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
Copyright policy )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-kappaB (p65/p50) transcription factors display dynamic induction in the mammary gland during pregnancy. To further elucidate the role of NF-kappaB factors in breast development, we generated a transgenic mouse expressing the IkappaB-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-IkappaB-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-kappaB complexes. RelB/p52 complexes induced cyclin D1 and c-myc promoter activities and failed in electrophoretic mobility shift assay to interact with IkappaB-alpha-glutathione S-transferase, indicating that their weak interaction with IkappaB-alpha can account for the observed recovery of mammary gland development. Activation of IKKalpha and NF-kappaB-inducing kinase was detected by d5.5, implicating the alternative NF-kappaB signaling pathway in RelB/p52 induction. Constitutively active IKKalpha 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.
- Boston College United States
- Boston University United States
Cell Nucleus, 9,10-Dimethyl-1,2-benzanthracene, Immunoblotting, NF-kappa B, Breast Neoplasms, Mammary Neoplasms, Animal, Mice, Transgenic, I-kappa B Kinase, Agar, Mice, Mammary Glands, Animal, NF-KappaB Inhibitor alpha, NF-kappa B p52 Subunit, Cell Line, Tumor, Animals, Humans, Cyclin D1, Female, I-kappa B Proteins, Glutathione Transferase
Cell Nucleus, 9,10-Dimethyl-1,2-benzanthracene, Immunoblotting, NF-kappa B, Breast Neoplasms, Mammary Neoplasms, Animal, Mice, Transgenic, I-kappa B Kinase, Agar, Mice, Mammary Glands, Animal, NF-KappaB Inhibitor alpha, NF-kappa B p52 Subunit, Cell Line, Tumor, Animals, Humans, Cyclin D1, Female, I-kappa B Proteins, Glutathione Transferase
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