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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number13
JournalSignal Transduction and Targeted Therapy
Volume3
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

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Triple Negative Breast Neoplasms
B-Cell Lymphoma
Proteins
Apoptosis Regulatory Proteins
Oncogene Proteins
Drug Resistance
Pharmaceutical Preparations
Neoplasms
Up-Regulation
Down-Regulation
Peptides

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Genetics

Cite this

Hiraki, M., Maeda, T., Mehrotra, N., Jin, C., Alam, M., Bouillez, A., ... Kufe, D. (2018). Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. Signal Transduction and Targeted Therapy, 3(1), [13]. https://doi.org/10.1038/s41392-018-0013-x

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. / Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha; Jin, Caining; Alam, Maroof; Bouillez, Audrey; Hata, Tsuyoshi; Tagde, Ashujit; Keating, Amy; Kharbanda, Surender; Singh, Harpal; Kufe, Donald.

In: Signal Transduction and Targeted Therapy, Vol. 3, No. 1, 13, 01.12.2018.

Research output: Contribution to journalArticle

Hiraki, M, Maeda, T, Mehrotra, N, Jin, C, Alam, M, Bouillez, A, Hata, T, Tagde, A, Keating, A, Kharbanda, S, Singh, H & Kufe, D 2018, 'Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer', Signal Transduction and Targeted Therapy, vol. 3, no. 1, 13. https://doi.org/10.1038/s41392-018-0013-x
Hiraki, Masayuki ; Maeda, Takahiro ; Mehrotra, Neha ; Jin, Caining ; Alam, Maroof ; Bouillez, Audrey ; Hata, Tsuyoshi ; Tagde, Ashujit ; Keating, Amy ; Kharbanda, Surender ; Singh, Harpal ; Kufe, Donald. / Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. In: Signal Transduction and Targeted Therapy. 2018 ; Vol. 3, No. 1.
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