Abstract B43: A novel breast cancer metastasis suppressor upstream of Hippo signaling

Abstract

Abstract There is a pressing need to identify prognostic markers of metastatic diseases and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies, and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the miR-9 microRNA and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention, and functional inactivation of the transcriptional co-activator YAP. Conversely, loss of LIFR in non-metastatic breast cancer cells induces migration, invasion, and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, loss of LIFR in non-metastatic Stage I-III breast tumors is highly associated with poor metastasis-free, recurrence-free and overall survival outcomes in approximately 1,000 patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power. As the next step, we will dissect the role of LIFR in spontaneous breast tumorigenesis and metastasis using genetically engineered mouse models, elucidate the mechanisms by which LIFR activates Hippo signaling using biochemical approaches, and develop methods to restore LIFR expression or function as new anti-metastatic therapeutic strategies. Citation Format: Li Ma. A novel breast cancer metastasis suppressor upstream of Hippo signaling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B43.