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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001, Vol.61 (1), p.261-269
• Main Authors: ZAHNOW, Cynthia A, CARDIFF, Robert D, LAUCIRICA, Rodolfo, MEDINA, Daniel, ROSEN, Jeffrey M
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; CCAAT-Enhancer-Binding Protein-beta - biosynthesis; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - physiology; Cell Division - physiology; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - pathology; Cell Transplantation; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Hyperplasia - metabolism; Mammary gland diseases; Mammary Glands, Animal - cytology; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular and cellular biology; Rats; Transfection; Tumors
• ISSN: 0008-5472; 1538-7445

The transcription factor, CCAAT/enhancer binding protein beta (C/EBPbeta), regulates the expression of genes involved in proliferation and terminal differentiation. Dimerization of the dominant-negative C/EBPbeta-liver-enriched inhibitory protein (LIP) isoform with the C/EBPbeta-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/EBPbeta-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., 12: 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. Cancer Inst., 89: 1887-1891, 1997); however, little is known about how these isoforms differentially regulate cell cycle progression. To address this question, C/EBPbeta-LIP was overexpressed in both the mammary glands of transgenic mice and in cultured TM3 mammary epithelial cells. Here we report that the involuted mammary glands from transgenic mice overexpressing C/EBPbeta-LIP contain both focal and diffuse alveolar hyperplasia and, less frequently, contain mammary intraepithelial neoplasias (high grade) and invasive and noninvasive carcinomas. Likewise, cultured TM3 cells, stably expressing C/EBPbeta-LIP, showed an increase in proliferation and foci formation attributable to a reentry into S-phase during cellular confluence. These results demonstrate that C/EBPbeta-LIP can induce epithelial proliferation and the formation of mammary hyperplasias and suggest that a C/EBPbeta-LIP-initiated growth cascade may be susceptible to additional oncogenic hits, which could result in the initiation and progression of neoplasia.