Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer.
Although mutation of APC or CTNNB1 (beta-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a beta-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis.
Suzuki
H
H
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Toyota
M
M
Carraway
H
H
Caraway
H
H
Gabrielson
E
E
Ohmura
T
T
Fujikane
T
T
Nishikawa
N
N
Sogabe
Y
Y
Nojima
M
M
Sonoda
T
T
Mori
M
M
Hirata
K
K
Imai
K
K
Shinomura
Y
Y
Baylin
S B
SB
Tokino
T
T
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051153:Wnt Proteins / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118511:SFRP5 protein, human