title: Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer.
abstract: Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar(9), \Met(O2)(11)] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 were used to inhibit NK-1. The in vitro regulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathway were analyzed using western blot and real-time quantitative PCR. We found that the proportion of EGFR positive cases was increased with the increasement of NK-1 levels. SMSP could promote the proliferation of TNBC cells, while L-733060 and siRNA could inhibit cell proliferation and induce apoptosis. Moreover, SMSP could enhance expressions of phosphorylation (p)-EGFR and EGFR, and activate p-Akt and p-Erk. NK1-siRNA could decrease p-EGFR, p-Akt and p-Erk. In the presence of cetuximab (0.2mg/mL), SMSP still could stimulate cell proliferation, and activate p-EGFR. However, in the presence of erlotinib (10μM), SMSP could not stimulate cell proliferation and could not activate p-EGFR. Our study showed the interaction between NK-1 and EGFR in TNBCs. These results suggested that NK-1 may regulate TNBC proliferation through EGFR phosphorylation, and the curative effect of EGFR monoclonal antibodies may be affected by NK-1 activation.
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Ji-Gang
authors: JG
authors: Wang
authors: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Juan
authors: J
authors: Yu
authors: Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
authors: Ji-Lin
authors: JL
authors: Hu
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Wen-Lin
authors: WL
authors: Yang
authors: Department of Breast Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors: Hong
authors: H
authors: Ren
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Di
authors: D
authors: Ding
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Pathology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China; Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: xpliu1228@fudan.edu.cn.
authors: Xiu-Ping
authors: XP
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018040:Receptors, Neurokinin-1; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D013373:Substance P; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000068818:Cetuximab
keywords: Cetuximab; EGFR; Neurokinin-1; Substance P; Triple negative breast cancer