Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.
Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.
Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Harriet
H
Wikman
Laura
L
Westphal
Felicitas
F
Schmid
Sirkku
S
Pollari
Jolanthe
J
Kropidlowski
Bettina
B
Sielaff-Frimpong
Markus
M
Glatzel
Jakob
J
Matschke
Manfred
M
Westphal
Kristiina
K
Iljin
Heini
H
Huhtala
Luigi
L
Terracciano
Anne
A
Kallioniemi
Guido
G
Sauter
Volkmar
V
Müller
Isabell
I
Witzel
Katrin
K
Lamszus
Dirk
D
Kemming
Klaus
K
Pantel
D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins