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J Biol Chem. 2013 Oct 25;288(43):30892-903. doi: 10.1074/jbc.M113.477158. Epub 2013 Sep 16.

MUC1-C oncoprotein activates ERK→C/EBPβ signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells.

Author information

1
From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.

Abstract

Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is used as a marker of breast cancer stem cells; however, little is known about the regulation of ALDH1A1 expression. Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in most human breast cancers. In studies of breast cancer cells stably silenced for MUC1 or overexpressing the oncogenic MUC1-C subunit, we demonstrate that MUC1-C is sufficient for induction of MEK → ERK signaling and that treatment with a MUC1-C inhibitor suppresses ERK activation. In turn, MUC1-C induces ERK-mediated phosphorylation and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor. The results further show that MUC1-C and C/EBPβ form a complex on the ALDH1A1 gene promoter and activate ALDH1A1 gene transcription. MUC1-C-induced up-regulation of ALDH1A1 expression is associated with increases in ALDH activity and is detectable in stem-like cells when expanded as mammospheres. These findings demonstrate that MUC1-C (i) activates a previously unrecognized ERK→C/EBPβ→ALDH1A1 pathway, and (ii) promotes the induction of ALDH activity in breast cancer cells.

KEYWORDS:

Breast Cancer; C/EBP Transcription Factor; Cancer; ERK; Muc1; aldh1

PMID:
24043631
PMCID:
PMC3829404
DOI:
10.1074/jbc.M113.477158
[Indexed for MEDLINE]
Free PMC Article

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