Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer
Name
s41392-018-0013-x.pdf
Description
Published version
Size
1.7 MB
Format
Adobe PDF
Checksum (MD5)
4bf3840a60590b4e1886ef22728eb517
Author(s)
Hiraki, Masayuki
Maeda, Takahiro
Mehrotra, Neha
Jin, Caining
Alam, Maroof
Bouillez, Audrey
Hata, Tsuyoshi
Tagde, Ashujit
Keating, Amy E.
Kharbanda, Surender
Date Issued
May 2018
Journal
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Citation
Hiraki, Masayuki et al. "Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer." Signal Transduction and Targeted Therapy 3, 1 (May 2018): 13 © 2018 The Author(s)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41392-018-0013-x
