title: Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.
abstract: ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored.
authors.affiliation: Authors' Affiliations: Department of Medical Oncology and Pathology, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, Department of Medicine, University of Barcelona; Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain; Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; Department of Genetics, Oslo University Hospital Radiumhospitalet, Norway; and Department of Medicine and Experimental Oncology, Torino University, Turin, Italy.
authors.forename: Susana
authors.initials: S
authors.lastname: Garcia-Recio
authors.forename: Gemma
authors.initials: G
authors.lastname: Fuster
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez-Nogueira
authors.forename: Eva M
authors.initials: EM
authors.lastname: Pastor-Arroyo
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Cristina
authors.initials: C
authors.lastname: Mayordomo
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ametller
authors.forename: Mario
authors.initials: M
authors.lastname: Mancino
authors.forename: Xavier
authors.initials: X
authors.lastname: Gonzalez-Farre
authors.forename: Hege G
authors.initials: HG
authors.lastname: Russnes
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.forename: Domiziana
authors.initials: D
authors.lastname: Costamagna
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernandez
authors.forename: Pedro
authors.initials: P
authors.lastname: Gascón
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
mesh_terms: D017209:Apoptosis; D019898:Autocrine Communication / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018377:Neurotransmitter Agents; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D018040:Receptors, Neurokinin-1; D013373:Substance P; C512478:EGFR protein, human