YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer
Breast Cancer Research volume 14, Article number: 326 (2012)
The proto-oncogenes YAP and TAZ have previously gained much attention as downstream effectors of Hippo tumour suppressor signalling. While the regulation of YAP/TAZ by MST/LATS kinases is reasonably well understood, the nature of factors functioning upstream of MST/LATS is yet to be elucidated in detail. A recent paper by Ma and co-workers defines a novel role for leukemia inhibitory factor receptor (LIFR) signalling upstream of the Hippo-YAP pathway in breast cancer metastasis. Moreover, a whole genome in vivo RNA interference screen by Lippmann and colleagues identified LIFR as a breast tumour suppressor. Here, we discuss the implications of these studies for breast cancer research and treatment.
Hippo signalling is a tumour suppressor cascade highly conserved from yeast to man . In mammals, Hippo signalling is deregulated in various cancers; hence, mammalian Hippo signalling has gained much attention over the past years . In a nutshell, the canonical Hippo pathway functions as follows: activated MST1/2 kinases (mammalian Ste20-like serine/threonine kinase 1/2) phosphorylate hMOB1 (human Mps one binder 1) and LATS1/2 (large tumour suppressor serine/threonine kinase 1/2), resulting in the formation of an active hMOB1-LATS complex that phosphorylates the protooncogenes YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), which finally leads to the accumulation of inactive cytoplasmic YAP/TAZ .
YAP is overexpressed in various human cancers [4, 5], supporting a role for it as a proto-oncogene. In breast cancer, however, gain or loss of YAP expression has been reported [6–9], suggesting that YAP might have oncogenic and tumour suppressive functions dependent on the breast cancer subtype. TAZ is overexpressed in breast cancer [10, 11], but a recent report  suggests also a tumour suppressive role for TAZ. Therefore, the roles of YAP/TAZ-Hippo signalling in breast cancer are debatable. Considering that metastases at distant sites, and not the primary breast tumour, are the main cause of death, we must further consider YAP/TAZ functions in metastasis, as highlighted by a recent report by Ma and colleagues .
To uncover novel factors involved in the initiation/progression of tumours, Lippman and colleagues  screened in vivo the entire human genome by RNA interference, thereby identifying LIFR as a novel tumour suppressor. Silencing of LIFR was sufficient to transform normal mammary cells, and reciprocally, LIFR over-expression in breast cancer cells suppressed tumour growth , suggesting that LIFR is a clinically important breast tumour suppressor. However, Iorns and colleagues  did not define how LIFR functions as a tumour suppressor.
In parallel, Ma and co-workers discovered a role for LIFR as a novel breast cancer metastasis suppressor . In full agreement with Iorns and colleagues , they also found that LIFR is downregulated in breast cancer , but controversially reported that LIFR silencing did not affect primary tumour growth . However, over-expression of LIFR in metastatic breast cancer cell lines dramatically reduced metastases formation . Furthermore, Ma and colleagues investigated the mechanisms downstream of LIFR. Based on a recent report  linking LIF (the ligand for LIFR) to the regulation of YAP, they examined the role of LIFR in YAP-Hippo signalling. Unlike in embryonic stem cells , addition of LIF resulted in increased YAP phosphorylation in breast cancer cell lines, thereby resulting in the inactivation of YAP . Since phosphorylation of MST/LATS was increased upon LIFR overexpression , it is possible that the effect on YAP is driven by canonical Hippo signalling. Moreover, they provided evidence suggesting that LIFR signals to MST/LATS via Scribble , an adaptor that can link MST/LATS/YAP/TAZ complexes .
Two recent reports highlight LIFR as a novel player in breast cancer. The work by Iorns and colleagues  defines LIFR as a breast tumour suppressor, while Ma and co-workers  define LIFR as a breast cancer metastasis suppressor. Current evidence strongly suggests that LIFR functions by inhibiting YAP . This novel role for YAP in breast cancer metastasis is supported by a recent paper from the Hynes laboratory , but the involvement of canonical Hippo signalling is not so evident. They show that LIFR overexpression correlates with increased LATS1 phosphorylation, while YAP(S112A) drives metastases despite LIFR overexpression . This suggests that LIFR triggers YAP phosphorylation by activating LATS1. However, given that YAP phosphorylation appears to be independent of LATS1/2 in other cancer settings , it will be important to confirm the identity of the kinase(s) targeting YAP in these settings before we can make final conclusions.
