The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive du...
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MDPI AG
2020-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/9/1329 |
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| author | Nathan Griffin Mark Marsland Severine Roselli Christopher Oldmeadow John Attia Marjorie M. Walker Hubert Hondermarck Sam Faulkner |
| author_facet | Nathan Griffin Mark Marsland Severine Roselli Christopher Oldmeadow John Attia Marjorie M. Walker Hubert Hondermarck Sam Faulkner |
| author_sort | Nathan Griffin |
| collection | DOAJ |
| description | The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (<i>p</i> < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (<i>p</i> = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours. |
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| last_indexed | 2024-03-10T16:16:33Z |
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| series | Biomolecules |
| spelling | doaj.art-d05ee3772c834ec783d6cb2411f3dfc22023-11-20T14:02:27ZengMDPI AGBiomolecules2218-273X2020-09-01109132910.3390/biom10091329The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast CancerNathan Griffin0Mark Marsland1Severine Roselli2Christopher Oldmeadow3John Attia4Marjorie M. Walker5Hubert Hondermarck6Sam Faulkner7School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, AustraliaSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, AustraliaSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, AustraliaHunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, AustraliaHunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, AustraliaHunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, AustraliaSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, AustraliaSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, AustraliaThe tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (<i>p</i> < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (<i>p</i> = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.https://www.mdpi.com/2218-273X/10/9/1329breast cancertyrosine kinase receptor A (NTRK1/TrkA)human epidermal growth factor receptor 2 (HER2)clinical biomarkertherapeutic target |
| spellingShingle | Nathan Griffin Mark Marsland Severine Roselli Christopher Oldmeadow John Attia Marjorie M. Walker Hubert Hondermarck Sam Faulkner The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer Biomolecules breast cancer tyrosine kinase receptor A (NTRK1/TrkA) human epidermal growth factor receptor 2 (HER2) clinical biomarker therapeutic target |
| title | The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer |
| title_full | The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer |
| title_fullStr | The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer |
| title_full_unstemmed | The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer |
| title_short | The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer |
| title_sort | receptor tyrosine kinase trka is increased and targetable in her2 positive breast cancer |
| topic | breast cancer tyrosine kinase receptor A (NTRK1/TrkA) human epidermal growth factor receptor 2 (HER2) clinical biomarker therapeutic target |
| url | https://www.mdpi.com/2218-273X/10/9/1329 |
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