The inhibitory effects of transforming growth factor beta 1 on breast cancer cell proliferation are mediated through regulation of aberrant nuclear factor-kappa B/Rel expression

Nuclear factor (NF)-kappa B/Rel transcription factors normally exist in non -B cells, such as epithelial cells, in inactive forms sequestered in the cy toplasm with specific inhibitory proteins, termed I kappa Bs, Recently, how ever, we discovered that breast cancer is typified by aberrant constitutive expression of NF-kappa B/Rel factors. Because these factors control genes that regulate cell proliferation, here we analyzed the potential role of NF -kappa B/Rel in the ability of transforming growth factor (TGF)-beta 1 to i nhibit the growth of breast cancer cells. The decreased growth of Hs578T an d MCF7 breast cancer cell lines on TGF-beta 1 treatment correlated with a d rop in NF-kappa B/Rel binding. This decrease was due to the stabilization o f the inhibitory protein I kappa B-alpha. Ectopic expression of c-Rel in Hs 578T cells led to the maintenance of NF-kappa B/Rel binding and resistance to TGF-beta 1-mediated inhibition of proliferation. Similarly, expression o f the p65 subunit ablated the inhibition of Hs578T cell growth mediated by TGF-beta 1. Thus, the inhibition of the aberrantly activated, constitutive NF-kappa B/Rel plays an important role in the arrest of the proliferation o f breast cancer cells, which suggests that NF-kappa B/Rel may be a useful t arget in the treatment of breast cancer.