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J. Biol. Chem., Vol. 280, Issue 43, 36301-36309, October 28, 2005

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Cell Cycle Defects Contribute to a Block in Hormone-induced Mammary Gland Proliferation in CCAAT/Enhancer-binding Protein (C/EBP)-null Mice^*

Sandra L. Grimm, Alejandro Contreras, Mary-Helen Barcellos-Hoff, and Jeffrey M. Rosen1

From the Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and The Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94710

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/EBP)-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/EBP-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBP-null MECs is blocked at the G₁/S transition. C/EBP-null mammary glands display substantially increased levels of the activated form of transforming growth factor , 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/EBP-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/EBP-null mammary epithelial cells from responding to hormone-induced proliferative signals.

Received for publication, July 26, 2005 , and in revised form, August 24, 2005.

^* This work was supported by Grant CA16303 from the NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular & Cellular Biology, 1 Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6210; Fax: 713-798-8012; E-mail: jrosen{at}bcm.tmc.edu.

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