Inhibition of MUC1 expression by indole-3-carbinol

MUCI is a large transmembrane glycoprotein overexpressed by a majority of carcinomas. High expression of MUCI is associated with aggressive tumors, and MUCI antigen is used as a marker to monitor disease progression in breast cancer patients. Several lines of evidence strongly suggest that the overexpression of MUCI contributes to cancer progression and metastasis. In this report, we demonstrate that the naturally occurring cancer preventative, indole-3-carbinol (13C), inhibits the expression of MUCI in breast cancer cells. 13C inhibited both MUCI mRNA and protein levels in a dose- and time-dependent manner. This inhibition was seen in the estrogen responsive MCF-7 cells as well as unresponsive MDA-MB-468 cells, indicating that the inhibitory pathway is independent of estrogen receptor. Gene expression studies using the human MUCI gene promoter connected to a luciferase reporter demonstrated that 13C inhibits the transcription of the MUCI gene. Promoter deletion studies indicate that the region containing up to 600 bp upstream (-600) of the initiation site is sufficient for inhibition by 13C. Furthermore, 13C represses the activation of transcription mediated by the region between -600 and -450 bp. A putative xenobiotic response element was located within this region but the binding of AhR/Arnt heterodimer to this site was undetectable by electrophoretic mobility shift assays. Our results may point to the existence of a novel pathway of transcriptional inhibition by 13C in cancer cells as well as a new mechanism of MUCI gene inhibition. Our findings might have implications in the use of 13C as a preventative as well as a therapeutic agent for breast cancer. (C) 2004 Wiley-Liss, Inc.