N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell invasion through suppressing NF-KB activation and inhibiting matrix metalloproteinase-9 expression

Synthetic retinoid N‐(4‐hydroxyphenyl)retinamide (4‐HPR) has been reported to exhibit anti‐invasive and anti‐metastatic activities by suppressing the enzymatic activity of matrix metalloproteinase (MMP)‐9, but the underlying mechanism remains unclear. Here, we show that 4‐HPR blocks the activity of MMP‐9 in two ways: by reducing phorbol 12‐myristate 13‐acetate (PMA)‐induced MMP‐9 secretion and by suppressing cell invasion through the downregulation of MMP‐9 gene transcription in MCF‐7 breast cancer cells. 4‐HPR inhibits the transcriptional activity of MMP‐9 by reducing the DNA‐binding activity of NF‐κB on the MMP‐9 promoter as well as by inhibiting the degradation of IκBα, leading to cytoplasmic accumulation of NF‐κB. We also found that 4‐HPR inhibits invasion and MMP‐9 expression in the highly metastatic breast cancer cell line MDA‐MB‐231. Thus, 4‐HPR might be a potent anti‐invasive agent that works by suppressing MMP‐9 expression via the NF‐κB signaling pathway. J. Cell. Biochem. 113: 2845–2855, 2012. © 2012 Wiley Periodicals, Inc.