PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway
Abstract Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinica...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06502-2 |
| _version_ | 1797208981453668352 |
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| author | Yuanzhen Ma Zhiyu Fang Hongning Zhang Yijun Qi Yuke Mao Junfang Zheng |
| author_facet | Yuanzhen Ma Zhiyu Fang Hongning Zhang Yijun Qi Yuke Mao Junfang Zheng |
| author_sort | Yuanzhen Ma |
| collection | DOAJ |
| description | Abstract Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells. |
| first_indexed | 2024-04-24T09:47:26Z |
| format | Article |
| id | doaj.art-34642f5ad4f9469085c41078cc86ff04 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-24T09:47:26Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-34642f5ad4f9469085c41078cc86ff042024-04-14T11:30:54ZengNature Publishing GroupCell Death and Disease2041-48892024-04-0115311410.1038/s41419-024-06502-2PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathwayYuanzhen Ma0Zhiyu Fang1Hongning Zhang2Yijun Qi3Yuke Mao4Junfang Zheng5Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical UniversityBeijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityBeijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical UniversityBeijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical UniversityBeijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical UniversityAbstract Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells.https://doi.org/10.1038/s41419-024-06502-2 |
| spellingShingle | Yuanzhen Ma Zhiyu Fang Hongning Zhang Yijun Qi Yuke Mao Junfang Zheng PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway Cell Death and Disease |
| title | PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway |
| title_full | PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway |
| title_fullStr | PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway |
| title_full_unstemmed | PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway |
| title_short | PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway |
| title_sort | pdzk1 suppresses tnbc development and sensitizes tnbc cells to erlotinib via the egfr pathway |
| url | https://doi.org/10.1038/s41419-024-06502-2 |
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