A STAT-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells

The mucin-like glycoprotein episialin (MUC1) is highly overproduced by a nu mber of human carcinomas. We have shown previously in a variety of mammalia n cell lines that overexpression of this very large transmembrane molecule diminishes cellular adhesion, suggesting that episialin/MUC1 overexpression may play an important role in tumor invasion and metastasis. By using in s itu hybridization, we show here that episialin/MUC1 mRNA expression can be increased more than 10-fold in breast carcinoma cells relative to the expre ssion in adjacent normal breast epithelium. In search of the molecular mech anism of this overexpression, we observed that the episialin/MUC1 promoter contains a candidate binding site for transcription factors of the STAT fam ily similar to 500 base pairs upstream of the transcription start site. Cyt okines and/or growth factors such as interleukin-6 or interferon-gamma can activate STATs. In the human breast carcinoma cell line T47D, both compound s are able to stimulate transcription of a luciferase reporter gene under t he control of a 750-base pair MUC1 promoter fragment proximal to the transc ription start site. The observed increase is entirely mediated by the singl e STAT-binding site, since mutation of this site abolishes stimulation of t he reporter by interleukin-6 and interferon-gamma. In addition, mutation of the STAT site also decreased the promoter activity in nonstimulated T47D c ells, suggesting that the STAT-binding site is among the elements that are involved in the overexpression of MUC1 in tumor cells.