RelB/p52 NF-kappaB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IkappaB-alpha 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.
Demicco
Elizabeth G
EG
Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA.
Kavanagh
Kathryn T
KT
Romieu-Mourez
Raphaëlle
R
Wang
Xiaobo
X
Shin
Sangmin R
SR
Landesman-Bollag
Esther
E
Seldin
David C
DC
Sonenshein
Gail E
GE
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000362:Agar / Q000737:chemistry; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D015151:Immunoblotting; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000737:chemistry / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy; D011270:Pregnancy, Animal; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000737:chemistry / Q000502:physiology*; D014162:Transfection; D019076:Transgenes
D020672:I-kappa B Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C497593:RELB protein, human; D051996:Transcription Factor RelA; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB; D015127:9,10-Dimethyl-1,2-benzanthracene; D012313:RNA; D000362:Agar; D005982:Glutathione Transferase; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase