The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway
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Emilie Laprevotte1, Stéphanie Cochaud1, Stanislas du Manoir2, Marion Lapierre2, Cécile Dejou1, Marion Philippe1, Jérome Giustiniani3,4, Kathryn A. Frewer5, Andrew J. Sanders5, Wen G. Jiang5, Henri-Alexandre Michaud2, Pierre-Emmanuel Colombo6, Armand Bensussan3, Gilles Alberici1, Jérémy Bastid1, Jean-François Eliaou2,7 and Nathalie Bonnefoy2
1OREGA Biotech, Ecully, F-69130 France
2IRCM, INSERM, Université de Montpellier, ICM, Montpellier, F-34298 France
3Institut 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
4Institut Jean Godinot, Unicancer, Reims, F-51726 France
5Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
6Département de chirurgie oncologique, Institut Régional du Cancer de Montpellier, Université de Montpellier, Montpellier, F-34298 France
7Département d’Immunologie, Centre Hospitalier Régional Universitaire de Montpellier et Faculté de Médecine, Université de Montpellier, F-34295 France
Nathalie Bonnefoy, email: [email protected]
Keywords: interleukin-17; interleukin-17B; breast cancer; chemoresistance; paclitaxel
Received: July 14, 2017 Accepted: November 13, 2017 Published: December 06, 2017
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.
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