TY - JOUR
T1 - Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling
AU - Van De Wetering, Marc
AU - Barker, Nick
AU - Harkes, I. Clara
AU - Van Der Heyden, Marcel
AU - Dijk, Nicolette J.
AU - Hollesteue, Antoinette
AU - Klijn, Jan G.M.
AU - Clevers, Hans
AU - Schutte, Mieke
PY - 2001/1/1
Y1 - 2001/1/1
N2 - Participation of E-cadherin in the Wnt signaling pathway was suggested because of the dual role of β-catenin in cell adhesion and the Wnt signaling cascade. Whereas β-catenin interacts at the cell membrane with the cell adhesion protein E-cadherin, in the nucleus it activates Wnt target genes through formation of transcriptionally active complexes with members of the Tcf/Lef family of transcription factors. Here, we analyzed by PCR and direct cycle sequencing 26 human breast cancer cell lines for alterations in the E-cadherin gene. Genetic alterations were identified in eight cell lines. Five cell lines had truncating mutations, whereas three cell lines had in-frame deletions in the gene transcript and expressed mutant E-cadherin proteins at the cell membrane. Involvement of E-cadherin in the Wnt pathway was evaluated through determination of the activity of a Tcf reporter gene, which had been transiently transfected into 15 breast cancer cell lines. None of six E-cadherin mutant cell lines and four cell lines that exhibit transcriptional silencing of the E-cadherin gene showed Tcf-mediated transcriptional activation. E-cadherin wild-type cell line DU4475 exhibited constitutive Tcf-β-catenin signaling activity and was found to express truncated APC proteins. These results indicate that if cellular transformation occurred through mutation of E-cadherin, it is not mediated via constitutive activation of the Wnt signaling pathway.
AB - Participation of E-cadherin in the Wnt signaling pathway was suggested because of the dual role of β-catenin in cell adhesion and the Wnt signaling cascade. Whereas β-catenin interacts at the cell membrane with the cell adhesion protein E-cadherin, in the nucleus it activates Wnt target genes through formation of transcriptionally active complexes with members of the Tcf/Lef family of transcription factors. Here, we analyzed by PCR and direct cycle sequencing 26 human breast cancer cell lines for alterations in the E-cadherin gene. Genetic alterations were identified in eight cell lines. Five cell lines had truncating mutations, whereas three cell lines had in-frame deletions in the gene transcript and expressed mutant E-cadherin proteins at the cell membrane. Involvement of E-cadherin in the Wnt pathway was evaluated through determination of the activity of a Tcf reporter gene, which had been transiently transfected into 15 breast cancer cell lines. None of six E-cadherin mutant cell lines and four cell lines that exhibit transcriptional silencing of the E-cadherin gene showed Tcf-mediated transcriptional activation. E-cadherin wild-type cell line DU4475 exhibited constitutive Tcf-β-catenin signaling activity and was found to express truncated APC proteins. These results indicate that if cellular transformation occurred through mutation of E-cadherin, it is not mediated via constitutive activation of the Wnt signaling pathway.
UR - http://www.scopus.com/inward/record.url?scp=0035138178&partnerID=8YFLogxK
M3 - Article
C2 - 11196175
AN - SCOPUS:0035138178
SN - 0008-5472
VL - 61
SP - 278
EP - 284
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -