Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer.
The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers β-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for β-catenin was found in 64% and for E-cadherin in 80% with strong correlation between these markers (P = 0.001). Nuclear β-catenin staining was detected in 19% of the tumors. Overexpression of TCF-4, which is activated by β-catenin, was found in 89% and downregulation of PTEN, which suppresses nuclear accumulation of β-catenin, was present in 54% of the tumors. In summary, altered expression of target molecules in the Wnt signaling pathway was demonstrated in the vast majority of the HNPCC-associated tumors, which support deranged Wnt-signaling as a central tumorigenic mechanism also in MMR defective colorectal cancer.
Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden. anna.ekstrand@med.lu.se
Anna
A
Isinger-Ekstrand
Christina
C
Therkildsen
Inge
I
Bernstein
Mef
M
Nilbert
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000032:analysis; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human