메뉴 건너뛰기




Volumn 4, Issue 9, 2011, Pages 1436-1448

Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression

Author keywords

[No Author keywords available]

Indexed keywords

AMPHIREGULIN; BRCA1 PROTEIN; CYTOKERATIN 18; CYTOKERATIN 5; DIMETHYLBENZ[A]ANTHRACENE; ESTROGEN RECEPTOR ALPHA; GENISTEIN; MESSENGER RNA; OSTEOCLAST DIFFERENTIATION FACTOR; PROGESTERONE RECEPTOR;

EID: 80052605877     PISSN: 19406207     EISSN: 19406215     Source Type: Journal    
DOI: 10.1158/1940-6207.CAPR-10-0346     Document Type: Article
Times cited : (27)

References (57)
  • 3
    • 0036714766 scopus 로고    scopus 로고
    • Adolescent and adult soy intake and risk of breast cancer in Asian-Americans
    • Wu A.H., Wan P., Hankin J., Tseng C.C., Yu M.C., Pike M.C. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 2002;23:1491-1496 (Pubitemid 35012429)
    • (2002) Carcinogenesis , vol.23 , Issue.9 , pp. 1491-1496
    • Wu, A.H.1    Wan, P.2    Hankin, J.3    Tseng, C.-C.4    Yu, M.C.5    Pike, M.C.6
  • 4
    • 33751096466 scopus 로고    scopus 로고
    • Adolescent dietary phytoestrogen intake and breast cancer risk (Canada)
    • DOI 10.1007/s10552-006-0062-2
    • Thanos J., Cotterchio M., Boucher B.A., Kreiger N., Thompson L.U. Adolescent dietary phytoestrogen intake and breast cancer risk (Canada). Cancer Causes Control 2006;17:1253-1261 (Pubitemid 44772825)
    • (2006) Cancer Causes and Control , vol.17 , Issue.10 , pp. 1253-1261
    • Thanos, J.1    Cotterchio, M.2    Boucher, B.A.3    Kreiger, N.4    Thompson, L.U.5
  • 5
    • 66849115652 scopus 로고    scopus 로고
    • Adolescent and adult soy food intake and breast cancer risk: Results from the Shanghai Women's Health Study
    • Lee S.A., Shu X.O., Li H., Yang G., Cai H., Wen W., et al. Adolescent and adult soy food intake and breast cancer risk: Results from the Shanghai Women's Health Study. Am J Clin Nutr 2009;89:1920-1926
    • (2009) Am J Clin Nutr , vol.89 , pp. 1920-1926
    • Lee, S.A.1    Shu, X.O.2    Li, H.3    Yang, G.4    Cai, H.5    Wen, W.6
  • 6
    • 43249085452 scopus 로고    scopus 로고
    • The role of early life genistein exposures in modifying breast cancer risk
    • DOI 10.1038/sj.bjc.6604321, PII 6604321
    • Warri A., Saarinen N.M., Makela S.I., Hilakivi-Clarke L. The role of early life genistein exposures in modifying breast cancer risk. Br J Cancer 2008;98:1485-1493 (Pubitemid 351652325)
    • (2008) British Journal of Cancer , vol.98 , Issue.9 , pp. 1485-1493
    • Warri, A.1    Saarinen, N.M.2    Makela, S.3    Hilakivi-Clarke, L.4
  • 7
    • 0035169454 scopus 로고    scopus 로고
    • A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice
    • Newmark H.L., Yang K., Lipkin M., Kopelovich L., Liu Y., Fan K., Shinozaki H.A. Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis 2001;22:1871-1875 (Pubitemid 33064854)
    • (2001) Carcinogenesis , vol.22 , Issue.11 , pp. 1871-1875
    • Newmark, H.L.1    Yang, K.2    Lipkin, M.3    Kopelovich, L.4    Liu, Y.5    Fan, K.6    Shinozaki, H.7
  • 10
    • 77249116901 scopus 로고    scopus 로고
    • Genistein induces enhanced growth promotion in ER-positive/erbB- 2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/ kip1 downregulation
    • Yang X., Yang S., McKimmey C., Liu B., Edgerton S.M., Bales W., et al. Genistein induces enhanced growth promotion in ER-positive/erbB- 2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/ kip1 downregulation. Carcinogenesis 2010;31:695-702.
    • (2010) Carcinogenesis , vol.31 , pp. 695-702
    • Yang, X.1    Yang, S.2    McKimmey, C.3    Liu, B.4    Edgerton, S.M.5    Bales, W.6
  • 11
    • 47649110244 scopus 로고    scopus 로고
    • A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells
    • DOI 10.1093/humrep/den087
    • Di X., Yu L., Moore A.B., Castro L., Zheng X., Hermon T., Dixon D. A low concentration of genistein induces estrogen receptor-alpha and insulin- like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells. Hum Reprod 2008;23:1873-1883 (Pubitemid 352019996)
    • (2008) Human Reproduction , vol.23 , Issue.8 , pp. 1873-1883
    • Di, X.1    Yu, L.2    Moore, A.B.3    Castro, L.4    Zheng, X.5    Hermon, T.6    Dixon, D.7
  • 12
    • 2442535038 scopus 로고    scopus 로고
    • Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis
    • DOI 10.1093/carcin/bgh065
    • Cabanes A., Wang M., Olivo S., De Assis S., Gustafsson J.A., Khan G., et al. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis 2004;25:741-748 (Pubitemid 38618526)
    • (2004) Carcinogenesis , vol.25 , Issue.5 , pp. 741-748
    • Cabanes, A.1    Wang, M.2    Olivo, S.3    DeAssis, S.4    Gustafsson, J.-A.5    Khan, G.6    Hilakivi-Clarke, L.7
  • 13
    • 34447092455 scopus 로고    scopus 로고
    • In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis
    • DOI 10.1093/carcin/bgl240
    • Su Y., Eason R.R., Geng Y., Till S.R., Badger T.M., Simmen R.C. In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis. Carcinogenesis 2007;28:1046-1051 (Pubitemid 47072189)
    • (2007) Carcinogenesis , vol.28 , Issue.5 , pp. 1046-1051
    • Su, Y.1    Eason, R.R.2    Geng, Y.3    Till, S.R.4    Badger, T.M.5    Simmen, R.C.M.6
  • 14
    • 77954988073 scopus 로고    scopus 로고
    • Effect of dietary intake of isoflavones on the estrogen and progesterone receptor status of breast cancer
    • Zhang M., Liu X., Holman C.D. Effect of dietary intake of isoflavones on the estrogen and progesterone receptor status of breast cancer. Nutr Cancer 2010;62:765-773
    • (2010) Nutr Cancer , vol.62 , pp. 765-773
    • Zhang, M.1    Liu, X.2    Holman, C.D.3
  • 17
    • 0028809236 scopus 로고
    • Evaluation of the biochemical targets of genistein in tumor cells
    • Peterson G. Evaluation of the biochemical targets of genistein in tumor cells. J Nutr 1995;125:784S-7849
    • (1995) J Nutr , vol.125
    • Peterson, G.1
  • 18
    • 36949040840 scopus 로고    scopus 로고
    • Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells
    • DOI 10.1007/s12020-007-9006-1
    • Sakla M.S., Shenouda N.S., Ansell P.J., MacDonald R.S., Lubahn D.B. Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells. Endocrine 2007;32:69-78. (Pubitemid 350242549)
    • (2007) Endocrine , vol.32 , Issue.1 , pp. 69-78
    • Sakla, M.S.1    Shenouda, N.S.2    Ansell, P.J.3    MacDonald, R.S.4    Lubahn, D.B.5
  • 19
    • 76449119846 scopus 로고    scopus 로고
    • Prepubertal genistein exposure affects erbB2/Akt signal and reduces rat mammary tumorigenesis
    • Peng J.H., Zhu J.D., Mi M.T., Li F.J., Cai L., Dong J.Z., et al. Prepubertal genistein exposure affects erbB2/Akt signal and reduces rat mammary tumorigenesis. Eur J Cancer Prev 2010;19:110-119
    • (2010) Eur J Cancer Prev , vol.19 , pp. 110-119
    • Peng, J.H.1    Zhu, J.D.2    Mi, M.T.3    Li, F.J.4    Cai, L.5    Dong, J.Z.6
  • 20
    • 32544442522 scopus 로고    scopus 로고
    • BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells
    • DOI 10.1038/sj.bjc.6602935, PII 6602935
    • Fan S., Meng Q., Auborn K., Carter T., Rosen E.M. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 2006;94:407-426 (Pubitemid 43237565)
    • (2006) British Journal of Cancer , vol.94 , Issue.3 , pp. 407-426
    • Fan, S.1    Meng, Q.2    Auborn, K.3    Carter, T.4    Rosen, E.M.5
  • 22
    • 0038743059 scopus 로고    scopus 로고
