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CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL t...

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Autores principales: Xing, Fei, Gao, Hongli, Chen, Guanglei, Sun, Lisha, Sun, Jiayi, Qiao, Xinbo, Xue, Jinqi, Liu, Caigang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830830/
https://www.ncbi.nlm.nih.gov/pubmed/36627608
http://dx.doi.org/10.1186/s12943-023-01716-y
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author Xing, Fei
Gao, Hongli
Chen, Guanglei
Sun, Lisha
Sun, Jiayi
Qiao, Xinbo
Xue, Jinqi
Liu, Caigang
author_facet Xing, Fei
Gao, Hongli
Chen, Guanglei
Sun, Lisha
Sun, Jiayi
Qiao, Xinbo
Xue, Jinqi
Liu, Caigang
author_sort Xing, Fei
collection PubMed
description Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01716-y.
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spelling pubmed-98308302023-01-11 CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer Xing, Fei Gao, Hongli Chen, Guanglei Sun, Lisha Sun, Jiayi Qiao, Xinbo Xue, Jinqi Liu, Caigang Mol Cancer Research Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01716-y. BioMed Central 2023-01-10 /pmc/articles/PMC9830830/ /pubmed/36627608 http://dx.doi.org/10.1186/s12943-023-01716-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xing, Fei
Gao, Hongli
Chen, Guanglei
Sun, Lisha
Sun, Jiayi
Qiao, Xinbo
Xue, Jinqi
Liu, Caigang
CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title_full CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title_fullStr CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title_full_unstemmed CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title_short CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer
title_sort cmtm6 overexpression confers trastuzumab resistance in her2-positive breast cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830830/
https://www.ncbi.nlm.nih.gov/pubmed/36627608
http://dx.doi.org/10.1186/s12943-023-01716-y
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