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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-B Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor IB- Expression and Promote Carcinogenesis of the Mammary Gland

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-B (p65/p50) transcription factors display dynamic induction in the mammary gland during pregnancy. To further elucidate the role of NF-B factors in breast development, we generated a transgenic mouse expressing the IB- 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-IB- 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-B complexes. RelB/p52 complexes induced cyclin D1 and c-myc promoter activities and failed in electrophoretic mobility shift assay to interact with IB--glutathione S-transferase, indicating that their weak interaction with IB- can account for the observed recovery of mammary gland development. Activation of IKK and NF-B-inducing kinase was detected by d5.5, implicating the alternative NF-B signaling pathway in RelB/p52 induction. Constitutively active IKK 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.

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