Non-classical nuclear factor-kappa B complexes in mammary gland development and tumorigenesis

Thesis (Ph.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Post-natal mammary gland development is a complex process in which epithelial proliferation and branching of lactiferous ducts is followed by extensive formation of lobuloalveolar units that produce milk. Classical nuclear factor-kappa B (NF-κB) p65/p50 transcription factors are dynamically induced in the mammary gland during pregnancy, and inhibitor of NF-κB-alpha (IκB-α) deficiency leads to hyperplasia of the mammary epithelium. To further elucidate the role of NF-κB factors in mammary development, we examined NF-κB subunit expression in the mammary glands of transgenic mice expressing the IκB-α S32/36A super-repressor (SR) protein under control of the mouse mammary tumor virus (MMTV)-long terminal repeat promoter, in which mammary gland development is transiently delayed, but not completely blocked. Developmental recovery correlated with induction of RelB/p52 NF-κB complexes, which failed to interact with an IκB-α fusion protein and potently induced cyclin D1 and c-myc promoter activities. Activation of IκB-α kinase alpha (IKKα) and NF-κB inducing kinase (NIK) was detected by day 5.5, and were hypothesized to be responsible for the induction of ReIB/p52. In support of this hypothesis, we found that constitutively active IKKα induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mammary tumors induced by high-dose 7,12-dimethylbenz(a)anthracene (DMBA) treatment in wild type FVB/N mice, displayed increased RelB/p52 binding activity. These results implicate activation of RelB/p52 complexes by the alternative NF-κB signaling pathway in branching of lateral ducts and alveolar development during mammary gland development, and in mammary carcinogenesis.2031-01-0