TY - JOUR
T1 - A role for CCAAT/enhancer binding protein β-liver-enriched inhibitory protein in mammary epithelial cell proliferation
AU - Zahnow, Cynthia A.
AU - Cardiff, Robert D.
AU - Laucirica, Rodolfo
AU - Medina, Daniel
AU - Rosen, Jeffrey M.
PY - 2001/1/1
Y1 - 2001/1/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 11196172
AN - SCOPUS:0035138818
SN - 0008-5472
VL - 61
SP - 261
EP - 269
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -