title: Is upregulation of BCL2 a determinant of tumor development driven by inactivation of CDH1/E-cadherin?
abstract: Inactivation of CDH1, encoding E-cadherin, promotes cancer initiation and progression. According to a newly proposed molecular mechanism, loss of E-cadherin triggers an upregulation of the anti-apoptotic oncoprotein BCL2. Conversely, reconstitution of E-cadherin counteracts overexpression of BCL2. This reciprocal regulation is thought to be critical for early tumor development. We determined the relevance of this new concept in human infiltrating lobular breast cancer (ILBC), the prime tumor entity associated with CDH1 inactivation. BCL2 expression was examined in human ILBC cell lines (IPH-926, MDA-MB-134, SUM-44) harboring deleterious CDH1 mutations. To test for an intact regulatory axis between E-cadherin and BCL2, wild-type E-cadherin was reconstituted in ILBC cells by ectopic expression. Moreover, BCL2 and E-cadherin were evaluated in primary invasive breast cancers and in synchronous lobular carcinomas in situ (LCIS). MDA-MB-134 and IPH-926 showed little or no BCL2 expression, while SUM-44 ILBC cells were BCL2-positive. Reconstitution of E-cadherin failed to impact on BCL2 expression in all cell lines tested. Primary ILBCs were almost uniformly E-cadherin-negative (97%) and were frequently BCL2-negative (46%). When compared with an appropriate control group, ILBCs showed a trend towards an increased frequency of BCL2-negative cases (P = 0.064). In terminal duct-lobular units affected by LCIS, the E-cadherin-negative neoplastic component showed a similar or a reduced BCL2-immunoreactivity, when compared with the adjacent epithelium. In conclusion, upregulation of BCL2 is not involved in lobular breast carcinogenesis and is unlikely to represent an important determinant of tumor development driven by CDH1 inactivation.
authors.affiliation: Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Karch
authors.forename: Elisa
authors.initials: E
authors.lastname: Schipper
authors.forename: Henriette
authors.initials: H
authors.lastname: Christgen
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Christgen
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015203:Reproducibility of Results; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D019253:Proto-Oncogene Proteins c-bcl-2
references.citation: Cell Motil Cytoskeleton. 2004 Sep;59(1):50-61
references.pmid: 15259055
references.citation: Cancer Res. 2001 Jan 1;61(1):278-84
references.pmid: 11196175
references.citation: Br J Cancer. 2002 Nov 4;87(10):1105-11
references.pmid: 12402149
references.citation: Mol Cell Biochem. 2007 Dec;306(1-2):201-12
references.pmid: 17660947
references.citation: J Natl Cancer Inst. 1974 Sep;53(3):661-74
references.pmid: 4412247
references.citation: J Pathol. 2012 Jan;226(1):97-107
references.pmid: 21953021
references.citation: Clin Exp Metastasis. 2011 Dec;28(8):811-8
references.pmid: 21789718
references.citation: Cancer Biol Ther. 2007 Sep;6(9):1355-7
references.pmid: 17786032
references.citation: JAMA. 2007 Jun 6;297(21):2360-72
references.pmid: 17545690
references.citation: Pathologe. 1987 May;8(3):138-40
references.pmid: 3303008
references.citation: Cancer Res. 1993 Feb 1;53(3):627-35
references.pmid: 8425198
references.citation: Int J Cancer. 2003 Aug 20;106(2):208-15
references.pmid: 12800196
references.citation: J Pathol. 2009 Apr;217(5):620-32
references.pmid: 19191266
references.citation: Breast Cancer Res Treat. 2004 Feb;83(3):249-89
references.pmid: 14758095
references.citation: Clin Cancer Res. 2006 Nov 15;12(22):6652-62
references.pmid: 17121884
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961-5
references.pmid: 1871110
references.citation: Genes Chromosomes Cancer. 2013 Jan;52(1):69-80
references.pmid: 22997091
references.citation: J Cell Sci. 1994 Jun;107 ( Pt 6):1705-12
references.pmid: 7962211
references.citation: Cancer Res. 1998 May 1;58(9):1972-7
references.pmid: 9581841
references.citation: Cancer Discov. 2013 Jan;3(1):27-34
references.pmid: 23319768
references.citation: Int J Cancer. 2008 Nov 15;123(10):2239-46
references.pmid: 18712725
references.citation: Br J Cancer. 2006 Mar 13;94(5):661-71
references.pmid: 16495925
references.citation: Histopathology. 2008 Jan;52(1):58-66
references.pmid: 18171417
references.citation: Cancer. 2011 Jul 15;117(14):3112-7
references.pmid: 21271559
references.citation: Oncogene. 2004 Apr 22;23(19):3272-83
references.pmid: 15077190
references.citation: Oncogene. 2008 Sep 11;27(40):5359-72
references.pmid: 18490921
references.citation: Oncogene. 2008 Nov 24;27(55):6920-9
references.pmid: 19029934
references.citation: J Clin Invest. 2011 Aug;121(8):3176-88
references.pmid: 21747168
references.citation: EMBO J. 1995 Dec 15;14(24):6107-15
references.pmid: 8557030
references.citation: Pathol Oncol Res. 2002;8(1):26-30
references.pmid: 11994759
references.citation: Cancer Lett. 2012 Feb 28;315(2):153-60
references.pmid: 22118813
references.citation: Breast Cancer Res Treat. 2012 Apr;132(2):641-52
references.pmid: 22080244
references.citation: J Cell Biol. 1999 Jul 12;146(1):219-32
references.pmid: 10402472
references.citation: Lab Invest. 2012 Nov;92(11):1635-47
references.pmid: 22945757
references.citation: Breast Cancer Res Treat. 2007 Jul;104(1):13-9
references.pmid: 17004106
references.citation: Cell. 2004 Jun 25;117(7):927-39
references.pmid: 15210113
references.citation: Eur J Cancer. 2008 Jan;44(1):73-83
references.pmid: 18035533
references.citation: Int J Cancer. 2012 Oct 1;131(7):E1109-19
references.pmid: 22418857
references.citation: Hum Mol Genet. 2012 Jan 15;21(2):334-43
references.pmid: 21989054
references.citation: J Biol Chem. 2010 Feb 26;285(9):6412-8
references.pmid: 20040597
references.citation: Histopathology. 2005 Jun;46(6):685-93
references.pmid: 15910600
references.citation: PLoS One. 2012;7(5):e37864
references.pmid: 22662240
references.citation: Steroids. 2013 Jun;78(6):568-75
references.pmid: 23178159