ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

Avais M Daulat,Mônica Silveira Wagner,François Bertucci,Diego Revinski,Luc Camoin,Jean-Paul Borg,Pascal Finetti,Stéphane Audebert,Laurent Kodjabachian,Daniel Birnbaum

doi:10.1038/s41416-019-0448-z

Abstract

BackgroundTriple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment. We previously found that PRICKLE1, a prometastatic protein involved in planar cell polarity, is upregulated in TNBC. We investigated the protein complex associated with PRICKLE1 in TNBC to identify proteins possibly involved in metastatic dissemination, which might provide new prognostic and/or therapeutic targets.MethodsWe used a proteomic approach to identify protein complexes associated with PRICKLE1. The mRNA expression levels of the corresponding genes were assessed in 8982 patients with invasive primary breast cancer. We then characterised the molecular interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus were carried out to determine their evolutionarily conserved interaction.ResultsAmong the PRICKLE1 proteins network, we identified several small G-protein regulators. Combined analysis of the expression of PRICKLE1 and small G-protein regulators had a strong prognostic value in TNBC. Notably, the combined expression of ECT2 and PRICKLE1 provided a worst prognosis than PRICKLE1 expression alone in TNBC. PRICKLE1 regulated ECT2 activity and this interaction was evolutionary conserved.ConclusionsThis work supports the idea that an evolutionarily conserved signalling pathway required for embryogenesis and activated in cancer may represent a suitable therapeutic target.

Highlights

Triple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment
Prognostic value of PRICKLE1-interacting small G-protein regulators in TNBC Based on these proteomic data describing the protein complex associated to PRICKLE1, we focused our attention on the 10 regulators of small G-proteins (i.e. Rho-guanylyl exchange factor (GEF) and Rho-GAP) that were identified, including ARHGAP21, ARGHAP22, ARHGAP23, ARHGEF2, ARHGEF40, BCR, epithelial cell transforming sequence 2 (ECT2), IQGAP3, MYO9B, and STARD13
Cooperation between PRICKLE1 and ECT2 as poor-prognosis markers in TNBC We have previously shown that PRICKLE1 upregulation is associated with poor Metastasisfree survival (MFS) in basal breast cancer,[2] a molecular subtype mainly composed of TNBC

Summary

Introduction

Triple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment. Homologous genes are involved in the regulation of convergent-extension (CE) during the early stages of gastrulation which leads to the organisation of cells to generate the head-to-tail axis.[3,4] Prickle[1] plays a pivotal role to regulate PCP in Drosophila[5], as well as CE in Zebrafish[6] and Xenopus.[7] PRICKLE1 is an evolutionary conserved cytoplasmic protein It contains a PET domain at the N-terminus followed by three LIM domains and a Cterminal farnesylation site.[8] Recently, we and others have demonstrated the prominent role of PRICKLE1 during cancer progression.[2,9,10,11] PRICKLE1 is a prometastatic protein and regulates oriented cell migration in various cell lines including the MDA-MB-231 prototype TNBC cell line.[2,10] At the molecular level, PRICKLE1 regulates the subcellular localisation of associated proteins such as VANGL2,8,12 RICTOR,[2] ARHGAP22/24,10 and LL5β11 to coordinate oriented cellular migration

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Conclusion