RelB/p52 NF-κB Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor IκB-α Expression and Promote Carcinogenesis of the Mammary Gland

Abstract

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