Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPbeta)-null mice.
In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBPbeta)-null mouse model. Loss of this transcription factor results in increased steroid and prolactin receptor expression concomitant with a 10-fold decrease in proliferation in response to pregnancy hormones. To determine the basis for this decrease, several markers of cell cycle progression were analyzed in wild type and C/EBPbeta-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBPbeta-null MECs is blocked at the G1/S transition. C/EBPbeta-null mammary glands display substantially increased levels of the activated form of transforming growth factor beta, a potent inhibitor of epithelial cell proliferation, as well as increased downstream Smad2 expression and signaling. While cyclin D1 levels were equivalent, cyclin E expression was markedly reduced in C/EBPbeta-null as compared with wildtype MECs. In addition, increased p27 stability and retention in the nucleus and decreased levels of the cdc25a phosphatase contributed to a significant loss of cdk2 kinase activity. Collectively, these changes prevent C/EBPbeta-null mammary epithelial cells from responding to hormone-induced proliferative signals.
Grimm
Sandra L
SL
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Contreras
Alejandro
A
Barcellos-Hoff
Mary-Helen
MH
Rosen
Jeffrey M
JM
D000818:Animals; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D006657:Histones / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D019927:Cyclin E; D006657:Histones; D006728:Hormones; D019394:Ki-67 Antigen; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases