Acquired tamoxifen-resistance is an important cause of death in patients with hormone-dependent breast tumors. Therefore, understanding the molecular mechanisms underlying the development of tamoxifen-resistance is critical for successful endocrine therapy. This study aimed to define the role of WW domain-containing oxidoreductase (WWOX) in acquired tamoxifen-resistance. Our results show that low WWOX expression was significantly related to tamoxifen-resistance. Moreover, WWOX-knockdown increased resistance to tamoxifen, while WWOX overexpression decreased the resistance. Furthermore, WWOX silencing decreased Yes-associated protein (YAP) phosphorylation and increased YAP nuclear translocation. Finally, YAP silencing decreased tamoxifen-resistance in WWOX-knockdown cells. Our findings demonstrate that WWOX downregulation can lead to the development of tamoxifen-resistance by inactivating Hippo signaling. Thus, WWOX might be a valuable target and prognostic marker for tamoxifen-resistance.
Impact statement
Understanding the molecular pathways leading to the development of tamoxifen-resistance is an important research focus as acquired tamoxifen-resistance is the main cause of death in patients with benign primary prognosis. Although WW domain-containing oxidoreductase (WWOX) has been related to breast tumorigenesis, its role in acquired tamoxifen-resistance has not yet been demonstrated. Our findings show that WWOX might be a valuable therapeutic target and prognostic marker for tamoxifen-resistance.
LumachiFLuisettoGBassoSMBassoUBrunelloACamozziV.Endocrine therapy of breast cancer. Curr Med Chem2011;
18:513–22
2.
OrlandoLSchiavoneaPFedeleaPCalvaniaNNacciaARizzoaPMarinoaAD’AmicoaMSponzielloaFMazzoniECinefraaMFaziobNMaiellocESilvestrisdNColuccidGCinieriaS.Molecularly targeted endocrine therapies for breast cancer. Cancer Treat Rev2010;
36:S67–71
3.
Group* EBCTC.
Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet1998;
351:1451–67
4.
ShiauAKBarstadDLoriaPMChengLKushnerPJAgardDAGreeneGL.The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell1998;
95:927–37
AqeilanRITrapassoFHussainSCostineanSMarshallDPekarskyY.Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A2007;
104:3949–54
9.
LinJTTzaiTSLiaoCYWangJSWuTTWangHY.WWOX protein expression varies among RCC histotypes and downregulation of WWOX protein correlates with less-favorable prognosis in clear RCC. Ann Surg Oncol2013;
20:193–9
10.
NunezMIRosenDGLudes-MeyersJHAbbaMCKilHPageR.WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome. BMC Cancer2005;
5:1–10
11.
PaigeAJWZucknickMJanczarSPaulJMeinCATaylorKStewantMGourleyCRichardsonSPerrenTGaneasanTSSmythJFBrownRGabraH.WWOX tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis. Eur J Cancer2010;
46:818–25
12.
Ludes-MeyersJHKilHParker-ThornburgJKusewittDFBedfordMTAldazCM.Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One2009;
4:e7775
13.
Gothlin EremoAWegmanPWegmanPStalONordenskjoldBFornanderTWingrenS.Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncol Rep2013;
29:1467–74
14.
CoserKRWittnerBS.Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor. Proc Natl Acad Sci U S A2009;
106:14536–41
15.
LiangZLiWLiuP.Simvastatin suppresses DNA replication licensing factor MCM7 and inhibits growth of tamoxifen resistant breast cancer cells. Sci Rep2017;
7:41776–87
16.
MaGPanYZhouCLiuPRenYHeJ.Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells. Oncol Rep2015;
34:2423–30
17.
LiJLiuJ.Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion. J Exp Clin Cancer Res2014;
33:70–83
18.
TouilYIgoudjilWCorvaisierMDesseinAFVandommeJMonteDStechlyLSkrypekNLangloisCGrardG.Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis. Clin Cancer Res2014;
20:837–46
19.
SalahZAqeilanRI.WW domain interactions regulate the Hippo tumor suppressor pathway. Cell Death Dis2011;
2:e172
20.
WangDYWuYNHuangJQWangWXuMJiaJPHanGMaoBBBiWZ.Hippo/YAP signaling pathway is involved in osteosarcoma chemoresistance. Chin J Cancer2016;
35:47
21.
SudolMHarveyKF.Modularity in the Hippo signaling pathway. Trends Biochem Sci2010;
35:627–33
22.
ZhaoBTumanengKGuanKL.The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol2011;
13:877–83
23.
AqeilanRIDonatiVGaudioENicolosoMSSundvallMKorhonenALundinJIsolaJSudolMJoensuuH.Association of Wwox with ErbB4 in breast cancer. Cancer Res2007;
67:9330–6
24.
