Abstract 4373: LRP5: a potential therapeutic target in triple-negative breast cancer.

Abstract

Abstract Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, only partial response to chemotherapy and lack of clinically established targeted therapies [1]. A deregulation of the Wnt signaling pathway has been described in breast cancers, particularly in TNBC [2–6]. Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) serve as Wnt co-receptors for the canonical beta-catenin pathway. An overexpression of LRP6 has been reported to enhance Wnt signaling favoring in vitro cell proliferation and in vivo mammary gland hyperplasia and tumor growth [5,7,8]. LRP6 has been claimed to be a potential TNBC therapeutic target [5]. Material and Methods: RNA microarray analysis and reverse phase protein array were performed on 154 samples including biopsies of the various subclasses of breast cancer. MDA-MB-468 and HCC38 cell lines were defined as the most representative in vitro models of the Wnt pathway status found in TNBC biopsies. In order to study the functions of LRP5 or LRP6 in TNBC, we examined in these cell lines the effects of their depletions using RNAi technology on tumorigenesis and on the Wnt3a-induced signaling pathway. Results: Our transcriptomic and proteomic data revealed that both LRP5 and LRP6 are overexpressed in TNBC compared to the other breast cancer subtypes i.e. HER2+/ER-, luminal A and luminal B. Our in vitro studies indicated that the transcriptional activity of beta-catenin/Tcf was strongly reduced when LRP6 was silenced and to a lesser extend when LRP5 was depleted. In accordance with these results, the expression of AXIN2 and other newly identified Wnt target genes, was mainly down-regulated in cells silenced for LRP6. LRP5 and LRP6 knockdown impaired colony formation in soft agar and weakly decreased the number of mammospheres. The inhibition of cell viability observed after LRP5 depletion was the consequence of a programmed cell death as revealed by the increase of annexin V-positive cells, the activation of initiator and effector caspases (8,9,3/7) and the cleavage of poly(ADP-ribose) polymerase. On the contrary, LRP6 depletion inhibited cell viability without promoting apoptosis as reported by others [5]. Conclusions: Altogether our data demonstrate that in TNBC cell lines, LRP5 or LRP6 silencing has an impact on Wnt signaling, cancer stem cell-like activity, tumorigenic properties and cell viability. Most importantly, LRP5 silencing promotes apoptosis, suggesting that LRP5 could represent a promising therapeutic candidate to target in TNBC. Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, David Gentien, Bérengère Marty-Prouvost, Francisco Cruzalegui, Stéphane Depil, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. LRP5: a potential therapeutic target in triple-negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4373. doi:10.1158/1538-7445.AM2013-4373