title: Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells.
abstract: Acquisition of resistance to tamoxifen is a critical therapeutic problem in breast cancer patients. Epithelial-mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype, is associated with invasion and motility of cancer cells. Here, we found that tamoxifen-resistant (TAMR)-MCF-7 cells had undergone EMT, as evidenced by mesenchymal-like cell shape, downregulation of basal E-cadherin expression, and overexpression of N-cadherin and vimentin, as well as increased Snail transcriptional activity and protein expression. Given the roles of glycogen synthase kinase (GSK)-3beta and nuclear factor (NF)-kappaB in Snail-mediated E-cadherin deregulation during EMT, we examined the role of these signaling pathways in the EMT of TAMR-MCF-7 cells. Both Ser9-phosphorylated GSK-3beta (inactive form) and NF-kappaB reporter activity were increased in TAMR-MCF-7 cells, as was activation of the phosphatase and tensin homolog depleted on chromosome ten (PTEN)-phosphoinositide 3 (PI3)-kinase-Akt pathway. Pin1, a peptidyl-prolyl isomerase, was overexpressed in TAMR-MCF-7 cells, and Snail transcription and the expression of EMT markers could be decreased by Pin1 siRNA treatment. These results imply that Pin1 overexpression in TAMR-MCF-7 cells is involved in the EMT process via PTEN-PI3-kinase-Akt-GSK-3beta and/or GSK-3beta-NF-kappaB-dependent Snail activation, and suggest the potential involvement of Pin1 in EMT during breast cancer development.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, South Korea.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Kim
authors.forename: Hoo-Kyun
authors.initials: HK
authors.lastname: Choi
authors.forename: Kyoung Bin
authors.initials: KB
authors.lastname: Cho
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D008648:Mesoderm / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009361:Neoplasm Invasiveness / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D013629:Tamoxifen; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
references.citation: Nat Cell Biol. 2001 Sep;3(9):793-801
references.pmid: 11533658
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: Nat Rev Mol Cell Biol. 2002 Mar;3(3):155-66
references.pmid: 11994736
references.citation: Nature. 2001 May 17;411(6835):355-65
references.pmid: 11357143
references.citation: Biochim Biophys Acta. 1994 May 27;1198(1):11-26
references.pmid: 8199193
references.citation: J Steroid Biochem Mol Biol. 1994 Jun;49(4-6):327-31
references.pmid: 8043496
references.citation: Endocr Relat Cancer. 2007 Jun;14(2):293-303
references.pmid: 17639045
references.citation: Int J Dev Biol. 2004;48(5-6):365-75
references.pmid: 15349812
references.citation: Nat Cell Biol. 2004 Oct;6(10):931-40
references.pmid: 15448698
references.citation: Cancer Cell. 2005 Sep;8(3):197-209
references.pmid: 16169465
references.citation: Int J Cancer. 2003 Apr 10;104(3):318-27
references.pmid: 12569555
references.citation: Nat Rev Cancer. 2002 Feb;2(2):101-12
references.pmid: 12635173
references.citation: Oncogene. 2002 May 9;21(20):3241-6
references.pmid: 12082640
references.citation: Nat Cell Biol. 2000 Feb;2(2):84-9
references.pmid: 10655587
references.citation: Trends Mol Med. 2002 Aug;8(8):385-9
references.pmid: 12127724
references.citation: Cancer Biol Ther. 2004 Mar;3(3):268-75
references.pmid: 15034304
references.citation: J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86
references.pmid: 12615961
references.citation: Cancer Res. 2003 May 1;63(9):2172-8
references.pmid: 12727836
references.citation: EMBO J. 2001 Jul 2;20(13):3459-72
references.pmid: 11432833
references.citation: Cancer Res. 2004 Sep 1;64(17):6349-56
references.pmid: 15342425
references.citation: Mol Cell. 2003 Dec;12(6):1413-26
references.pmid: 14690596
references.citation: Nat Rev Cancer. 2003 May;3(5):362-74
references.pmid: 12724734
references.citation: Trends Cell Biol. 2002 Apr;12(4):164-72
references.pmid: 11978535
references.citation: Cells Tissues Organs. 2007;185(1-3):73-84
references.pmid: 17587811
references.citation: Clin Exp Metastasis. 2004;21(3):201-12
references.pmid: 15387370
references.citation: Breast Cancer Res Treat. 1994;32(1):49-55
references.pmid: 7819585
references.citation: Trends Biochem Sci. 2004 Apr;29(4):200-9
references.pmid: 15082314
references.citation: Am J Pathol. 2004 May;164(5):1727-37
references.pmid: 15111319
references.citation: J Cell Biol. 2005 Jan 3;168(1):29-33
references.pmid: 15631989
references.citation: Mol Cell Biol. 2002 Aug;22(15):5281-95
references.pmid: 12101225
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):10983-5
references.pmid: 11572954
references.citation: Cancer Res. 2000 Oct 1;60(19):5390-4
references.pmid: 11034077
references.citation: Cancer Res. 2005 Jul 15;65(14):5991-5; discussion 5995
references.pmid: 16024595
references.citation: Oncogene. 2004 Sep 23;23(44):7345-54
references.pmid: 15286702
references.citation: Cell. 2003 Apr 18;113(2):207-19
references.pmid: 12705869
references.citation: Trends Biochem Sci. 1999 Feb;24(2):73-6
references.pmid: 10098402
references.citation: Nat Cell Biol. 2000 Feb;2(2):76-83
references.pmid: 10655586
references.citation: Carcinogenesis. 2000 May;21(5):871-9
references.pmid: 10783306
references.citation: Endocrinology. 2002 Jun;143(6):2357-65
references.pmid: 12021201
references.citation: Oncogene. 2007 Nov 22;26(53):7445-56
references.pmid: 17563753
references.citation: Cancer Cell. 2003 Sep;4(3):175-80
references.pmid: 14522251
references.citation: Nat Rev Cancer. 2002 Jun;2(6):442-54
references.pmid: 12189386
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):548-58
references.pmid: 16098727
references.citation: Lancet. 1985 Jan 5;1(8419):16-9
references.pmid: 2856949
references.citation: Oncogene. 2000 Feb 24;19(9):1123-31
references.pmid: 10713699
references.citation: Endocrinology. 2003 Mar;144(3):1032-44
references.pmid: 12586780
references.citation: J Cell Sci. 2004 Jun 1;117(Pt 13):2827-39
references.pmid: 15169839
references.citation: Oncogene. 2007 Feb 1;26(5):711-24
references.pmid: 16862183
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Int J Cancer. 2006 Jan 15;118(2):290-301
references.pmid: 16080193
references.citation: Oncogene. 2007 Mar 22;26(13):1862-74
references.pmid: 17043660
references.citation: J Biol Chem. 2003 Jul 11;278(28):26183-93
references.pmid: 12721297
references.citation: Toxicol Appl Pharmacol. 2001 Sep 15;175(3):260-8
references.pmid: 11559025
references.citation: Cell Mol Biol Lett. 2007 Sep;12(3):457-72
references.pmid: 17457524
references.citation: Cancer Res. 2003 Oct 1;63(19):6244-51
references.pmid: 14559810
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1335-40
references.pmid: 11805292