The mucin-like glycoprotein episialin (MUC1) is highly overproduced by a number of human carcinomas. We have shown previously in a variety of mammalian 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 situ hybridization, we show here that episialin/ MUC1 mRNA expression can be increased more than 10-fold in breast carcinoma cells relative to the expression in adjacent normal breast epithelium. In search of the molecular mechanism of this overexpression, we observed that the episialin/MUC1 promoter contains a candidate binding site for transcription factors of the STAT family ϳ500 base pairs upstream of the transcription start site. Cytokines and/or growth factors such as interleukin-6 or interferon-␥ can activate STATs. In the human breast carcinoma cell line T47D, both compounds are able to stimulate transcription of a luciferase reporter gene under the control of a 750-base pair MUC1 promoter fragment proximal to the transcription start site. The observed increase is entirely mediated by the single STAT-binding site, since mutation of this site abolishes stimulation of the reporter by interleukin-6 and interferon-␥. In addition, mutation of the STAT site also decreased the promoter activity in nonstimulated T47D cells, suggesting that the STAT-binding site is among the elements that are involved in the overexpression of MUC1 in tumor cells.
Episialin/MUC11 (also known as MUC1, PEM, CA 15-3 antigen, or EMA) is a transmembrane molecule with a large extracellular mucin-like domain. In normal cells episialin/ MUC1 is exclusively present at the apical side of the cell, but in carcinoma cells normal polarization is lost and episialin/MUC1 co-localizes with adhesion molecules such as integrins and cadherins. The long and relatively rigid extracellular domain of episialin/MUC1 can shield these adhesion molecules and diminish cellular adhesion, if present at a sufficiently high density on the cell surface (1-3). Overexpression of episialin/MUC1 in carcinoma cells has been frequently reported (4 -6) and is expected to have a similar effect on cellular behavior as loss of E-cadherin, the major epithelial cell-cell adhesion molecule, which has been shown to promote invasion and metastasis of carcinoma cells (for review see Refs. 7-9). Therefore, we have proposed that episialin/MUC1 also plays an important role in invasion and metastasis in vivo (10). Indeed, transgenic mice overexpressing episialin/MUC1 develop more aggressive lung tumors than nontransgenic mice, 2 whereas episialin/MUC1 null mice show a slower rate of tumor progression (11).Recent reports have shown that episialin overexpression in various types of neoplasia correlates with poor survival (12)(13)(14). Episialin/MUC1 is also the antigen that is measured in the CA 15-3 assay (the main blood marker to detect recurrence of breast cancer), and it is a molecule that is widely considered as ...