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Molecular and Cellular Biology, November 2005, p. 10136-10147, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10136-10147.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

RelB/p52 NF-{kappa}B Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor I{kappa}B-{alpha} Expression and Promote Carcinogenesis of the Mammary Gland

Elizabeth G. Demicco,1,3 Kathryn T. Kavanagh,1,3 Raphaëlle Romieu-Mourez,1,3 Xiaobo Wang,1,3 Sangmin R. Shin,1,3 Esther Landesman-Bollag,2,3 David C. Seldin,2,3 and Gail E. Sonenshein1,3*

Departments of Biochemistry,1 Medicine,2 Women's Health Interdisciplinary Research Center, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 021183

Received 10 February 2005/ Returned for modification 12 April 2005/ Accepted 19 July 2005

Classical NF-{kappa}B (p65/p50) transcription factors display dynamic induction in the mammary gland during pregnancy. To further elucidate the role of NF-{kappa}B factors in breast development, we generated a transgenic mouse expressing the I{kappa}B-{alpha} S32/36A superrepressor (SR) protein under control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. A transient delay in mammary ductal branching was observed in MMTV-SR-I{kappa}B-{alpha} mice early during pregnancy at day 5.5 (d5.5) and d7.5; however, development recovered by mid- to late pregnancy (d14.5). Recovery correlated with induction of nuclear cyclin D1 and RelB/p52 NF-{kappa}B complexes. RelB/p52 complexes induced cyclin D1 and c-myc promoter activities and failed in electrophoretic mobility shift assay to interact with I{kappa}B-{alpha}-glutathione S-transferase, indicating that their weak interaction with I{kappa}B-{alpha} can account for the observed recovery of mammary gland development. Activation of IKK{alpha} and NF-{kappa}B-inducing kinase was detected by d5.5, implicating the alternative NF-{kappa}B signaling pathway in RelB/p52 induction. Constitutively active IKK{alpha} induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mouse mammary tumors induced by 7,12-dimethylbenz(a)anthracene treatment displayed increased RelB/p52 activity. Inhibition of RelB in breast cancer cells repressed cyclin D1 and c-Myc levels and growth in soft agar. These results implicate RelB/p52 complexes in mammary gland development and carcinogenesis.

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston MA 02118. Phone: (617) 638-4120. Fax: (617) 638-4252. E-mail: gsonensh{at}bu.edu.

Molecular and Cellular Biology, November 2005, p. 10136-10147, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10136-10147.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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