Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.
OBJECTIVE
The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer-specific survival.


METHODS
The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer.


RESULTS
The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, beta(1) integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer-specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either.


CONCLUSIONS
Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.
Dejmek
Janna
J
Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
Leandersson
Karin
K
Manjer
Jonas
J
Bjartell
Anders
A
Emdin
Stefan O
SO
Vogel
Wolfgang F
WF
Landberg
Göran
G
Andersson
Tommy
T
D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D000070819:Discoidin Domain Receptor 1; D004792:Enzyme Precursors / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D018299:Neoplasms, Ductal, Lobular, and Medullary / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D000072377:Syk Kinase; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
D004792:Enzyme Precursors; D039641:Integrin beta Chains; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase