Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer

Masayuki Hiraki, Takahiro Maeda, Neha Mehrotra, Caining Jin, Maroof Alam, Audrey Bouillez, Tsuyoshi Hata, Ashujit Tagde, Amy Keating, Surender Kharbanda, Harpal Singh, Donald Kufe

研究成果: ジャーナルへの寄稿学術誌査読

22 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号13
ジャーナルSignal Transduction and Targeted Therapy
3
1
DOI
出版ステータス出版済み - 12月 1 2018
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 癌研究
  • 遺伝学

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