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(C/EBP) Knockout Mice Exhibit Mammary Gland Ductal Hyperlasia
* Department of Veterinary Biosciences and Division of Molecular Biology and Cancer Genetics, Ohio State Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210;
Eukaryotic Transcriptional Regulation Section, Regulation of Cell Growth Laboratory, and
Molecular Mechanisms in Development Group, National Cancer Institute, Frederick, Maryland 21702–1201
CCAAT/Enhancer binding proteins (C/EBPs) are a family of nuclear proteins that function in the control of cell growth, death, and differentiation. We previously reported that C/EBP
plays a key role in mammary epithelial cell G0 growth arrest. In this report, we investigated the role of C/EBP in mammary gland development and function using female mice homozygous for a targeted deletion of C/EBP (C/EBP -/-). C/EBP -/- females develop normally and exhibit normal reproductive and lactational performance. Adult nulliparous C/EBP -/- females, however, exhibit mammary epithelial cell growth control defects. The mean number of mammary ductal branches is significantly higher in adult nulliparous C/EBP -/- females compared with C/EBP +/+ (wild-type control) females (66.8 ± 5.2 vs 42.9 ± 6.3 branch points/field, P < 0.01). In addition, the mean total mammary gland cellular volume occupied by epithelium is significantly higher in adult nulliparous C/EBP -/- females compared with C/EBP +/+ controls (29.0 ± 1.4 vs 20.4 ± 1.3, P < 0.001). Our results showed that the BrdU labeling index was significantly higher in mammary epithelial cells from nulliparous C/EBP -/- females compared with C/EBP +/+ controls during the proestrus/estrus (4.55 ± 0.70 vs 2.14 ± 0.43, P < 0.01) and metestrus/diestrus (6.92 ± 0.75 vs 3.98 ± 0.43 P < 0.01) phases of the estrus cycle. In contrast, the percentage of mammary epithelial cells undergoing apoptosis during both phases of the estrus cycle did not differ between C/EBP -/- and C/EBP +/+ females. The increased epithelial cell content and proliferative capacity was restricted to the nulliparous C/EBP -/- females as no differences in mammary gland morphology, ductal branching or total epithelial content were observed between multiparous C/EBP -/- and C/EBP +/+ females. These results demonstrate that C/EBP plays a novel role in mammary epithelial cell growth control that appears to be restricted to the nulliparous mammary gland.
Key Words: C/EBP • mammary epithelial cell • involution • estrus cycle • nulliparous
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