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

Cynthia A. Zahnow, Robert Cardiff, Rodolfo Laucirica, Daniel Medina, Jeffrey M. Rosen

Research output: Contribution to journalArticle

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Abstract

The transcription factor, CCAAT/enhancer binding protein β (C/EBPβ), regulates the expression of genes involved in proliferation and terminal differentiation. Dimerization of the dominant-negative C/EBPβliver-enriched inhibitory protein (LIP) isoform with the C/EBPβ-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/EBPβ-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/EBPβ-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/EBPβ-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/EBPβ-LIP, showed an increase in proliferation and foci formation attributable to a reentry into S-phase during cellular confluence. These results demonstrate that C/EBPβ-LIP can induce epithelial proliferation and the formation of mammary hyperplasias and suggest that a C/EBPβ-LIP-initiated growth cascade may be susceptible to additional oncogenic hits, which could result in the initiation and progression of neoplasia.

Original languageEnglish (US)
Pages (from-to)261-269
Number of pages9
JournalCancer Research
Volume61
Issue number1
StatePublished - Jan 1 2001

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CCAAT-Enhancer-Binding Proteins
Breast
Epithelial Cells
Cell Proliferation
Liver
Proteins
Human Mammary Glands
Protein Isoforms
Transgenic Mice
Hyperplasia
Neoplasms
Genes
Dimerization
S Phase
Transcriptional Activation
Cultured Cells
Cell Cycle
Transcription Factors
Breast Neoplasms
Carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A role for CCAAT/enhancer binding protein β-liver-enriched inhibitory protein in mammary epithelial cell proliferation. / Zahnow, Cynthia A.; Cardiff, Robert; Laucirica, Rodolfo; Medina, Daniel; Rosen, Jeffrey M.

In: Cancer Research, Vol. 61, No. 1, 01.01.2001, p. 261-269.

Research output: Contribution to journalArticle

Zahnow, Cynthia A. ; Cardiff, Robert ; Laucirica, Rodolfo ; Medina, Daniel ; Rosen, Jeffrey M. / A role for CCAAT/enhancer binding protein β-liver-enriched inhibitory protein in mammary epithelial cell proliferation. In: Cancer Research. 2001 ; Vol. 61, No. 1. pp. 261-269.
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