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Papers In Press, published online ahead of print August 24, 2005
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3498
Corresponding Author: jrosen{at}bcm.edu
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. In order to help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a C/EBPß-null mouse model. Loss of this transcription factor results in increased steroid and prolactin receptor expression concomitant with a ten-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 wildtype and C/EBPß-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBPß-null MECs is blocked at the G1/S transition. C/EBPß-null mammary glands display substantially increased levels of the activated form of TGF-ß, 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/EBPß-null as compared to 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/EBPß-null mammary epithelial cells from responding to hormone-induced proliferative signals.
J. Biol. Chem, 10.1074/jbc.M508167200
Submitted on July 26, 2005
Revised on August 24, 2005
Accepted on August 24, 2005
Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in C/EBP
-null mice
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