Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer
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 ca...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125967 |
| _version_ | 1826195452171649024 |
|---|---|
| author | Hiraki, Masayuki Maeda, Takahiro Mehrotra, Neha Jin, Caining Alam, Maroof Bouillez, Audrey Hata, Tsuyoshi Tagde, Ashujit Keating, Amy E. Kharbanda, Surender Singh, Harpal Kufe, Donald |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hiraki, Masayuki Maeda, Takahiro Mehrotra, Neha Jin, Caining Alam, Maroof Bouillez, Audrey Hata, Tsuyoshi Tagde, Ashujit Keating, Amy E. Kharbanda, Surender Singh, Harpal Kufe, Donald |
| author_sort | Hiraki, Masayuki |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:12:54Z |
| format | Article |
| id | mit-1721.1/125967 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:12:54Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1259672022-09-26T16:31:10Z 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 E. Kharbanda, Surender Singh, Harpal Kufe, Donald Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Biological Engineering 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. US Department of Defense (Award BC151648) National Cancer Institute (Award R01 CA097098) National Cancer Institute (Award R21 CA216553) National Cancer Institute (Award R01 CA166480) 2020-06-23T21:35:05Z 2020-06-23T21:35:05Z 2018-05 2018-02 2019-12-12T14:25:32Z Article http://purl.org/eprint/type/JournalArticle 2059-3635 https://hdl.handle.net/1721.1/125967 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) en http://dx.doi.org/10.1038/s41392-018-0013-x Signal Transduction and Targeted Therapy Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Hiraki, Masayuki Maeda, Takahiro Mehrotra, Neha Jin, Caining Alam, Maroof Bouillez, Audrey Hata, Tsuyoshi Tagde, Ashujit Keating, Amy E. Kharbanda, Surender Singh, Harpal Kufe, Donald Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title | Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title_full | Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title_fullStr | Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title_full_unstemmed | Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title_short | Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer |
| title_sort | targeting muc1 c suppresses bcl2a1 in triple negative breast cancer |
| url | https://hdl.handle.net/1721.1/125967 |
| work_keys_str_mv | AT hirakimasayuki targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT maedatakahiro targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT mehrotraneha targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT jincaining targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT alammaroof targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT bouillezaudrey targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT hatatsuyoshi targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT tagdeashujit targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT keatingamye targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT kharbandasurender targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT singhharpal targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer AT kufedonald targetingmuc1csuppressesbcl2a1intriplenegativebreastcancer |