    • Regulation of BRCA1 expression and its relationship to sporadic breast cancer
    • DOI 10.1186/bcr557
    • Mueller C.R., Roskelley C.D. Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res 2003;5: 45-52. (Pubitemid 36553579)
    • (2003) Breast Cancer Research , vol.5 , Issue.1 , pp. 45-52
    • Mueller, C.R.1    Roskelley, C.D.2
  • 23
    • 0029115660 scopus 로고
    • The developmental pattern of BRCA1 expression implies a role in differentiation of the breast and other tissues
    • Marquis S.T., Rajan J.V., Wynshaw-Boris A., Xu J., Yin G.Y., Abel K.J., et al. The developmental pattern of BRCA1 expression implies a role in differentiation of the breast and other tissues. Nat Genet 1995;11: 17-26.
    • (1995) Nat Genet , vol.11 , pp. 17-26
    • Marquis, S.T.1    Rajan, J.V.2    Wynshaw-Boris, A.3    Xu, J.4    Yin, G.Y.5    Abel, K.J.6
  • 26
    • 0142178215 scopus 로고    scopus 로고
    • Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2
    • DOI 10.1126/science.1088759
    • King M.C., Marks J.H., Mandell J.B. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302: 643-646 (Pubitemid 37310920)
    • (2003) Science , vol.302 , Issue.5645 , pp. 643-646
    • King, M.-C.1    Marks, J.H.2    Mandell, J.B.3
  • 29
    • 0029847417 scopus 로고    scopus 로고
    • Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland
    • Kenney N.J., Smith G.H., Rosenberg K., Cutler M.L., Dickson R.B. Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland. Cell Growth Differ 1996;17:1769-1781 (Pubitemid 26415174)
    • (1996) Cell Growth and Differentiation , vol.7 , Issue.12 , pp. 1769-1781
    • Kenney, N.J.1    Smith, G.H.2    Rosenberg, K.3    Cutler, M.L.4    Dickson, R.B.5
  • 31
    • 76249108620 scopus 로고    scopus 로고
    • BRCA1 represses amphiregulin gene expression
    • Lamber E.P., Horwitz A.A., Parvin J.D. BRCA1 represses amphiregulin gene expression. Cancer Res 2010;70:996-1005.
    • (2010) Cancer Res , vol.70 , pp. 996-1005
    • Lamber, E.P.1    Horwitz, A.A.2    Parvin, J.D.3
  • 32
    • 72149099866 scopus 로고    scopus 로고
    • Amphiregulin mediates self-renewal in an immortal mammary epithelial cell line with stem cell characteristics
    • Booth B.W., Boulanger C.A., Anderson L.H., Jimenez-Rojo L., Brisken C., Smith G.H. Amphiregulin mediates self-renewal in an immortal mammary epithelial cell line with stem cell characteristics. Exp Cell Res 2010;316:422-432
    • (2010) Exp Cell Res , vol.316 , pp. 422-432
    • Booth, B.W.1    Boulanger, C.A.2    Anderson, L.H.3    Jimenez-Rojo, L.4    Brisken, C.5    Smith, G.H.6
  • 34
    • 72249103224 scopus 로고    scopus 로고
    • Genistein and a soy extract differentially affect three-dimensional bone parameters and bone-specific gene expression in ovariectomized mice
    • Zhang Y., Li Q., Wan H.Y., Helferich W.G., Wong M.S. Genistein and a soy extract differentially affect three-dimensional bone parameters and bone-specific gene expression in ovariectomized mice. J Nutr 2009;139:2230-2236
    • (2009) J Nutr , vol.139 , pp. 2230-2236
    • Zhang, Y.1    Li, Q.2    Wan, H.Y.3    Helferich, W.G.4    Wong, M.S.5
  • 35
    • 33646397565 scopus 로고    scopus 로고
    • Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer
    • Li Y., Kucuk O., Hussain M., Abrams J., Cher M.L., Sarkar F.H. Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer. Cancer Res 2006;66:4816-4825
    • (2006) Cancer Res , vol.66 , pp. 4816-4825
    • Li, Y.1    Kucuk, O.2    Hussain, M.3    Abrams, J.4    Cher, M.L.5    Sarkar, F.H.6
  • 37
    • 0030980461 scopus 로고    scopus 로고
    • Alterations in mammary gland development following neonatal exposure to estradiol, transforming growth factor alpha, and estrogen receptor antagonist ICI 182,780
