2. Academic Validation
  3. The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway

The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway

  • Oncotarget. 2017 Dec 6;8(69):113360-113372. doi: 10.18632/oncotarget.23008.
Emilie Laprevotte 1,  Stéphanie Cochaud 1,  Stanislas du Manoir 2,  Marion Lapierre 2,  Cécile Dejou 1,  Marion Philippe 1,  Jérome Giustiniani 3 4,  Kathryn A Frewer 5,  Andrew J Sanders 5,  Wen G Jiang 5,  Henri-Alexandre Michaud 2,  Pierre-Emmanuel Colombo 6,  Armand Bensussan 3,  Gilles Alberici 1,  Jérémy Bastid 1,  Jean-François Eliaou 2 7,  Nathalie Bonnefoy 2
Affiliations

Affiliations

  • 1 OREGA Biotech, Ecully, F-69130 France.
  • 2 IRCM, INSERM, Université de Montpellier, ICM, Montpellier, F-34298 France.
  • 3 Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, Paris, F-75475 France.
  • 4 Institut Jean Godinot, Unicancer, Reims, F-51726 France.
  • 5 Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
  • 6 Département de chirurgie oncologique, Institut Régional du Cancer de Montpellier, Université de Montpellier, Montpellier, F-34298 France.
  • 7 Département d'Immunologie, Centre Hospitalier Régional Universitaire de Montpellier et Faculté de Médecine, Université de Montpellier, F-34295 France.
PMID: 29371916 DOI: 10.18632/oncotarget.23008
Abstract

Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 Receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast Cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast Cancer. We thus focused on IL-17B role in breast Cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents. In vivo, IL-17B induced resistance to paclitaxel and treatment with an anti-IL-17RB neutralizing antibody completely restored breast tumor chemosensitivity, leading to tumor shrinkage. We next focused on the signaling pathways activated in human breast Cancer cell lines upon incubation with IL-17B. We observed that IL-17B induces ERK1/2 pathway activation, leading to upregulation of anti-apoptotic proteins of the Bcl-2 Family. IL-17B-induced chemoresistance was completely abolished by incubation with PD98059, an inhibitor of the MAPK/ERK pathway, indicating that the ERK pathway plays a crucial role. Altogether our results emphasize the role of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as attractive therapeutic targets for potentiating breast Cancer chemotherapy.

Keywords

breast cancer; chemoresistance; interleukin-17; interleukin-17B; paclitaxel.

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