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

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, Refill, 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.