Tumor necrosis factor-alpha (TNF-alpha) exerts many cytological effects on a wide range of cells. TNF-alpha can activate nuclear factor-kappaB (NF-kappaB). Activation of NF-kappaB by TNF-alpha mediates many functions of TNF-alpha. The NF-kappaB inhibitor, I kappaB alpha, negatively regulates the activity of NF-kappaB. In MCF-7 cells (an estrogen and TNF-alpha receptor positive cell line), treatment with 17 beta -estradiol (E-2) inhibited TNF-alpha -induced NF-kappaB DNA binding activity in the gel retardation assays. But, the level of the I kappaB alpha and the TNF-alpha receptor, TNF-R1, were not obviously affected, The NF-kappaB precursor, NF-kappaB p105, has been shown to be associated with NF-kappaB in the cytoplasm and efficiently blocks its nuclear translocation and activation. Treatment of MCF-7 cells with E-2 increased the level of NF-kappaB p105 protein. The anti-estrogen, 4OH-tamoxifen, treatment inhibited E-2-induced NF-kappaB p105 expression. Our findings indicate that NF-kappaB p105 plays a role in modulating the functions of TNF-alpha in the estrogen receptor positive breast cancer cells.