메뉴 건너뛰기




Volumn 1843, Issue 4, 2014, Pages 815-826

Microenvironmental stimuli affect Endothelin-1 signaling responsible for invasiveness and osteomimicry of bone metastasis from breast cancer

Author keywords

Bone metastasis; Endothelin 1 axis; Growth factors; Microenvironment; Osteomimicry

Indexed keywords

BONE METASTASIS; ENDOTHELIN-1 AXIS; GROWTH FACTORS; MICROENVIRONMENT; OSTEOMIMICRY;

EID: 84893758552     PISSN: 01674889     EISSN: 18792596     Source Type: Journal    
DOI: 10.1016/j.bbamcr.2013.12.015     Document Type: Article
Times cited : (31)

References (58)
  • 1
    • 36348941863 scopus 로고    scopus 로고
    • Bone metastasis: pathogenesis and therapeutic implication
    • Clezardin P., Teti A. Bone metastasis: pathogenesis and therapeutic implication. Clin. Exp. Metastasis 2007, 24:599-608.
    • (2007) Clin. Exp. Metastasis , vol.24 , pp. 599-608
    • Clezardin, P.1    Teti, A.2
  • 2
    • 84867574271 scopus 로고    scopus 로고
    • Permissive role of Endothelin receptors in tumor metastasis
    • Said N., Theodorescu D. Permissive role of Endothelin receptors in tumor metastasis. Life Sci. 2012, 91:522-527.
    • (2012) Life Sci. , vol.91 , pp. 522-527
    • Said, N.1    Theodorescu, D.2
  • 3
    • 0942279599 scopus 로고    scopus 로고
    • Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB231 human breast cancer cells
    • Adwan H., Bäuerle T.J., Berger M.R. Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB231 human breast cancer cells. Cancer Gene Ther. 2004, 11:109-120.
    • (2004) Cancer Gene Ther. , vol.11 , pp. 109-120
    • Adwan, H.1    Bäuerle, T.J.2    Berger, M.R.3
  • 5
    • 84864245984 scopus 로고    scopus 로고
    • Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment
    • Cox R.F., Jenkinson A., Pohl K., O'Brien F.J., Morgan M.P. Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment. PLoS One 2012, 7:e41679.
    • (2012) PLoS One , vol.7
    • Cox, R.F.1    Jenkinson, A.2    Pohl, K.3    O'Brien, F.J.4    Morgan, M.P.5
  • 7
    • 84867999300 scopus 로고    scopus 로고
    • Growth factor signaling in metastasis: current understanding and future opportunities
    • Lowery F.J., Yu D. Growth factor signaling in metastasis: current understanding and future opportunities. Cancer Metastasis Rev. 2012, 31:479-491.
    • (2012) Cancer Metastasis Rev. , vol.31 , pp. 479-491
    • Lowery, F.J.1    Yu, D.2
  • 8
    • 84864708409 scopus 로고    scopus 로고
    • The tumor microenvironment
    • Weber C.E., Kuo P.C. The tumor microenvironment. Surg. Oncol. 2012, 21:172-177.
    • (2012) Surg. Oncol. , vol.21 , pp. 172-177
    • Weber, C.E.1    Kuo, P.C.2
  • 9
    • 84871425210 scopus 로고    scopus 로고
    • Bone metastatic process of breast cancer involves methylation state affecting E-cadherin expression through TAZ and WWOX nuclear effectors
    • Matteucci E., Maroni P., Luzzati A., Perrucchini G., Bendinelli P., Desiderio M.A. Bone metastatic process of breast cancer involves methylation state affecting E-cadherin expression through TAZ and WWOX nuclear effectors. Eur. J. Cancer 2013, 49:231-244.
    • (2013) Eur. J. Cancer , vol.49 , pp. 231-244
    • Matteucci, E.1    Maroni, P.2    Luzzati, A.3    Perrucchini, G.4    Bendinelli, P.5    Desiderio, M.A.6
  • 13
    • 77952581424 scopus 로고    scopus 로고
    • Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways
    • Previdi S., Maroni P., Matteucci E., Broggini M., Bendinelli P., Desiderio M.A. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways. Eur. J. Cancer 2010, 46:1679-1691.
