By decreasing the abundance of the adhesion molecule E-cadherin, the microRNA miR-9 promotes the metastasis of breast carcinoma cells. Chen et al. (see also Piccolo) found that stable expression of miR-9 enabled SUM159 breast cancer cells, which are E-cadherin–negative and normally nonmetastatic, to metastasize in a xenograft tumor model. Gene expression profiling of miR-9–expressing SUM159 cells revealed reduced expression of the gene encoding leukemia inhibitory factor receptor (LIFR), which contained a miR-9–binding site in its 3′ UTR and showed decreased expression in various cancers, including breast cancer. E-cadherin and LIFR were more abundant in nonmetastatic tumor cell lines than in metastatic cell lines. Increasing the abundance of LIFR through ectopic expression in metastatic 4T1 or MDA-MB-231 cells attenuated metastasis of these cells when introduced into mice. Stimulation of the Hippo pathway results in the phosphorylation, nuclear exclusion, and inhibition of the transcriptional coactivator Yap, and LIF-treated 4T1 or MDA-MB-231 cells showed increased phosphorylation of Hippo pathway kinases (which indicates increased activity) and Yap (which indicates inhibition). The membrane-localized pool of the adaptor protein Scribble promotes signaling through the Hippo pathway by acting as a scaffold for Hippo pathway kinases and Yap, and membrane localization of Scribble was increased in 4T1 cells by expression of LIFR and decreased in SUM159 cells by expression of miR-9. Metastasis of SUM159 cells injected into mice was increased by expression of a short hairpin RNA (shRNA) directed against LIFR. The increased metastasis of LIFR shRNA-expressing SUM159 cells was attenuated by coexpression of an shRNA directed against Yap, an effect that was blocked by reexpression of a phosphorylation-deficient mutant of Yap but not wild-type Yap. In various human cancer data sets, LIFR abundance was lower in tumor tissue, including invasive breast cancer, than in normal tissue, and immunohistochemistry revealed that ductal carcinoma in situ and invasive breast carcinoma showed low abundance of LIFR compared with normal mammary tissue. Furthermore, lymph node metastasis in invasive breast cancer inversely correlated with the abundance of LIFR. Retrospective analysis indicated that decreased abundance of LIFR correlated with development of metastases to distant sites or lymph nodes, reduced recurrence, and poorer overall survival. Thus, in addition to its function in limiting cell proliferation and tissue growth, the Hippo pathway also inhibits metastasis, a role that is stimulated by LIFR and inhibited by miR-9.
D. Chen, Y. Sun, Y. Wei, P. Zhang, A. H. Rezaeian, J. Teruya-Feldstein, S. Gupta, H. Liang, H.-K. Lin, M.-C. Hung, L. Ma, LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat. Med. 18, 1511–1517 (2012). [PubMed]
S. Piccolo, LIF-ting Hippo averts metastasis. Nat. Med. 18, 1463–1465 (2012). [PubMed]