Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases
| العنوان: | Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases |
|---|---|
| المؤلفون: | Nagarajan Vaidehi, Cecilia Choy, Hubert Li, Khairul I. Ansari, Josh Neman, Sarah Hsu, Rahul Jandial, Matthew J. Duenas |
| المصدر: | Breast Cancer Research : BCR Breast Cancer Research, Vol 19, Iss 1, Pp 1-11 (2017) |
| بيانات النشر: | BioMed Central, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Pathology, Receptor, ErbB-2, Tropomyosin receptor kinase B, Metastasis, Mice, 0302 clinical medicine, Glial cells, Cyclotraxin-B, skin and connective tissue diseases, Membrane Glycoproteins, biology, Brain Neoplasms, musculoskeletal, neural, and ocular physiology, Epidermal growth factor receptor 2 (Her2+), lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Metastatic breast cancer, 3. Good health, Neural microenvironment, Tropomyosin-related kinase B (TrkB), 030220 oncology & carcinogenesis, Female, Astrocyte, Dimerization, Neurotrophin, Research Article, Signal Transduction, medicine.medical_specialty, Neurotrophic factor, Breast Neoplasms, lcsh:RC254-282, Neurotrophins, 03 medical and health sciences, Paracrine signalling, Breast cancer, Cell Line, Tumor, medicine, Animals, Humans, Receptor, trkB, Cyclotraxin B, Cell Proliferation, business.industry, Brain-Derived Neurotrophic Factor, Lapatinib, Breast cancer brain metastasis, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, nervous system, biology.protein, Cancer research, Brain-derived neurotrophic factor (BDNF), business, Brain metastasis |
| الوصف: | Background Patients with primary breast cancer that is positive for human epidermal growth factor receptor 2 (Her2+) have a high risk of developing metastases in the brain. Despite gains with systemic control of Her2+ disease using molecular therapies, brain metastases remain recalcitrant to therapeutic discovery. The clinical predilection of Her2+ breast cancer cells to colonize the brain likely relies on paracrine mechanisms. The neural niche poses unique selection pressures, and neoplastic cells that utilize the brain microenvironment may have a survival advantage. Methods Tropomyosin-related kinase B (TrkB), Her2, and downstream targets were analyzed in primary breast cancer, breast-to-brain metastasis (BBM) tissues, and tumor-derived cell lines using quantitative real-time PCR, western blot, and immunohistochemical assessment. TrkB function on BBM was confirmed with intracranial, intracardiac, or mammary fat pad xenografts in non-obese diabetic/severe combined immunodeficiency mice. The function of brain-derived neurotrophic factor (BDNF) on cell proliferation and TrkB/Her2 signaling and interactions were confirmed using selective shRNA knockdown and selective inhibitors. The physical interaction of Her2-TrkB was analyzed using electron microscopy, co-immunoprecipitation, and in silico analysis. Dual targeting of Her2 and TrkB was analyzed using clinically utilized treatments. Results We observed that patient tissues and cell lines derived from Her2+ human BBM displayed increased activation of TrkB, a neurotrophin receptor. BDNF, an extracellular neurotrophin, with roles in neuronal maturation and homeostasis, specifically binds to TrkB. TrkB knockdown in breast cancer cells led to decreased frequency and growth of brain metastasis in animal models, suggesting that circulating breast cancer cells entering the brain may take advantage of paracrine BDNF-TrkB signaling for colonization. In addition, we investigated a possible interaction between TrkB and Her2 receptors on brain metastatic breast cancer cells, and found that BDNF phosphorylated both its cognate TrkB receptor and the Her2 receptor in brain metastatic breast cancer cells. Conclusion Collectively, our findings suggest that heterodimerization of Her2 and TrkB receptors gives breast cancer cells a survival advantage in the brain and that dual inhibition of these receptors may hold therapeutic potential. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0844-3) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1465-542X 1465-5411 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7fee919947aa97af673e5c3e9e33099 http://europepmc.org/articles/PMC5406906 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d7fee919947aa97af673e5c3e9e33099 |
| قاعدة البيانات: | OpenAIRE |
كن أول من يترك تعليقا!