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YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer

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Abstract

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.

Background

Hippo signalling is a tumour suppressor cascade highly conserved from yeast to man [1]. In mammals, Hippo signalling is deregulated in various cancers; hence, mammalian Hippo signalling has gained much attention over the past years [2]. 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 [3].

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 [69], 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 [12] 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 [13].

The articles

To uncover novel factors involved in the initiation/progression of tumours, Lippman and colleagues [12] 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 [12], suggesting that LIFR is a clinically important breast tumour suppressor. However, Iorns and colleagues [12] 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 [13]. In full agreement with Iorns and colleagues [12], they also found that LIFR is downregulated in breast cancer [13], but controversially reported that LIFR silencing did not affect primary tumour growth [13]. However, over-expression of LIFR in metastatic breast cancer cell lines dramatically reduced metastases formation [13]. Furthermore, Ma and colleagues investigated the mechanisms downstream of LIFR. Based on a recent report [14] 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 [14], addition of LIF resulted in increased YAP phosphorylation in breast cancer cell lines, thereby resulting in the inactivation of YAP [13]. Since phosphorylation of MST/LATS was increased upon LIFR overexpression [13], 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 [13], an adaptor that can link MST/LATS/YAP/TAZ complexes [11].

The viewpoint

Two recent reports highlight LIFR as a novel player in breast cancer. The work by Iorns and colleagues [12] defines LIFR as a breast tumour suppressor, while Ma and co-workers [13] define LIFR as a breast cancer metastasis suppressor. Current evidence strongly suggests that LIFR functions by inhibiting YAP [13]. This novel role for YAP in breast cancer metastasis is supported by a recent paper from the Hynes laboratory [15], 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 [13]. 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 [16], 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 [17] is controlled by LIFR. However, Iorns and colleagues identified TAZ (WWTR1) as a potential breast tumour suppressor in their screen [12]. At first glance, these observations do not seem to make sense, but as already speculated for YAP [4, 69], 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 [18]. 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.

Abbreviations

LIF:

leukemia inhibitory factor

LIFR:

leukemia inhibitory factor receptor.

References

  1. 1.

    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.

  2. 2.

    Pan D: The hippo signaling pathway in development and cancer. Dev Cell. 2010, 19: 491-505. 10.1016/j.devcel.2010.09.011.

  3. 3.

    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.

  4. 4.

    Hergovich A, Hemmings BA: Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling. Biofactors. 2009, 35: 338-345. 10.1002/biof.47.

  5. 5.

    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.

  6. 6.

    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.

  7. 7.

    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.

  8. 8.

    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.

  9. 9.

    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.

  10. 10.

    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.

  11. 11.

    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.

  12. 12.

    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.

  13. 13.

    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.

  14. 14.

    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.

  15. 15.

    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.

  16. 16.

    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.

  17. 17.

    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]

  18. 18.

    Rowland BD, Peeper DS: KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 2006, 6: 11-23. 10.1038/nrc1780.

  19. 19.

    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.

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Acknowledgements

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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Correspondence to Alexander Hergovich.

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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) doi:10.1186/bcr3349

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Keywords

  • Breast Cancer
  • Breast Cancer Subtype
  • Breast Cancer Metastasis
  • Hippo Pathway
  • Hippo Signalling