Effect of genetic variants in two chemokine decoy receptor genes, DARC and CCBP2, on metastatic potential of breast cancer

• Published in: PloS one Vol. 8; no. 11; p. e78901
• Main Authors: Yang, Chen, Yu, Ke-Da, Xu, Wen-Huan, Chen, Ao-Xiang, Fan, Lei, Ou, Zhou-Luo, Shao, Zhi-Ming
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.11.2013; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Animals; Antigens; Biopsy; Blood; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer genetics; Cancer metastasis; Cancer research; Cell Line, Tumor; Chemokines; Confidence intervals; Cytokines; Development and progression; Duffy Blood-Group System - genetics; Duffy Blood-Group System - metabolism; Erythrocytes; Female; Gene expression; Genes; Genetic aspects; Genetic diversity; Genetic variance; Genotypes; Growth factors; Heterografts; Humans; Laboratory animals; Lymph nodes; Lymphatic system; Medical prognosis; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Patients; Polymorphism, Single Nucleotide; Proteins; Receptors; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; Risk analysis; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Surgery; Tagging; Tumors; Xenografts; Xenotransplantation; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078901

The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins.