title: Host genotype and tumor phenotype of chemokine decoy receptors integrally affect breast cancer relapse.
abstract: OBJECTIVE
  Chemokines may play vital roles in breast cancer progression and metastasis. The primary members of chemokine decoy receptors (CDR), DARC and D6, are expressed in breast tumors and lymphatic/hematogenous vessels. CDRs sequestrate the pro-malignant chemokines. We hypothesized that breast cancer patients carrying different levels of CDR expression in tumor and/or in host might have differing clinical outcomes.
  
  
  METHODS
  This prospective observational study measured both expression and germline genotype of DARC and D6 in 463 primary breast cancer patients enrolled between 2004 and 2006. The endpoint was breast cancer relapse-free survival (RFS).
  
  
  RESULTS
  There was a significant association between the co-expression of CDR (immunohistochemical expression of both DARC and D6) with RFS (hazard ratio [HR] of 0.32, 95% confidence interval [CI] 0.19 to 0.54). Furthermore, the co-genotype of two non-synonymous polymorphisms (with two major alleles of DARC-rs12075 and D6-rs2228468 versus the others) significantly related to relapse. Mechanistically, the variant-alleles of these two polymorphisms significantly decreased by 20-30% of CCL2/CCL5 (CDR ligands) levels relative to their major counterparts. Multivariate analysis highlighted that the co-expression and co-genotype of CDR were independent predictors of RFS, with HR of 0.46 (95% CI 0.27 to 0.80) and 0.56 (95% CI 0.37 to 0.85), respectively. The addition of host CDR genetic information to tumor-based factors (including co-expression of CDR) improved the relapse prediction ability (P = 0.02 of AUC comparison).
  
  
  CONCLUSIONS
  The host genotype and tumor phenotype of CDR integrally affect breast cancer relapse. Host-related factors should be considered for individualized prediction of prognosis.
authors: Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
authors: Ke-Da
authors: KD
authors: Yu
authors: Department of Anesthesiology, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
authors: Xin
authors: X
authors: Wang
authors: Department of Medical Oncology, Ruijin Hospital, Shanghai JiaoTong University, Shanghai, P.R. China.
authors: Chen
authors: C
authors: Yang
authors: Department of Breast Surgery, Chongqing Cancer Institute/Hospital, Chongqing, P.R. China.
authors: Xiao-Hua
authors: XH
authors: Zeng
authors: Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
authors: Zhi-Ming
authors: ZM
authors: Shao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D004375:Duffy Blood-Group System / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D054447:Receptors, CCR10 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D000097628:Chemokine Receptor D6
chemical_list: D014408:Biomarkers, Tumor; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D004375:Duffy Blood-Group System; D054447:Receptors, CCR10; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D000097628:Chemokine Receptor D6; C473745:ACKR1 protein, human; C111835:CCL2 protein, human; C483024:CCL5 protein, human
keywords: breast cancer; chemokine decoy receptor; genotype; metastasis; phenotype