    • DOI 10.1002/(SICI)1097-4652(199703)170:3<279::AID-JCP9>3.0.CO;2-L
    • Hilakivi-Clarke L., Cho E., Raygada M., Kenney N. Alterations in mammary gland development following neonatal exposure to estradiol, transforming growth factor alpha, and estrogen receptor antagonist ICI 182,780. J Cell Physiol 1997;170:279-289 (Pubitemid 27117912)
    • (1997) Journal of Cellular Physiology , vol.170 , Issue.3 , pp. 279-289
    • Hilakivi-Clarke, L.1    Cho, E.2    Raygada, M.3    Kenney, N.4
  • 38
    • 0029844233 scopus 로고    scopus 로고
    • Mammary gland neoplasia in long-term rodent studies
    • Russo I.H., Russo J. Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 1996;104:938-967 (Pubitemid 26372400)
    • (1996) Environmental Health Perspectives , vol.104 , Issue.9 , pp. 938-967
    • Russo, I.H.1    Russo, J.2
  • 39
    • 0031915998 scopus 로고    scopus 로고
    • Prognostic and predictive factors in breast cancer by immunohistochemical analysis
    • Allred D.C., Harvey J.M., Berardo M., Clark G.M. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998;11:155-168 (Pubitemid 28144151)
    • (1998) Modern Pathology , vol.11 , Issue.2 , pp. 155-168
    • Allred, D.C.1    Harvey, J.M.2    Berardo, M.3    Clark, G.M.4
  • 41
    • 71849109590 scopus 로고    scopus 로고
    • Enhanced expression and shedding of receptor activator of NF-kappaB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis
    • Nannuru K.C., Futakuchi M., Sadanandam A., Wilson T.J., Varney M.L., Myers K.J., et al. Enhanced expression and shedding of receptor activator of NF-kappaB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis. Clin Exp Metastasis 2009;26:797-808.
    • (2009) Clin Exp Metastasis , vol.26 , pp. 797-808
    • Nannuru, K.C.1    Futakuchi, M.2    Sadanandam, A.3    Wilson, T.J.4    Varney, M.L.5    Myers, K.J.6
  • 42
    • 44349125782 scopus 로고    scopus 로고
    • Musashi1 modulates mammary progenitor cell expansion through proliferinmediated activation of the Wnt and Notch pathways
    • Wang X.Y., Yin Y., Yuan H., Sakamaki T., Okano H., Glazer R.I. Musashi1 modulates mammary progenitor cell expansion through proliferinmediated activation of the Wnt and Notch pathways. Mol Cell Biol 2008;28:3589-99.
    • (2008) Mol Cell Biol , vol.28 , pp. 3589-3599
    • Wang, X.Y.1    Yin, Y.2    Yuan, H.3    Sakamaki, T.4    Okano, H.5    Glazer, R.I.6
  • 44
    • 33845315093 scopus 로고    scopus 로고
    • Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist
    • DOI 10.1126/science.1130471
    • Poole A.J., Li Y., Kim Y., Lin S.C., Lee W.H., Lee E.Y. Prevention of Brca1- mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 2006;314:1467-1470 (Pubitemid 44871955)
    • (2006) Science , vol.314 , Issue.5804 , pp. 1467-1470
    • Poole, A.J.1    Li, Y.2    Kim, Y.3    Lin, S.-C.J.4    Lee, W.-H.5    Lee, E.Y.-H.P.6
  • 45
    • 18144384743 scopus 로고    scopus 로고
    • Peroxisome proliferator-activated receptor delta and gamma agonists differentially alter tumor differentiation and progression during mammary carcinogenesis
    • DOI 10.1158/0008-5472.CAN-04-3990
    • Yin Y., Russell R.G., Dettin L.E., Bai R., Wei Z., Kozikowski A.P., et al. Peroxisome proliferator-activated receptor delta and gamma agonists differentially alter tumor differentiation and progression during mammary carcinogenesis. Cancer Res 2005;65:3950-3957 (Pubitemid 40616378)
    • (2005) Cancer Research , vol.65 , Issue.9 , pp. 3950-3957
    • Yin, Y.1    Russell, R.G.2    Dettin, L.E.3    Bai, R.4    Wei, Z.-L.5    Kozikowski, A.P.6    Kopleovich, L.7    Glazer, R.I.8
  • 46
    • 0043124292 scopus 로고    scopus 로고
