PMID- 28446206 OWN - NLM STAT- MEDLINE DCOM- 20180301 LR - 20211211 IS - 1465-542X (Electronic) IS - 1465-5411 (Print) IS - 1465-5411 (Linking) VI - 19 IP - 1 DP - 2017 Apr 26 TI - Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. PG - 51 LID - 10.1186/s13058-017-0844-3 [doi] LID - 51 AB - 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. FAU - Choy, Cecilia AU - Choy C AD - Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. AD - Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, 91010, USA. FAU - Ansari, Khairul I AU - Ansari KI AD - Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. FAU - Neman, Josh AU - Neman J AD - Department of Neurosurgery, Keck School of Medicine at University of Southern California, Los Angeles, CA, 90089, USA. FAU - Hsu, Sarah AU - Hsu S AD - Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90089, USA. FAU - Duenas, Matthew J AU - Duenas MJ AD - Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. FAU - Li, Hubert AU - Li H AD - Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, 91010, USA. AD - Department of Immunology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA. FAU - Vaidehi, Nagarajan AU - Vaidehi N AD - Department of Immunology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA. FAU - Jandial, Rahul AU - Jandial R AUID- ORCID: 0000-0002-9564-2107 AD - Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. Rjandial@coh.org. LA - eng GR - P30 CA033572/CA/NCI NIH HHS/United States GR - R01 GM097261/GM/NIGMS NIH HHS/United States GR - R01 GM082896/GM/NIGMS NIH HHS/United States GR - K12 CA001727/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170426 PL - England TA - Breast Cancer Res JT - Breast cancer research : BCR JID - 100927353 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Glycoproteins) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Animals MH - Brain Neoplasms/*genetics/pathology/secondary MH - Brain-Derived Neurotrophic Factor/genetics MH - Breast Neoplasms/*genetics/pathology MH - Cell Line, Tumor MH - Cell Proliferation/genetics MH - Dimerization MH - Female MH - Humans MH - Membrane Glycoproteins/chemistry/*genetics MH - Mice MH - Receptor, ErbB-2/chemistry/*genetics MH - Receptor, trkB/chemistry/*genetics MH - Signal Transduction/genetics MH - Xenograft Model Antitumor Assays PMC - PMC5406906 OTO - NOTNLM OT - Astrocyte OT - Brain-derived neurotrophic factor (BDNF) OT - Breast cancer brain metastasis OT - Cyclotraxin B OT - Epidermal growth factor receptor 2 (Her2+) OT - Glial cells OT - Lapatinib OT - Neural microenvironment OT - Neurotrophic factor OT - Neurotrophins OT - Tropomyosin-related kinase B (TrkB) EDAT- 2017/04/28 06:00 MHDA- 2018/03/02 06:00 PMCR- 2017/04/26 CRDT- 2017/04/28 06:00 PHST- 2016/06/25 00:00 [received] PHST- 2017/04/13 00:00 [accepted] PHST- 2017/04/28 06:00 [entrez] PHST- 2017/04/28 06:00 [pubmed] PHST- 2018/03/02 06:00 [medline] PHST- 2017/04/26 00:00 [pmc-release] AID - 10.1186/s13058-017-0844-3 [pii] AID - 844 [pii] AID - 10.1186/s13058-017-0844-3 [doi] PST - epublish SO - Breast Cancer Res. 2017 Apr 26;19(1):51. doi: 10.1186/s13058-017-0844-3.