Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression.
BACKGROUND
Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125-132).


METHODS
The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells.


RESULTS
Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells.


CONCLUSIONS
Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression in vitro.
Yasuoka
Hironao
H
Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan. hyasuoka@mail.wakayama-med.ac.jp
Kodama
Rieko
R
Tsujimoto
Masahiko
M
Yoshidome
Katsuhide
K
Akamatsu
Hiroki
H
Nakahara
Masaaki
M
Inagaki
Michiya
M
Sanke
Tokio
T
Nakamura
Yasushi
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009362:Neoplasm Metastasis; D039943:Neuropilin-2 / Q000096:biosynthesis*; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000235:genetics*
C527276:CXCR4 protein, human; D039943:Neuropilin-2; D019718:Receptors, CXCR4