AqeilanRIPalamarchukAWeigelRJHerreroJJPekarskyYCroceCM.Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer Res2004;
64:8256–61
25.
AqeilanRIPekarskyYHerreroJJPalamarchukALetofskyJDruckTTrapassoFHanSYMelinoGHuebnerKCroceCM.Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci U S A2004;
101:4401–6
26.
GaudioEPalamarchukAPalumboTTrapassoFPekarskyYCroceCMAqeilanRI.Physical association with WWOX suppresses c-Jun transcriptional activity. Cancer Res2006;
66:11585–9
27.
AqeilanRIDonatiVPalamarchukATrapassoFKaouMPekarskyYSudolMCroceCM.WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res2005;
65:6764–72
28.
NunezMILudes-MeyersJAladzCM.WWOX protein expression in normal human tissues. J Mol Histol2006;
37:115–25
29.
GulerGUnerAGulerNHanSYLliopoulosDMcCuePHuebnerK.Concordant loss of fragile gene expression early in breast cancer development. Pathol Int2005;
55:471–8
30.
EkizogluSMuslumanogluMDalayNBuyruN.Genetic alterations of the WWOX gene in breast cancer. Med Oncol2012;
29:1529–35
31.
WangXChaoLMaGChenLZangYSunJ.The prognostic significance of WWOX expression in patients with breast cancer and its association with the basal-like phenotype. J Cancer Res Clin Oncol2011;
137:271–8
32.
PluciennikEKusinskaRPotemskiPKubiakRKordekRBednarekAK.WWOX – the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis. Eur J Surg Oncol2006;
32:153–7
33.
FergusonBWGaoXKilHLeeJBenavidesFAbbaMCAldazCM.Conditional Wwox deletion in mouse mammary gland by means of two CRE recombinase approaches. PLoS One2012;
7:e36618
34.
SalahZAqeilanRHuebnerK.WWOX gene and gene product: tumor suppression through specific protein interactions. Future Oncol2010;
6:249–59
35.
GulerGUnerAGulerNHanSYLliopoulosDHauckWWMcCuePHuebnerK.The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Cancer2004;
100:1605–14
36.
GulerGIliopoulosDGulerNHimmetogluCHayranMHuebnerK.Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res2007;
13:6115–21
37.
LaiDHoKCHaoYYangX.Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res2011;
71:2728–38
38.
ChangJYHeRYLinHPHsuLJLaiFJHongQChenSJChangNS.Signaling from membrane receptors to tumor suppressor WW domain-containing oxidoreductase. Exp Biol Med2010;
235:796–804
39.
PlouffeSWHongAWGuanKL.Disease implications of the Hippo/YAP pathway. Trends Mol Med2015;
21:212–22
40.
ZhaoBLiLTumanengKWangCYGuanKL.A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev2010;
24:72–85
41.
LiuCYZhaZYZhouXZhangHHuangWZhaoDLiTChanSWLimCJHongWZhaoSXiongYLeiQYGuanKL.The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem2010;
285:37159–69
42.
WuSLiuYZhengYDongJPanD.The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell2008;
14:388–98
43.
LehnSTobinNPSimsAHStålOJirströmKAxelsonHLandbergG.Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response. BMC Cancer2014;
14:119–35
44.
MurphyLOBlenisJ.MAPK signal specificity: the right place at the right time. Trends Biochem Sci2006;
31:268–75
45.
XuYLiN.Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem Sci2014;
39:268–76
46.
HuangDLiX.Regulation of Hippo signalling by p38 signalling. J Mol Cell Biol2016;
8:328–37
47.
MuranenTLauraM.ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP. Cancer Res2016;
76:7168–80
48.
SunGIrvineKD.Ajuba family proteins link JNK to Hippo signaling. Sci Signal2014;
6:1–18
49.
SaitoANagaseT.Hippo and TGF-β interplay in the lung field. Am J Physiol Lung Cell Mol Physiol2015;
309:756–67
50.
GrannasKArngårdenL.Crosstalk between Hippo and TGFβ: subcellular localization of YAP/TAZ/Smad complexes. J Mol Biol2015;
427:3407–15
51.
ElshaerNPiulachsMD.Crosstalk of EGFR signalling with Notch and Hippo pathways to regulate cell specification, migration and proliferation in cockroach panoistic ovaries. Biol Cell2015;
107:273–85
52.
ZhaoKWangQ.EGFR/c-myc axis regulates TGFβ/Hippo/Notch pathway via epigenetic silencing miR-524 in gliomas. Cancer Lett2017;
406:12–21
