SNP rs4971059 Predisposes to Breast Carcinogenesis and Chemoresistance by Powering DNA Replication [ChIP-seq]

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single-nucleotide polymorphism (SNP) rs4971059, one of the 65 new breast cancer risk loci identified in a recent genome-wide association analysis, locates at the 6th intron of TRIM46 that functions as an active enhancer. We find that G to A polymorphic switch of the rs4971059 allele augments its chromosomal interaction with the promoter and boosts its enhancer activity. Accordingly, cells carry SNP[A] rs4971059 display an elevated TRIM46 expression. We find that TRIM46 is a ubiquitin ligase that targets HDAC1 for ubiquitination and degradation. Integrative genomic and transcriptomic studies reveal that the TRIM46-HDAC1 axis regulates a panel of genes including ones that are critically involved in DNA replication and repair. Consistently, depletion of TRIM46 impedes S phase progression and sensitizes cells to DNA-damaging reagents. We demonstrate that TRIM46 promotes breast cancer cell proliferation and chemoresistance in vitro and accelerates breast cancer growth in vivo. Importantly, TRIM46 is frequently overexpressed in breast carcinomas, and its level of expression is negatively correlated with that of HDAC1 as well as with higher histological grades and worse prognosis of breast cancer patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance, supporting the pursuit of TRIM46 as a potential target for breast cancer intervention.