Considering that TAZ-Hippo signalling is already implicated in breast cancer [10, 11], it is likely that LIFR also functions upstream of TAZ. In particular, it will be interesting to determine whether the recently reported role for TAZ in breast cancer metastasis  is controlled by LIFR. However, Iorns and colleagues identified TAZ (WWTR1) as a potential breast tumour suppressor in their screen . At first glance, these observations do not seem to make sense, but as already speculated for YAP [4, 6–9], TAZ might have oncogenic and tumour suppressive functions dependent on the breast cancer subtype or progression stage, a phenomenon already reported for other factors in different cancer types . Since increased YAP/TAZ levels correlate with taxol resistance [7, 19], YAP/TAZ have been considered as targets/biomarkers in breast cancer. Based on the work by the Ma and Lippman laboratories [12, 13], however, LIFR activation appears to be the more attractive clinical target for the treatment of breast cancer, since the roles of YAP/TAZ-Hippo signalling in breast cancer subtypes are yet to be defined in more detail.
leukemia inhibitory factor
leukemia inhibitory factor receptor.
Hergovich A, Stegert MR, Schmitz D, Hemmings BA: NDR kinases regulate essential cell processes from yeast to humans. Nat Rev Mol Cell Biol. 2006, 7: 253-264. 10.1038/nrm1891.
Pan D: The hippo signaling pathway in development and cancer. Dev Cell. 2010, 19: 491-505. 10.1016/j.devcel.2010.09.011.
Zhao B, Tumaneng K, Guan KL: The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011, 13: 877-883. 10.1038/ncb2303.
Hergovich A, Hemmings BA: Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling. Biofactors. 2009, 35: 338-345. 10.1002/biof.47.
Hong W, Guan KL: The YAP and TAZ transcription co-activators: Key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012, 23: 785-793. 10.1016/j.semcdb.2012.05.004.
Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, O'Neill E: RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell. 2007, 27: 962-975. 10.1016/j.molcel.2007.08.008.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA: Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006, 103: 12405-12410. 10.1073/pnas.0605579103.
Wang X, Su L, Ou Q: Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer. Eur J Cancer. 2012, 48: 1227-1234. 10.1016/j.ejca.2011.10.001.
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S: Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008, 15: 1752-1759. 10.1038/cdd.2008.108.
Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W, Zeng Q, Hong W: A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 2008, 68: 2592-2598. 10.1158/0008-5472.CAN-07-2696.
Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S: The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011, 147: 759-772. 10.1016/j.cell.2011.09.048.
Iorns E, Ward TM, Dean S, Jegg A, Thomas D, Murugaesu N, Sims D, Mitsopoulos C, Fenwick K, Kozarewa I, Naceur-Lombarelli C, Zvelebil M, Isacke CM, Lord CJ, Ashworth A, Hnatyszyn HJ, Pegram M, Lippman M: Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor. Breast Cancer Res Treat. 2012, 135: 79-91. 10.1007/s10549-012-2068-7.
Chen D, Sun Y, Wei Y, Zhang P, Rezaeian AH, Teruya-Feldstein J, Gupta S, Liang H, Lin HK, Hung MC, Ma L: LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med. 2012, 18: 1511-1517. 10.1038/nm.2940.
Tamm C, Bower N, Anneren C: Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF. J Cell Sci. 2011, 124: 1136-1144. 10.1242/jcs.075796.
Lamar JM, Stern P, Liu H, Schindler JW, Jiang ZG, Hynes RO: The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc Natl Acad Sci USA. 2012, 109: E2441-2450. 10.1073/pnas.1212021109.
Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, Bardeesy N: Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009, 16: 425-438. 10.1016/j.ccr.2009.09.026.
Matteucci E, Maroni P, Luzzati A, Perrucchini G, Bendinelli P, Desiderio MA: Bone metastatic process of breast cancer involves methylation state affecting E-cadherin expression through TAZ and WWOX nuclear effectors. Eur J Cancer. 2012, [Epub ahead of print]
Rowland BD, Peeper DS: KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 2006, 6: 11-23. 10.1038/nrc1780.
Lai D, Ho KC, Hao Y, Yang X: Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res. 2011, 71: 2728-2738. 10.1158/0008-5472.CAN-10-2711.
We thank J Lisztwan and C Gewinner for their feedback on this manuscript. This work was supported by the Wellcome Trust grant 090090/Z/09/Z.
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Hergovich, A. YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer. Breast Cancer Res 14, 326 (2012). https://doi.org/10.1186/bcr3349
- Breast Cancer
- Breast Cancer Subtype
- Breast Cancer Metastasis
- Hippo Pathway
- Hippo Signalling