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

Emilie Laprevotte,Stanislas Du Manoir,Marion Philippe,Stéphanie Cochaud,Wen G Jiang,Henri-Alexandre Michaud,Jérémy Bastid,Kathryn A Frewer,Pierre-Emmanuel Colombo,Jean-François Eliaou,Armand Bensussan,Nathalie Bonnefoy,Cécile Dejou,Marion Lapierre,Andrew J Sanders,Jérome Giustiniani,Gilles Alberici

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.

Highlights

Tumor development is regulated by many different factors that influence cancer cell proliferation, cell death resistance and dissemination within the organism [1]
High IL-17 receptor B (IL-17RB) expression was previously associated with poor prognosis in patients with breast cancer [12, 14], the prognostic value of Interleukin 17B (IL-17B) per se has never been investigated
overall survival (OS) (p = 0.016) and disease-free survival (DFS) (p = 0.029) were significantly reduced in patients with cancers in which both IL-17B and IL-17RB were overexpressed compared with patients with cancers where only one was upregulated or where both molecules were expressed at low level (Figure 1C)

Summary

Introduction

Tumor development is regulated by many different factors that influence cancer cell proliferation, cell death resistance and dissemination within the organism [1]. It is well established that inflammationassociated factors, such as chemokines and cytokines present within the tumor microenvironment, are crucial for modulating cancer progression and resistance to treatments [2]. The IL-17 family includes six members (IL-17A to IL-17F) with different homology and functions [3]. IL-17A and IL-17F are the closest members, with 50% homology. These cytokines exert their activities through binding to IL-17 receptor (IL-17R) family members (IL-17RA to IL17RE) that function as homo-or heterodimer complexes [4]. IL-17A has been detected in several human tumors, where it has been associated with protumorigenic effects, and with resistance to cancer therapies, by acting on cancer cells and on the tumor microenvironment [8, 9]

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