HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel
Abstract Background Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-023-03055-w |
| _version_ | 1797556310402662400 |
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| author | Hui Lyu Fei Shen Sanbao Ruan Congcong Tan Jundong Zhou Ann D. Thor Bolin Liu |
| author_facet | Hui Lyu Fei Shen Sanbao Ruan Congcong Tan Jundong Zhou Ann D. Thor Bolin Liu |
| author_sort | Hui Lyu |
| collection | DOAJ |
| description | Abstract Background Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC and develop effective therapy against the aggressive disease. Methods Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. Specific shRNA was used to knockdown HER3 expression. IncuCyte system was utilized to monitor cell growth and migration. LIVE/DEAD Cell Imaging was to detect live and dead cells. HER3 recognition by our anti-HER3 monoclonal antibody (mAb) 4A7 was verified by ELISA, flow cytometry, and co-immunoprecipitation assays. Orthotopic tumor models were established in nude mice to determine the capability of TNBC cells forming tumors and to test if our mAb 4A7 could potentiate the antitumor activity of paclitaxel in vivo. Results Elevated expression of HER3 was observed in approximately half of the TNBC specimens and cell lines tested. Analyses of TCGA databases found that the TNBC patients with high HER3 mRNA expression in the tumors showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low HER3 expression. Specific knockdown of HER3 markedly inhibited TNBC cell proliferation and mammosphere formation in vitro and tumor growth in vivo. Our mAb 4A7 abrogated heregulin (a ligand for HER3), but not SDF-1 (a ligand for CXCR4)-induced enhancement of TNBC cell migration. Combinations of 4A7 and the EGFR-tyrosine kinase inhibitor (TKI) gefitinib dramatically decreased the levels of phosphorylated HER3, EGFR, Akt, and ERK1/2 in TNBC cells and potently induced growth inhibition and cell death. Moreover, 4A7 in combination with paclitaxel exerted significant antitumor activity against TNBC in vitro and in vivo. Conclusions Our data demonstrate that increased HER3 is an effective therapeutic target for TNBC and our anti-HER3 mAb (4A7) may enhance the efficacy of gefitinib or paclitaxel in TNBC. |
| first_indexed | 2024-03-10T17:00:04Z |
| format | Article |
| id | doaj.art-92a5e08a19c24a24943b9ec17a0c687e |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-10T17:00:04Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-92a5e08a19c24a24943b9ec17a0c687e2023-11-20T10:59:44ZengBMCCancer Cell International1475-28672023-09-0123111610.1186/s12935-023-03055-wHER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxelHui Lyu0Fei Shen1Sanbao Ruan2Congcong Tan3Jundong Zhou4Ann D. Thor5Bolin Liu6Departments of Interdisciplinary Oncology and Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences CenterJiangsu Institute of Hematology, NHC Key Laboratory of Thrombosis and Hemostasis, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow UniversityDepartments of Interdisciplinary Oncology and Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences CenterDepartments of Interdisciplinary Oncology and Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences CenterSuzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou HospitalDepartment of Pathology, School of Medicine, University of Colorado Anschutz Medical CampusDepartments of Interdisciplinary Oncology and Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences CenterAbstract Background Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC and develop effective therapy against the aggressive disease. Methods Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. Specific shRNA was used to knockdown HER3 expression. IncuCyte system was utilized to monitor cell growth and migration. LIVE/DEAD Cell Imaging was to detect live and dead cells. HER3 recognition by our anti-HER3 monoclonal antibody (mAb) 4A7 was verified by ELISA, flow cytometry, and co-immunoprecipitation assays. Orthotopic tumor models were established in nude mice to determine the capability of TNBC cells forming tumors and to test if our mAb 4A7 could potentiate the antitumor activity of paclitaxel in vivo. Results Elevated expression of HER3 was observed in approximately half of the TNBC specimens and cell lines tested. Analyses of TCGA databases found that the TNBC patients with high HER3 mRNA expression in the tumors showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low HER3 expression. Specific knockdown of HER3 markedly inhibited TNBC cell proliferation and mammosphere formation in vitro and tumor growth in vivo. Our mAb 4A7 abrogated heregulin (a ligand for HER3), but not SDF-1 (a ligand for CXCR4)-induced enhancement of TNBC cell migration. Combinations of 4A7 and the EGFR-tyrosine kinase inhibitor (TKI) gefitinib dramatically decreased the levels of phosphorylated HER3, EGFR, Akt, and ERK1/2 in TNBC cells and potently induced growth inhibition and cell death. Moreover, 4A7 in combination with paclitaxel exerted significant antitumor activity against TNBC in vitro and in vivo. Conclusions Our data demonstrate that increased HER3 is an effective therapeutic target for TNBC and our anti-HER3 mAb (4A7) may enhance the efficacy of gefitinib or paclitaxel in TNBC.https://doi.org/10.1186/s12935-023-03055-wHER3EGFRBlocking antibodyTargeted therapyPaclitaxelTNBC |
| spellingShingle | Hui Lyu Fei Shen Sanbao Ruan Congcong Tan Jundong Zhou Ann D. Thor Bolin Liu HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel Cancer Cell International HER3 EGFR Blocking antibody Targeted therapy Paclitaxel TNBC |
| title | HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| title_full | HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| title_fullStr | HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| title_full_unstemmed | HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| title_short | HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| title_sort | her3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel |
| topic | HER3 EGFR Blocking antibody Targeted therapy Paclitaxel TNBC |
| url | https://doi.org/10.1186/s12935-023-03055-w |
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