Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.
High intracellular expression of death receptor TRAIL-R2 correlates with poor prognosis for different tumor entities and thus suggests tumor-promoting activity of intracellular TRAIL-R2. We demonstrate that TRAIL-R2 interacts with the core Microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45 and NF90 in the nucleus. Knockdown of TRAIL-R2 enhances Drosha-mediated processing of pri-let-7 resulting in increased levels of mature let-7, reduced expression of let-7-targets Lin28B and HMGA2 and inhibition of cell proliferation. In contrast, high abundance of nuclear TRAIL-R2, often detected in pancreatic cancer, correlates with enhanced expression of HMGA2 and dictates worse prognosis. Importantly, knockdown of TRAIL-R2 inhibits pancreatic tumor growth in an orthotopic xenotransplantation mouse model and reduced nuclear levels of TRAIL-R2 accompany differentiation of pancreatic epithelial cells in vitro. In conclusion, we define a novel function of nuclear TRAIL death receptor contributing to malignancy by inhibition of let-7-maturation (Haselmann et al., Gastroenterology epub ahead of print). In extension to our work on pancreatic cancer we further show nuclear TRAIL-R2 functions to be of relevance in breast cancer bone metastasis. Stably shRNA- transfected clones of MDAMB231 cells revealed metastatic lesions in only 2/12 mice upon TRAIL-R2 knock-down, whereas TRAIL-R1 and control knock-down clones exhibited multiple metastases throughout the groups of 12 mice each. Under in vitro conditions some decreased apoptosis rate was observed in both TRAIL-R knock-down clonal populations compared to the controls upon TRAIL treatment. Preliminary results suggest Mesenchymal-Epithelial-Transition (as indicated by increased E-Cadherin expression in TRAIL-R2 knock-down cells) as a mechanism for reduced metastasis. In summary, we show nuclear death receptor TRAIL-R2 to significantly contribute to malignant progression in two different pre-clinical tumor models. Thus, targeted intervention to prevent nuclear localization may serve as a novel therapeutic strategy. Supported by DFG (TR 1063/2-1 and TR 1063/3-1 - SKELMET FOR 1586). Citation Format: Holger Kalthoff, Verena Haselmann, Alexandra Kurz, Uwe Bertsch, Sebastian Huebner, Hendrik Fritsche, Charlotte Hauser, Christian Schem, Rob Tower, Thorsten Heilmann, Sanjay Tiwari, Claus C. Glüer, Anna Trauzold. Trail-R2: A death receptor turns malignant upon nuclear localization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2955. doi:10.1158/1538-7445.AM2014-2955
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.