| 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-kappaB) p65/p50 transcription factors are dynamically induced in the mammary gland during pregnancy, and inhibitor of NF-kappaB-alpha (IkappaB-alpha) deficiency leads to hyperplasia of the mammary epithelium. To further elucidate the role of NF-kappaB factors in mammary development, we examined NF-kappaB subunit expression in the mammary glands of transgenic mice expressing the IkappaB-alpha 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-kappaB complexes, which failed to interact with an IkappaB-alpha fusion protein and potently induced cyclin D1 and c-myc promoter activities. Activation of IkappaB-alpha kinase alpha (IKKalpha) and NF-kappaB 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 IKKalpha 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-kappaB signaling pathway in branching of lateral ducts and alveolar development during mammary gland development, and in mammary carcinogenesis.; Bcl-3/p52 NF-kappaB DNA-binding complexes were also highly induced by day 14.5 of pregnancy, and these potently transactivated the cyclin D1 but not the c-myc promoter in cultured mammary epithelial cells. Mammary tumors from female rats treated with DMBA uniformly displayed a diffuse NF-kappaB band containing p50 homodimers, although RelB, p65, p52 and p50 were all expressed in the nucleus, suggesting that there maybe mechanisms that inhibit NF-kappaB DNA binding. No cooperativity was found between low-dose DMBA treatment and MMTV-c-rel mediated mammary tumorigenesis in mice. Thus, the NF-kappaB family of transcription factors plays stage-specific roles in mammary gland development and in breast cancer. |