    • Effect of prenatal and prepubertal genistein exposure on N-methyl-N-nitrosourea-induced mammary tumorigenesis in female Sprague-Dawley rats
    • Pei R.J., Sato M., Yuri T., Danbara N., Nikaido Y., Tsubura A. Effect of prenatal and prepubertal genistein exposure on N-methyl-N-nitrosourea- induced mammary tumorigenesis in female Sprague-Dawley rats. In Vivo 2003;17:349-357 (Pubitemid 36958129)
    • (2003) In Vivo , vol.17 , Issue.4 , pp. 349-357
    • Pei, R.-J.1    Sato, M.2    Yuri, T.3    Danbara, N.4    Nikaido, Y.5    Tsubura, A.6
  • 48
    • 9144232430 scopus 로고    scopus 로고
    • Genistein alone or combined with cyclophosphamide may stimulate 16/C transplantable mouse mammary cancer growth
    • Wietrzyk J., Mazurkiewicz M., Madej J., Dzimira S., Grynkiewicz G., Radzikowski C., et al. Genistein alone or combined with cyclophosphamide may stimulate 16/C transplantable mouse mammary cancer growth. Med Sci Monit 2004;10:BR414-BR419
    • (2004) Med Sci Monit , vol.10
    • Wietrzyk, J.1    Mazurkiewicz, M.2    Madej, J.3    Dzimira, S.4    Grynkiewicz, G.5    Radzikowski, C.6
  • 49
    • 44149106310 scopus 로고    scopus 로고
    • The ADAM17-amphiregulin-EGFR axis in mammary development and cancer
    • Sternlicht M.D., Sunnarborg S.W. The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J Mammary Gland Biol Neoplasia 2008;13:181-194
    • (2008) J Mammary Gland Biol Neoplasia , vol.13 , pp. 181-194
    • Sternlicht, M.D.1    Sunnarborg, S.W.2
  • 51
    • 0029072015 scopus 로고
    • Detection and location of amphiregulin and Cripto-1 expression in the developing postnatal mouse mammary gland
    • Kenney N.J., Huang R.P., Johnson G.R., Wu J.X., Okamura D., Matheny W., et al. Detection and location of amphiregulin and Cripto-1 expression in the developing postnatal mouse mammary gland. Mol Reprod Dev 1995;41:277-286
    • (1995) Mol Reprod Dev , vol.41 , pp. 277-286
    • Kenney, N.J.1    Huang, R.P.2    Johnson, G.R.3    Wu, J.X.4    Okamura, D.5    Matheny, W.6
  • 52
    • 77955772783 scopus 로고    scopus 로고
    • Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer
    • Gierach G.L., Loud J.T., Chow C.K., Prindiville S.A., Eng-Wong J., Soballe P.W., et al. Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer. Breast Cancer Res Treat 2010;123:245-255
    • (2010) Breast Cancer Res Treat , vol.123 , pp. 245-255
    • Gierach, G.L.1    Loud, J.T.2    Chow, C.K.3    Prindiville, S.A.4    Eng-Wong, J.5    Soballe, P.W.6
  • 54
    • 57349198210 scopus 로고    scopus 로고
    • A mammary-specific, longrange deletion on mouse chromosome 11 accelerates Brca1-associated mammary tumorigenesis
    • Triplett A.A., Montagna C., Wagner K.U. A mammary-specific, longrange deletion on mouse chromosome 11 accelerates Brca1-associated mammary tumorigenesis. Neoplasia 2008;10:1325-1334
    • (2008) Neoplasia , vol.10 , pp. 1325-1334
    • Triplett, A.A.1    Montagna, C.2    Wagner, K.U.3
  • 57
    • 38749087231 scopus 로고    scopus 로고
    • Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERalpha-negative and ERalpha-positive mammary preneoplasia and cancer
    • DOI 10.1038/sj.onc.1210674, PII 1210674
    • Jones L.P., Tilli M.T., Assefnia S., Torre K., Halama E.D., Parrish A., et al. Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERa-negative and ERapositive mammary preneoplasia and cancer. Oncogene 2008;27: 794-802. (Pubitemid 351186312)
    • (2008) Oncogene , vol.27 , Issue.6 , pp. 794-802
    • Jones, L.P.1    Tilli, M.T.2    Assefnia, S.3    Torre, K.4    Halama, E.D.5    Parrish, A.6    Rosen, E.M.7    Furth, P.A.8


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.