Abstract
B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial–mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.
Highlights
Mucin 1 (MUC1) is a heterodimeric protein that is overexpressed in ~90% of triple-negative breast cancers (TNBCs).[1,2] The MUC1 transmembrane C-terminal (MUC1-C) subunit functions as an oncoprotein by interacting with diverse kinases and effectors that have been linked to transformation.[1,3] Along these lines, MUC1-C activates the inflammatory TAK1, TGF-β-activated kinase 1 (TAK1)→IKK→NF-κB p65 pathway.[4,5,6] The MUC1-C cytoplasmic domain interacts directly with NF-κB p65 and promotes the activation of NF-κB p65 target genes, including MUC1, in an autoinductive loop that increases MUC1-C expression.[6]
MUC1-C induces B-cell lymphoma 2-related protein A1 (BCL2A1) expression To assess the potential involvement of MUC1-C in the regulation of BCL2A1, we established MDA-MB-468 breast cancer cells stably expressing tetracycline-inducible control shRNA or MUC1 shRNA
The present study demonstrates that targeting MUC1-C in TNBC cells with genetic and pharmacological approaches suppresses the expression of the anti-apoptotic BCL2A1 protein
Summary
Mucin 1 (MUC1) is a heterodimeric protein that is overexpressed in ~90% of triple-negative breast cancers (TNBCs).[1,2] The MUC1 transmembrane C-terminal (MUC1-C) subunit functions as an oncoprotein by interacting with diverse kinases and effectors that have been linked to transformation.[1,3] Along these lines, MUC1-C activates the inflammatory TAK1, TGF-β-activated kinase 1 (TAK1)→IKK→NF-κB p65 pathway.[4,5,6] The MUC1-C cytoplasmic domain interacts directly with NF-κB p65 and promotes the activation of NF-κB p65 target genes, including MUC1, in an autoinductive loop that increases MUC1-C expression.[6] Activation of MUC1-C→NF-κB p65 signaling is, in turn, associated with induction of the ZEB1 gene, which encodes a transcriptional repressor that suppresses miR-200c and drives the epithelial–mesenchymal transition (EMT).[7] MUC1-C contributes to the loss of epithelial cell polarity by (i) ZEB1-mediated downregulation of the CRB3, HUGL2 and PATJ polarity factors and (ii) repression of the CDH1 gene and thereby the expression of
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
