Abstract B233: The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target.

Abstract

Abstract Introduction. Treatment of patients with triple-negative breast cancers (TNBCs) remains a major challenge for oncologists. Although they respond well to the current therapeutic strategies based on conventional chemotherapies, they represent a large proportion of breast cancer death due to a high recurrence rate. Alternative treatments are needed to improve survival of these patients. The Wnt/beta-catenin signaling, recently reported to be activated in TNBCs, may represent an interesting pathway to target. Methods. We analyzed mRNA, DNA and protein levels for the LRP5 and LRP6 Wnt coreceptors in our cohort of breast tumor biopsy specimens. We then identified which TNBC cell lines display the most similarity to TNBC tumors regarding the Wnt pathway status using a centroid approach. We investigated the effects of modulating LRP5 or LRP6 expression on Wnt signaling, cell viability and apoptosis. We evaluated the potential therapeutic value of targeting LRP5 and LRP6 in TNBCs, by performing depletion experiments and treating cells with a mixture of doxorubicin/cyclophosphamide. We also examined whether the depletion of LRP5 or LRP6 had an impact on tumorigenicicy in vitro, in soft-agar assays, and in vivo, in xenograft models. Results. Gene expression analyses revealed that both LRP5 and LRP6 Wnt coreceptors were more strongly expressed in TNBCs than in other breast tumor subtypes. HCC38 and MDA-MB-468 TNBC cells were more similar to TNBC biopsy specimens in terms of Wnt pathway gene expression profiles than any other tested cell line. Unlike LRP5, LRP6 was involved in activating the canonical Wnt pathway in response to Wnt3a. LRP5 knockdown induced caspase-dependent apoptosis, whereas LRP6 knockdown had no such effect. LRP5-depleted cells were also more sensitive to conventional chemotherapy than cells depleted of LRP6. The knockdown of LRP5 or LRP6 decreased tumorigenesis both in vitro and in vivo. Conclusions. These data indicate that the LRP5 and LRP6 have different functions in TNBCs, with LRP5 playing a preponderant role in survival control. Our data suggest that both coreceptors are potential treatment targets in TNBCs, but that LRP5 may be the most useful target, given the impact of its depletion on cell survival and the response to anti-cancer drugs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B233. Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Némati, Aurélie Dumont, David Gentien, Bérengère Marty-Prouvost, Guillem Rigaill, Leanne De Koning, Anne Vincent-Salomon, Emmanuel Barillot, Didier Decaudin, Alain Pierré, Stéphane Depil, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B233.