Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis
Abstract Multidrug resistance (MDR) is a primary limitation of breast cancer chemotherapy. The common mechanism of MDR is various anticancer drugs can be effluxed by the cell membrane protein P‐glycoprotein (P‐gp). Here, we found that ectopic overexpression of Shc3 was detected specifically in drug‐...
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.5768 |
| _version_ | 1827259886267793408 |
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| author | Yun Liu Fang Cao Fantong Xia Jie Li Xiaobao Dong Yan Guo Jun Zhang Qiang Zhao Yuanyuan Liu |
| author_facet | Yun Liu Fang Cao Fantong Xia Jie Li Xiaobao Dong Yan Guo Jun Zhang Qiang Zhao Yuanyuan Liu |
| author_sort | Yun Liu |
| collection | DOAJ |
| description | Abstract Multidrug resistance (MDR) is a primary limitation of breast cancer chemotherapy. The common mechanism of MDR is various anticancer drugs can be effluxed by the cell membrane protein P‐glycoprotein (P‐gp). Here, we found that ectopic overexpression of Shc3 was detected specifically in drug‐resistant breast cancer cells, consequently reducing sensitivity to chemotherapy and promoting cell migration by mediating P‐gp expression. However, the molecular mechanism underlying the interplay between P‐gp and Shc3 in breast cancer is unknown. We reported an additional resistance mechanism involving an increase in the active form of P‐gp after Shc3 upregulation. MCF‐7/ADR and SK‐BR‐3 cells can be sensitive to doxorubicin after knockdown of Shc3. Our results indicated that the interaction between ErbB2 and EphA2 is indirect and regulated by Shc3, and also, this complex is essential for activation of the MAPK and AKT pathways. Meanwhile, Shc3 promotes ErbB2 nuclear translocation, followed by a subsequent increase of the COX2 expression through ErbB2 binding to the COX2 promoter. We further demonstrated that COX2 expression was positively correlated with P‐gp expression and the Shc3/ErbB2/COX2 axis upregulates P‐gp activity in vivo. Our results show the crucial roles of Shc3 and ErbB2 in modulating P‐gp efficacy in breast cancer cells and suggest that Shc3 inhibition may enhance the sensitivity to chemotherapeutic drugs that target oncogene addiction pathways. |
| first_indexed | 2024-03-13T08:56:15Z |
| format | Article |
| id | doaj.art-47de9a7a46ea4836b17144258f2bf20a |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2025-03-22T02:33:42Z |
| publishDate | 2023-05-01 |
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| series | Cancer Medicine |
| spelling | doaj.art-47de9a7a46ea4836b17144258f2bf20a2024-05-04T06:40:57ZengWileyCancer Medicine2045-76342023-05-01129107681078010.1002/cam4.5768Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axisYun Liu0Fang Cao1Fantong Xia2Jie Li3Xiaobao Dong4Yan Guo5Jun Zhang6Qiang Zhao7Yuanyuan Liu8Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Thoracic Surgery The Second Hospital of Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaDepartment of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences Tianjin Medical University Tianjin ChinaAbstract Multidrug resistance (MDR) is a primary limitation of breast cancer chemotherapy. The common mechanism of MDR is various anticancer drugs can be effluxed by the cell membrane protein P‐glycoprotein (P‐gp). Here, we found that ectopic overexpression of Shc3 was detected specifically in drug‐resistant breast cancer cells, consequently reducing sensitivity to chemotherapy and promoting cell migration by mediating P‐gp expression. However, the molecular mechanism underlying the interplay between P‐gp and Shc3 in breast cancer is unknown. We reported an additional resistance mechanism involving an increase in the active form of P‐gp after Shc3 upregulation. MCF‐7/ADR and SK‐BR‐3 cells can be sensitive to doxorubicin after knockdown of Shc3. Our results indicated that the interaction between ErbB2 and EphA2 is indirect and regulated by Shc3, and also, this complex is essential for activation of the MAPK and AKT pathways. Meanwhile, Shc3 promotes ErbB2 nuclear translocation, followed by a subsequent increase of the COX2 expression through ErbB2 binding to the COX2 promoter. We further demonstrated that COX2 expression was positively correlated with P‐gp expression and the Shc3/ErbB2/COX2 axis upregulates P‐gp activity in vivo. Our results show the crucial roles of Shc3 and ErbB2 in modulating P‐gp efficacy in breast cancer cells and suggest that Shc3 inhibition may enhance the sensitivity to chemotherapeutic drugs that target oncogene addiction pathways.https://doi.org/10.1002/cam4.5768breast cancerchemoresistanceCOX2ErbB2MDR1Shc3 |
| spellingShingle | Yun Liu Fang Cao Fantong Xia Jie Li Xiaobao Dong Yan Guo Jun Zhang Qiang Zhao Yuanyuan Liu Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis Cancer Medicine breast cancer chemoresistance COX2 ErbB2 MDR1 Shc3 |
| title | Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis |
| title_full | Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis |
| title_fullStr | Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis |
| title_full_unstemmed | Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis |
| title_short | Shc3 facilitates breast cancer drug resistance by interacting with ErbB2 to initiate ErbB2/COX2/MDR1 axis |
| title_sort | shc3 facilitates breast cancer drug resistance by interacting with erbb2 to initiate erbb2 cox2 mdr1 axis |
| topic | breast cancer chemoresistance COX2 ErbB2 MDR1 Shc3 |
| url | https://doi.org/10.1002/cam4.5768 |
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