Abstract
LIFR suppresses breast cancer metastasis, and its loss correlates with poor prognosis.
Major finding: LIFR suppresses breast cancer metastasis, and its loss correlates with poor prognosis.
Mechanism: LIFR triggers a Hippo kinase cascade to inactivate YAP, and is suppressed by miR-9 in tumors.
Impact: Loss of LIFR expression may identify patients at a higher risk of developing metastases.
Several microRNAs (miRNA) have been implicated as metastasis promoters, including miR-9, which functions in part by downregulating E-cadherin. To characterize other miR-9–regulated genes that may regulate metastasis, Chen and colleagues used high-throughput RNA sequencing to identify leukemia inhibitory factor receptor (LIFR) as a direct miR-9 target that is downregulated in human breast cancer samples. LIFR expression was absent in metastatic breast cancer cell lines, and LIFR depletion in nonmetastatic cells enhanced cell migration and promoted metastatic foci formation in vivo, similar to the effects of miR-9 overexpression. In contrast, LIFR overexpression in metastatic breast cancer cells significantly impaired both cancer cell invasion and metastatic colonization in the lung, suggesting that LIFR suppresses both early and late steps of metastasis. LIFR enhanced the phosphorylation of the transcriptional coactivator YES-associated protein 1 (YAP), which prevented YAP nuclear translocation and decreased the expression of its target genes, particularly connective tissue growth factor (CTGF), which has been implicated in breast cancer metastasis. This inhibition of YAP activity was mediated by activation of a Hippo kinase cascade, as LIFR overexpression resulted in elevated phosphorylation of upstream kinases responsible for YAP inactivation and enrichment of the large tumor suppressor, homolog (LATS) adaptor protein Scribble at the plasma membrane. In addition, silencing of YAP reversed the prometastatic phenotype of LIFR-depleted cells, whereas expression of CTGF or a nonphosphorylatable YAP mutant in LIFR-expressing cells abolished metastasis suppression, further indicating that the antimetastatic activity of LIFR is dependent on modulation of Hippo signaling. Moreover, loss of LIFR expression was correlated with an increased risk of breast cancer metastasis and decreased survival in a large cohort of patients. These findings define LIFR as a critical metastasis suppressor and support its use as a prognostic marker in breast cancer.
