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LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker

Abstract

There is a pressing need to identify prognostic markers of metastatic disease 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 microRNA miR-9 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 coactivator YES-associated protein (YAP). Conversely, loss of LIFR in nonmetastatic 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, in approximately 1,000 nonmetastatic breast tumors, LIFR expression status correlated with metastasis-free, recurrence-free and overall survival outcomes in the patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power.

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Figure 1: LIFR is a target of miR-9 and mediates its effect on migration, invasion and metastasis.
Figure 2: Restoring LIFR expression in highly malignant breast cancer cells suppresses metastasis.
Figure 3: LIFR activates Hippo signaling and leads to phosphorylation and functional inactivation of YAP in breast cancer cells.
Figure 4: Inhibition of YAP and CTGF mediates the metastasis-suppressing effect of LIFR.
Figure 5: LIFR is downregulated in human breast cancer and correlates with clinical outcomes.

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Acknowledgements

We are grateful to R.A. Weinberg for his advice and reagents. We thank S. Ethier for providing cell lines; F. Reinhardt for advice on mouse surgery; the Genome Technology Core at the Whitehead Institute, the ShRNA and ORFeome Core at MD Anderson Cancer Center and the Histology Core Laboratories at MD Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center for technical assistance; and members of the Ma Lab for discussion. We thank J. Chen, K. Muller, W. Pagel, K. Keyomarsi, L. Li and R. Cleveland for critical reading of the manuscript. This work is supported by the US National Institutes of Health grants R00CA138572 (to L.M.), R01CA166051 (to L.M.), R01CA109311 (to M.-C.H.) and P01CA099031 (to M.-C.H.), a Cancer Prevention and Research Institute of Texas Scholar Award R1004 (to L.M.), a University of Texas STARS Award (to L.M.), a Faculty Development Award (to L.M.) from the MD Anderson Cancer Center Support grant CA016672 from the US National Institutes of Health, Center for Biological Pathways (to Y.S. and M.-C.H.), a Susan G. Komen for the Cure grant SAC110016 (to M.-C.H.), the National Breast Cancer Foundation, Inc. and the Sister Institution Fund of China Medical University and Hospital and MD Anderson Cancer Center (to M.-C.H.).

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Contributions

L.M. conceived of and supervised the project. D.C. and L.M. designed, performed and analyzed most of the experiments. Y.S. maintained shRNA and open reading frame (ORF) libraries, constructed RNA-Seq libraries and analyzed RNA-Seq data. Y.W. and M.-C.H. performed studies on tissue microarrays of human patient samples. P.Z. performed some biochemical work. A.H.R. and H.-K.L. performed tail vein injection experiments. J.T.-F. performed histopathological analysis. S.G. processed the raw data from the Solexa sequencer. H.L. performed TCGA data analysis. L.M. wrote the manuscript with input from all other authors.

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Correspondence to Li Ma.

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Chen, D., Sun, Y., Wei, Y. et al. LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med 18, 1511–1517 (2012). https://doi.org/10.1038/nm.2940

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