    • (2010) Eur. J. Cancer , vol.46 , pp. 1679-1691
    • Previdi, S.1    Maroni, P.2    Matteucci, E.3    Broggini, M.4    Bendinelli, P.5    Desiderio, M.A.6
  • 14
    • 84906898054 scopus 로고    scopus 로고
    • Osteolytic bone metastasis is hampered by oppositely impinging on autophagy/anoikis and ossification biological processes
    • Maroni P., Bendinelli P., Matteucci E., Locatelli A., Nakamura T., Scita G., Desiderio M.A. Osteolytic bone metastasis is hampered by oppositely impinging on autophagy/anoikis and ossification biological processes. Cell Death Dis. 2013, 10.1038/cddis.2013.465.
    • (2013) Cell Death Dis.
    • Maroni, P.1    Bendinelli, P.2    Matteucci, E.3    Locatelli, A.4    Nakamura, T.5    Scita, G.6    Desiderio, M.A.7
  • 15
    • 0038801663 scopus 로고    scopus 로고
    • Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-β-mediated induction of endothelin-1 expression
    • Rodríguez-Pascual F., Redondo-Horcajo M., Lamas S. Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-β-mediated induction of endothelin-1 expression. Circ. Res. 2003, 92:1288-1295.
    • (2003) Circ. Res. , vol.92 , pp. 1288-1295
    • Rodríguez-Pascual, F.1    Redondo-Horcajo, M.2    Lamas, S.3
  • 16
    • 33644545381 scopus 로고    scopus 로고
    • Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy
    • Overall C.M., Kleifeld O. Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 2006, 6:227-239.
    • (2006) Nat. Rev. Cancer , vol.6 , pp. 227-239
    • Overall, C.M.1    Kleifeld, O.2
  • 19
    • 63049104211 scopus 로고    scopus 로고
    • Microenvironmental regulation of metastasis
    • Joyce J.A., Pollard J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9:239-252.
    • (2009) Nat. Rev. Cancer , vol.9 , pp. 239-252
    • Joyce, J.A.1    Pollard, J.W.2
  • 20
    • 80051792139 scopus 로고    scopus 로고
    • Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma
    • Maroni P., Matteucci E., Luzzati A., Perrucchini G., Bendinelli P., Desiderio M.A. Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma. Breast Cancer Res. Treat. 2011, 129:433-450.
    • (2011) Breast Cancer Res. Treat. , vol.129 , pp. 433-450
    • Maroni, P.1    Matteucci, E.2    Luzzati, A.3    Perrucchini, G.4    Bendinelli, P.5    Desiderio, M.A.6
  • 21
    • 65349132693 scopus 로고    scopus 로고
    • EMT, the cytoskeleton, and cancer cell invasion
    • Yilmaz M., Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009, 28:15-33.
    • (2009) Cancer Metastasis Rev. , vol.28 , pp. 15-33
    • Yilmaz, M.1    Christofori, G.2
  • 22
    • 84887314092 scopus 로고    scopus 로고
    • Role of hypoxia-inducible factors in breast cancer metastasis
    • Gilkes D.M., Semenza G.L. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol. 2013, 9:1623-1636.
    • (2013) Future Oncol. , vol.9 , pp. 1623-1636
    • Gilkes, D.M.1    Semenza, G.L.2
  • 23
    • 84879298347 scopus 로고    scopus 로고
    • Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer
    • Bendinelli P., Maroni P., Matteucci E., Luzzati A., Perrucchini G., Desiderio M.A. Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer. Eur. J. Cancer 2013, 49:2608-2618.
    • (2013) Eur. J. Cancer , vol.49 , pp. 2608-2618
    • Bendinelli, P.1    Maroni, P.2    Matteucci, E.3    Luzzati, A.4    Perrucchini, G.5    Desiderio, M.A.6
  • 25
    • 84883153220 scopus 로고    scopus 로고
    • Endothelin 1 in cancer: biological implications and therapeutic opportunities
    • Rosanò L., Spinella F., Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 2013, 13:637-651.
