The inhibitory effects of transforming growth factor β1 on breast cancer cell proliferation are mediated through regulation of aberrant nuclear factor-κB/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 cytoplasm with specific inhibitory proteins, termed I kappa Bs, Recently, however, 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 inhibit the growth of breast cancer cells. The decreased growth of Hs578T and MCF7 breast cancer cell lines on TGF-beta 1 treatment correlated with a drop in NF-kappa B/Rel binding. This decrease was due to the stabilization of the inhibitory protein I kappa B-alpha. Ectopic expression of c-Rel in Hs578T cells led to the maintenance of NF-kappa B/Rel binding and resistance to TGF-beta 1-mediated inhibition of proliferation. Similarly, expression of 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 of breast cancer cells, which suggests that NF-kappa B/Rel may be a useful target in the treatment of breast cancer.