USP7 Induces Chemoresistance in Triple-Negative Breast Cancer via Deubiquitination and Stabilization of ABCB1

Cells. 2022 Oct 19;11(20):3294. doi: 10.3390/cells11203294.

Abstract

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer. TNBC does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. Cytotoxic chemotherapy and surgery are the current therapeutic strategies for TNBC patients, but the chemoresistance of TNBC limits the efficiency of this strategy and shortens the lifespan of patients. The exploration of targeted therapy is ongoing in TNBC research. The aim of the present study was to identify the mechanism underlying acquired resistance in TNBC through the exploration of the relationship between the expression of USP7 and of ABCB1. We found that ubiquitin specific protease 7 (USP7) is a potential therapeutic target for overcoming the chemoresistance of TNBC. USP7 overexpression increased the chemoresistance of TNBC, while the knockdown of USP7 effectively increased the chemosensitivity of chemoresistant TNBC. A USP7 inhibitor effectively induced apoptosis and suppressed metastasis in chemoresistant TNBC. We further clarified that USP7 is a specific deubiquitinating enzyme for ABCB1 that plays an essential role in drug resistance. USP7 directly interacted with ABCB1 and regulated its stability. We concluded that USP7 promotes the chemoresistance of TNBC by stabilizing the ABCB1 protein.

Keywords: ATP-binding cassette B1; chemoresistance; triple-negative breast cancer; ubiquitin specific protease 7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Estrogens / therapeutic use
  • Humans
  • Receptors, Progesterone / metabolism
  • Triple Negative Breast Neoplasms* / pathology
  • Ubiquitin-Specific Peptidase 7 / metabolism

Substances

  • Ubiquitin-Specific Peptidase 7
  • Receptors, Progesterone
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Estrogens
  • USP7 protein, human
  • ATP Binding Cassette Transporter, Subfamily B

Grants and funding

This work was supported to H.T.W. by the Ministry of Science and Technology Summit grant (MOST 110-2314-B-371-007-MY3) and Changhua Christian Hospital (111-CCH-IRP-037); Y.T.L. by the Ministry of Science and Technology Summit grant (MOST 110-2314-B-182A-011); K.W.H by China Medical University (CMU110-MF-10), and the “Drug Development Center, China Medical University” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project (Ministry of Education, Taiwan).