title: The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells.
abstract: In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy.
authors.affiliation: Cancer Research Program. IMIM (Institut Hospital del Mar d'Investigacions Mèdiques). Barcelona. Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Bosch
authors.forename: Konstantina
authors.initials: K
authors.lastname: Panoutsopoulou
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Corominas
authors.forename: Ramón
authors.initials: R
authors.lastname: Gimeno
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.forename: Saleta
authors.initials: S
authors.lastname: Morales
authors.forename: Tania
authors.initials: T
authors.lastname: Lobato
authors.forename: Carles
authors.initials: C
authors.lastname: Martínez-Romero
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Farias
authors.forename: Xavier
authors.initials: X
authors.lastname: Mayol
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Hernández-Muñoz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
references.citation: Clin Cancer Res. 2004 Oct 15;10(20):6962-8
references.pmid: 15501975
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68
references.pmid: 15688067
references.citation: Curr Opin Cell Biol. 2004 Jun;16(3):239-46
references.pmid: 15145347
references.citation: Breast Cancer Res Treat. 2013 Apr;138(3):741-52
references.pmid: 23539298
references.citation: PLoS One. 2012;7(12):e51239
references.pmid: 23251464
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
references.pmid: 14500907
references.citation: Nature. 2004 Oct 14;431(7010):873-8
references.pmid: 15386022
references.citation: Mol Carcinog. 2008 May;47(5):373-82
references.pmid: 17999388
references.citation: J Cell Sci. 2000 May;113 ( Pt 10):1661-70
references.pmid: 10769197
references.citation: Development. 1997 Feb;124(3):721-9
references.pmid: 9043087
references.citation: Mol Cell. 2011 Nov 18;44(4):621-34
references.pmid: 22099309
references.citation: Histol Histopathol. 2009 Apr;24(4):503-10
references.pmid: 19224453
references.citation: J Cell Biol. 2013 Jul 8;202(1):163-77
references.pmid: 23836933
references.citation: Mol Cell. 2012 Feb 10;45(3):344-56
references.pmid: 22325352
references.citation: Science. 2002 Nov 1;298(5595):1039-43
references.pmid: 12351676
references.citation: J Biol Chem. 2003 May 16;278(20):18214-20
references.pmid: 12611892
references.citation: Trends Biochem Sci. 2010 Jun;35(6):323-32
references.pmid: 20346678
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20302-7
references.pmid: 18056629
references.citation: EMBO J. 2006 Jul 12;25(13):3110-22
references.pmid: 16763550
references.citation: Cancer Res. 1995 Jul 1;55(13):2752-5
references.pmid: 7796399
references.citation: Development. 1998 Sep;125(18):3543-51
references.pmid: 9716520
references.citation: Methods. 2003 Jul;30(3):256-68
references.pmid: 12798140
references.citation: BMC Cancer. 2009 Feb 19;9:61
references.pmid: 19228380
references.citation: Cancer Sci. 2006 Oct;97(10):1061-9
references.pmid: 16984379
references.citation: J Pathol. 2009 Oct;219(2):205-13
references.pmid: 19585519
references.citation: J Immunol Methods. 1984 Mar 16;67(2):379-88
references.pmid: 6200537
references.citation: Development. 2001 May;128(9):1587-97
references.pmid: 11290297
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2468-73
references.pmid: 12589020
references.citation: J Cell Biol. 2006 Apr 10;173(1):19-26
references.pmid: 16606690
references.citation: Biochim Biophys Acta. 2004 May 25;1678(2-3):111-25
references.pmid: 15157737
references.citation: Cancer Res. 2005 Jun 1;65(11):4698-706
references.pmid: 15930288
references.citation: Cancer Res. 2007 Dec 15;67(24):11721-31
references.pmid: 18089802
references.citation: Nat Genet. 2008 Apr;40(4):411-20
references.pmid: 18311137
references.citation: Breast Cancer Res. 2008;10(6):R109
references.pmid: 19099573
references.citation: Mol Cancer. 2010 Feb 21;9:40
references.pmid: 20170541
references.citation: Cancer Res. 2006 Jun 15;66(12):6225-32
references.pmid: 16778197
references.citation: Am J Cancer Res. 2012;2(5):589-97
references.pmid: 22957310
references.citation: Carcinogenesis. 2010 Mar;31(3):512-20
references.pmid: 20042638
references.citation: J Natl Cancer Inst. 1993 Apr 7;85(7):570-4
references.pmid: 8455204
references.citation: PLoS One. 2008 May 21;3(5):e2235
references.pmid: 18493325
references.citation: Oncogene. 1999 Oct 7;18(41):5646-53
references.pmid: 10523844
references.citation: Oncogene. 2001 May 10;20(21):2626-35
references.pmid: 11420674
references.citation: J Surg Oncol. 2008 Mar 1;97(3):267-72
references.pmid: 18041745
references.citation: Biol Cell. 2010 Jan 14;102(4):203-213
references.pmid: 19883375
references.citation: Mol Cell Biochem. 2010 Jul;340(1-2):21-9
references.pmid: 20177740
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6788-93
references.pmid: 20351251
references.citation: Mol Cell. 1998 Sep;2(3):305-16
references.pmid: 9774969
references.citation: Science. 2002 Apr 19;296(5567):550-3
references.pmid: 11910072
references.citation: Eur J Cancer. 2010 Nov;46(16):2919-25
references.pmid: 20719498
references.citation: Mol Cell Biochem. 2011 May;351(1-2):109-16
references.pmid: 21246261
references.citation: Mol Cancer. 2011 Jan 28;10(1):10
references.pmid: 21276221