title: MUC1-C oncoprotein activates ERK→C/EBPβ signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells.
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.
authors.affiliation: From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Akriti
authors.initials: A
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D050697:Retinal Dehydrogenase; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C060192:MUC1 protein, human; D018396:Mucin-1; D009363:Neoplasm Proteins; D021122:Protein Subunits; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: Breast Cancer; C/EBP Transcription Factor; Cancer; ERK; Muc1; aldh1
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