Regulation of episialin/MUC1 expression in breast carcinomas: a complex interplay between stimulatory and inhibitory factors
© BioMed Central Ltd 2001
Received: 10 May 2001
Published: 31 May 2001
Episialin/MUC-1 is an epithelial mucin-like transmembrane glycoprotein, which is highly overexpressed in a majority of human carcinomas, in particular breast and ovarian carcinomas. We and others have shown that this overexpression results in reduced adhesion and a higher metastatic potential of the tumor cells . The overex-pression of episialin originates mainly at the transcriptional level (10-fold or more increased levels of episialin mRNA are found in breast tumor specimens and breast carcinoma cell lines [2,3]). Consequently, information on the regulation of the episialin promoter may provide a clue to the regulation of metastasis. Examination of the episialin promoter revealed several putative regulatory elements.
(1) We have shown that the episialin promoter is positively regulated by STATs (signal transducers and activators of transcription) in T47D breast and other carcinoma cell lines, using several established inducers of episialin expression (eg IFN-? and IL-6) as STAT-activating ligands . IL-6 (an activator of STAT3) can stimulate the episialin promoter, and binding of STAT3 to the STAT element in the episialin promoter is observed in bandshift assays . The possible involvement of STATs in tumor progression (eg via episialin expression) is also indicated by the increased levels of activated STAT3 that are found in breast carcinoma cell lines with a high episialin expression . Similar results are found in vivo, where constitutive activation of STAT1 and/or STAT3 is found in breast tumors .
(2) Glucocorticoids also can stimulate episialin expression in T47D cells through binding of the glucocorticoid receptor (GR) to GRE half sites present in the episialin promoter .
(3) In addition, we report that glucocorticoids can attenuate the effect of IL-6/STAT3, using reporter, bandshift and FACS assays . The effect of glucocorticoids on STAT3-mediated episialin expression occurs both through direct interactions between STAT3 and GR, as well as via indirect pathways. Conversely, addition of IL-6 can augment GR-mediated episialin expression .
(4) We have also identified a 200-bp sequence fragment far upstream in the episialin promoter that may bind a negative regulator of episialin expression. The identity and exact binding sequence of this putative inhibitor has not yet been determined.
We conclude that the expression of episialin/MUC1 is determined by a balance between positive and negative regulators, which is distorted in tumors, leading to a higher episialin expression and thus a more aggressive tumor type.
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