Abstract
Triple-negative breast cancer (TNBC) accounts for ~15–20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.
Highlights
Triple-negative breast cancer (TNBC) accounts for 15–20% of patients diagnosed breast tumors
The BC susceptibility locus CCL5 rs2107538 in our cohort was significantly associated with the risk for both TNBC and hormone receptor positive breast cancer (HRBC); the other breast cancer susceptibility locus rs2280789 was associated with an increased risk for TNBC but only had a marginal effect on HRBC, while rs2280788 had a weak association with TNBC risk
TNBC specific Single Nucleotide Polymorphisms (SNPs) rs614367 was associated with prognosis in a BC subgroup-TNBC but not in all breast cancer patients
Summary
Triple-negative breast cancer (TNBC) accounts for 15–20% of patients diagnosed breast tumors. TNBC tumors relapse early after standard chemotherapy treatments and often develop visceral metastases; it represents a subtype with the poorest prognosis among all breast cancers. Others and our group showed that Arab women might experience an early disease onset and a preponderance of aggressive breast cancer phenotypes [1]. In TNBC, the density of tumor infiltrating lymphocytes has been associated with favorable prognosis [6, 7]. The immune checkpoint blockade Atezolizumab (monoclonal antibody against the protein programmed cell death-ligand 1) has been approved by the FDA for the treatment of metastatic TNBC based on the positive results of a phase III trial [8]. Posttreatment chemokine (C-C motif) ligand 5 (CCL5) increase has been associated with responsiveness to immunotherapy (Imiquimod) in breast cancer skin metastasis [9]
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