    • (2013) Nat. Rev. Cancer , vol.13 , pp. 637-651
    • Rosanò, L.1    Spinella, F.2    Bagnato, A.3
  • 26
    • 1942471854 scopus 로고    scopus 로고
    • Angiogenesis and the ET-1/ETA receptor system: immunohistochemical expression analysis in bone metastases from patients with different primary tumors
    • Medinger M., Adler C.P., Schmidt-Gersbach C., Soltau J., Droll A., Unger C., Drevs J. Angiogenesis and the ET-1/ETA receptor system: immunohistochemical expression analysis in bone metastases from patients with different primary tumors. Angiogenesis 2003, 6:225-231.
    • (2003) Angiogenesis , vol.6 , pp. 225-231
    • Medinger, M.1    Adler, C.P.2    Schmidt-Gersbach, C.3    Soltau, J.4    Droll, A.5    Unger, C.6    Drevs, J.7
  • 27
    • 84879604260 scopus 로고    scopus 로고
    • Epigenetic control of endothelin-1 axis affects invasiveness of breast carcinoma cells with bone tropism
    • Matteucci E., Maroni P., Locatelli A., Bendinelli P., Desiderio M.A. Epigenetic control of endothelin-1 axis affects invasiveness of breast carcinoma cells with bone tropism. Exp. Cell Res. 2013, 319:1865-1874.
    • (2013) Exp. Cell Res. , vol.319 , pp. 1865-1874
    • Matteucci, E.1    Maroni, P.2    Locatelli, A.3    Bendinelli, P.4    Desiderio, M.A.5
  • 28
    • 17144449019 scopus 로고    scopus 로고
    • Expression of endothelin-1, endothelin-A, and endothelin-B receptor in human breast cancer and correlation with long-term follow-up
    • Wülfing P., Diallo R., Kersting C., Wülfing C., Poremba C., Rody A., Greb R.R., Böcker W., Kiesel L. Expression of endothelin-1, endothelin-A, and endothelin-B receptor in human breast cancer and correlation with long-term follow-up. Clin. Cancer Res. 2003, 9:4125-4131.
    • (2003) Clin. Cancer Res. , vol.9 , pp. 4125-4131
    • Wülfing, P.1    Diallo, R.2    Kersting, C.3    Wülfing, C.4    Poremba, C.5    Rody, A.6    Greb, R.R.7    Böcker, W.8    Kiesel, L.9
  • 29
    • 33750728404 scopus 로고    scopus 로고
    • Targeting bone metastasis in prostate cancer with endothelin receptor antagonists
    • Carducci M.A., Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin. Cancer Res. 2006, 12:6296s-6300s.
    • (2006) Clin. Cancer Res. , vol.12
    • Carducci, M.A.1    Jimeno, A.2
  • 30
    • 55949086629 scopus 로고    scopus 로고
    • Inhibitory effect of HGF on invasiveness of aggressive MDA-MB231 breast carcinoma cells, and role of HDACs
    • Ridolfi E., Matteucci E., Maroni P., Desiderio M.A. Inhibitory effect of HGF on invasiveness of aggressive MDA-MB231 breast carcinoma cells, and role of HDACs. Br. J. Cancer 2008, 99:1623-1634.
    • (2008) Br. J. Cancer , vol.99 , pp. 1623-1634
    • Ridolfi, E.1    Matteucci, E.2    Maroni, P.3    Desiderio, M.A.4
  • 32
    • 62949128877 scopus 로고    scopus 로고
    • TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells
    • Ding J., Ghali O., Lencel P., Broux O., Chauveau C., Devedjian J.C., Hardouin P., Magne D. TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci. 2009, 84:499-504.
    • (2009) Life Sci. , vol.84 , pp. 499-504
    • Ding, J.1    Ghali, O.2    Lencel, P.3    Broux, O.4    Chauveau, C.5    Devedjian, J.C.6    Hardouin, P.7    Magne, D.8
  • 33
    • 55249126420 scopus 로고    scopus 로고
    • Targeting the endothelin system: novel therapeutic options in gynecological, urological and breast cancers
    • Smollich M., Wülfing P. Targeting the endothelin system: novel therapeutic options in gynecological, urological and breast cancers. Expert. Rev. Anticancer. Ther. 2008, 8:1481-1493.
