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

Signal Transduction and Targeted Therapy - Tập 3 Số 1
Masayuki Hiraki1, Takahiro Maeda1, Neha Mehrotra2, Caining Jin1, Maroof Alam1, Audrey Bouillez1, Tsuyoshi Hata1, Ashujit Tagde1, Amy E. Keating3, Surender Kharbanda1, Harpal Singh2, Donald Küfe1
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
2Center for Biomedical, Indian Institute of Technology, Delhi, India
3Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

Tóm tắt

AbstractB-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.

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Signal Transduction and Targeted Therapy

Tập 3 Số 1

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