proliferation. C/EBP beta -LIP and LAP are crucial for mammary gland development (G. W. Robinson et al., Genes Dev., 12: 1907-1916, 1998; T. N. Seagroves et al., Genes Dev., 1 2: 1917-1928, 1998) and are also overexpressed in breast cancer (B. Raught et al., Cancer Res., 56: 4382-4386. 1996; C. A. Zahnow et al., J. Natl. Can cer Inst., 89: 1887-1891, 1997); however, little is known about how these i soforms differentially regulate cell cycle progression. To address this que stion, C/EBP beta -LIP was overexpressed in both the mammary glands of tran sgenic mice and in cultured TM3 mammary epithelial cells. Here we report th at the involuted mammary glands from transgenic mice overexpressing C/EBP b eta -LIP contain both focal and diffuse alveolar hyperplasia and, less freq uently, contain mammary intraepithelial neoplasias (high grade) and invasiv e and noninvasive carcinomas. Likewise, cultured TM3 cells, stably expressi ng C/EBP beta -LIP, showed an increase in proliferation and foci formation attributable to a reentry into S-phase during cellular confluence. These re sults demonstrate that C/EBP beta -LIP can induce epithelial proliferation and the formation of mammary hyperplasias and suggest that a C/EBP beta -LI P-initiated growth cascade may be susceptible to additional oncogenic hits, which could result in the initiation and progression of neoplasia.