    • (2008) Expert. Rev. Anticancer. Ther. , vol.8 , pp. 1481-1493
    • Smollich, M.1    Wülfing, P.2
  • 35
    • 77956189521 scopus 로고    scopus 로고
    • ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole
    • Smollich M., Götte M., Fischgräbe J., Macedo L.F., Brodie A., Chen S., Radke I., Kiesel L., Wülfing P. ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole. Breast Cancer Res. Treat. 2010, 123:345-357.
    • (2010) Breast Cancer Res. Treat. , vol.123 , pp. 345-357
    • Smollich, M.1    Götte, M.2    Fischgräbe, J.3    Macedo, L.F.4    Brodie, A.5    Chen, S.6    Radke, I.7    Kiesel, L.8    Wülfing, P.9
  • 36
    • 0041706091 scopus 로고    scopus 로고
    • Functional endothelin receptors are present on nuclei in cardiac ventricular myocytes
    • Boivin B., Chevalier D., Villeneuve L.R., Rousseau E., Allen B.G. Functional endothelin receptors are present on nuclei in cardiac ventricular myocytes. J. Biol. Chem. 2003, 278:29153-29163.
    • (2003) J. Biol. Chem. , vol.278 , pp. 29153-29163
    • Boivin, B.1    Chevalier, D.2    Villeneuve, L.R.3    Rousseau, E.4    Allen, B.G.5
  • 38
    • 18844362863 scopus 로고    scopus 로고
    • Endothelin-1 expression is strongly repressed by AU-rich elements in the 3'-untranslated region of the gene
    • Reimunde F.M., Castañares C., Redondo-Horcajo M., Lamas S., Rodríguez-Pascual F. Endothelin-1 expression is strongly repressed by AU-rich elements in the 3'-untranslated region of the gene. Biochem. J. 2005, 387:763-772.
    • (2005) Biochem. J. , vol.387 , pp. 763-772
    • Reimunde, F.M.1    Castañares, C.2    Redondo-Horcajo, M.3    Lamas, S.4    Rodríguez-Pascual, F.5
  • 39
    • 33644861794 scopus 로고    scopus 로고
    • Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells
    • He F., Li J., Mu Y., Kuruba R., Ma Z., Wilson A. Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. Circ. Res. 2006, 98:192-199.
    • (2006) Circ. Res. , vol.98 , pp. 192-199
    • He, F.1    Li, J.2    Mu, Y.3    Kuruba, R.4    Ma, Z.5    Wilson, A.6
  • 40
    • 25444473106 scopus 로고    scopus 로고
    • The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion
    • Pratap J., Javed A., Languino L.R., van Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol. Cell. Biol. 2005, 25:8581-8591.
    • (2005) Mol. Cell. Biol. , vol.25 , pp. 8581-8591
    • Pratap, J.1    Javed, A.2    Languino, L.R.3    van Wijnen, A.J.4    Stein, J.L.5    Stein, G.S.6    Lian, J.B.7
  • 42
    • 0034650207 scopus 로고    scopus 로고
    • TCF is the nuclear effector of the beta-catenin signal that patterns the sea urchin animal-vegetal axis
    • Vonica A., Weng W., Gumbiner B.M., Venuti J.M. TCF is the nuclear effector of the beta-catenin signal that patterns the sea urchin animal-vegetal axis. Dev. Biol. 2000, 217:230-243.
    • (2000) Dev. Biol. , vol.217 , pp. 230-243
    • Vonica, A.1    Weng, W.2    Gumbiner, B.M.3    Venuti, J.M.4
  • 44
    • 67650252530 scopus 로고    scopus 로고
    • Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery
    • Kao J., Salari K., Bocanegra M., Choi Y.L., Girard L., Gandhi J. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One 2009, 4:e6146.
    • (2009) PLoS One , vol.4
    • Kao, J.1    Salari, K.2    Bocanegra, M.3    Choi, Y.L.4    Girard, L.5    Gandhi, J.6
  • 46
    • 28444494000 scopus 로고    scopus 로고
    • Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells
    • Hagemann T., Binder C., Binder L., Pukrop T., Trümper L., Grimshaw M.J. Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells. DNA Cell Biol. 2005, 24:766-776.
    • (2005) DNA Cell Biol. , vol.24 , pp. 766-776
    • Hagemann, T.1    Binder, C.2    Binder, L.3    Pukrop, T.4    Trümper, L.5    Grimshaw, M.J.6
  • 49
    • 13444306377 scopus 로고    scopus 로고
    • Crosstalk between cancer cells and bone microenvironment in bone metastasis
    • Yoneda T., Hiraga T. Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem. Biophys. Res. Commun. 2005, 328:679-687.
    • (2005) Biochem. Biophys. Res. Commun. , vol.328 , pp. 679-687
    • Yoneda, T.1    Hiraga, T.2
  • 50
    • 84860325176 scopus 로고    scopus 로고
    • Bone metastases: molecular mechanisms and novel therapeutic interventions
    • Papachristou D.J., Basdra E.K., Papavassiliou A.G. Bone metastases: molecular mechanisms and novel therapeutic interventions. Med. Res. Rev. 2012, 32:611-636.
    • (2012) Med. Res. Rev. , vol.32 , pp. 611-636
    • Papachristou, D.J.1    Basdra, E.K.2    Papavassiliou, A.G.3
  • 51
    • 84867984708 scopus 로고    scopus 로고
    • Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonization in breast cancer
    • Gunasinghe N.P.A.D., Wells A., Thompson E.W., Hugo H.J. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonization in breast cancer. Cancer Metastasis Rev. 2012, 31:469-478.
    • (2012) Cancer Metastasis Rev. , vol.31 , pp. 469-478
    • Gunasinghe, N.P.A.D.1    Wells, A.2    Thompson, E.W.3    Hugo, H.J.4
  • 52
    • 0035918213 scopus 로고    scopus 로고
    • Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP
    • Yamashita K., Discher D.J., Hu J., Bishopric N.H., Webster K.A. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J. Biol. Chem. 2001, 276:12645-12653.
    • (2001) J. Biol. Chem. , vol.276 , pp. 12645-12653
    • Yamashita, K.1    Discher, D.J.2    Hu, J.3    Bishopric, N.H.4    Webster, K.A.5
  • 53
    • 57249103576 scopus 로고    scopus 로고
    • Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter
    • Lim S.O., Gu J.M., Kim M.S., Kim H.S., Park Y.N., Park C.K., Cho J.W., Park Y.M., Jung G. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 2008, 135:2128-2140.
    • (2008) Gastroenterology , vol.135 , pp. 2128-2140
    • Lim, S.O.1    Gu, J.M.2    Kim, M.S.3    Kim, H.S.4    Park, Y.N.5    Park, C.K.6    Cho, J.W.7    Park, Y.M.8    Jung, G.9
  • 55
    • 84887621878 scopus 로고    scopus 로고
    • Anoikis molecular pathways and its role in cancer progression
    • Paoli P., Giannoni E., Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim. Biophys. Acta 2013, 10.1016/j.bbamcr.2013.06.026.
    • (2013) Biochim. Biophys. Acta
    • Paoli, P.1    Giannoni, E.2    Chiarugi, P.3
  • 57
    • 34250016782 scopus 로고    scopus 로고
    • Hepatocyte growth factor in invasive growth of carcinomas
    • Desiderio M.A. Hepatocyte growth factor in invasive growth of carcinomas. Cell. Mol. Life Sci. 2007, 64:1341-1354.
    • (2007) Cell. Mol. Life Sci. , vol.64 , pp. 1341-1354
    • Desiderio, M.A.1
  • 58
    • 79960838436 scopus 로고    scopus 로고
    • The TGF-β/Smad pathway induces breast cancer cell invasion trough the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system
    • Wiercinska E., Naber H.P.H., Pardali E., van der Pluijm G., van Dam H., ten Dijke P. The TGF-β/Smad pathway induces breast cancer cell invasion trough the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res. Treat. 2011, 128:657-666.
    • (2011) Breast Cancer Res. Treat. , vol.128 , pp. 657-666
    • Wiercinska, E.1    Naber, H.P.H.2    Pardali, E.3    van der Pluijm, G.4    van Dam, H.5    ten Dijke, P.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.