Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families

Abstract

ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%. However, based on their frequency observed in breast cancer and unrelated healthy individuals, these are not statistically associated with breast cancer risk. Luciferase promoter assays in two breast cancer cell lines identified two haplotypes (H11 and H12) stimulating significantly the expression of ZNF350 transcript compared with the common haplotype H8. The high expression of the H11 allele was associated with the variant c.-874A. Using MatInspector and Transcription Element Search softwares, in silico analyses predicted that the variant c.-874A created a binding site for the factors c-Myc and myogenin. This study represents the first characterization step of the ZNF350 promoter. Additional studies in larger cohorts and other populations will be needed to further evaluate whether common and/or rare ZNF350 promoter variants and haplotypes could be associated with a modest risk of breast cancer.

The role of zinc finger proteins in malignant tumors

“…Additionally, ZNF350/ZBRK1 (Zinc-finger and BRCA1-interacting protein with a KRAB domain 1), which associates with BRCA1 to regulate the transcription of DNA damage response genes, such as GADD45A, p21, Bax, and GADD153, is potentially involved in breast cancer susceptibility. 28,29 ZNF703, as a novel oncogene, its high expression triggers poor survival in luminal B breast cancer patients and further study shows ZNF703 can be up-regulated by long non-coding RNA SPRY4-IT1. [30][31][32] Another set of publications point to the involvement of ZNFs in clinical treatment.…”

“…Moreover, ZNFs can also improve breast cancer cell survival by regulating cellular autophagy, such as ZNF143 regulating the p53‐Beclin1 axis, 26 ZNF32 activating the AKT/mTOR pathway, 27 respectively. Additionally, ZNF350/ZBRK1 (Zinc‐finger and BRCA1‐interacting protein with a KRAB domain 1), which associates with BRCA1 to regulate the transcription of DNA damage response genes, such as GADD45A, p21, Bax, and GADD153, is potentially involved in breast cancer susceptibility 28,29 . ZNF703, as a novel oncogene, its high expression triggers poor survival in luminal B breast cancer patients and further study shows ZNF703 can be up‐regulated by long non‐coding RNA SPRY4‐IT1 30–32 …”

Gene Signatures of Breast Cancer Development and the Potential for Novel Targeted Treatments

“…An interesting study by Lo et al demonstrated that, in many cases, it is not the effect of mutations in one single gene, but rather a cumulative effect of SNPs in 16 BRCA1/2 interactors, namely, CASP8, BARD1, PIK3CA, ESR1, RB1CC1, TCG101, SLC22A18, ATM, PALB2, KRAS2, RAD51, TP53, PHB, BRIP1, PPM1D and CHEK2 [14]. Another study has shown that the c.1518C>T variant in BARD1, a BRCA1 interactor, increases the risk of BC [15], while a possible role of ZBRK1 variants/haplotypes and ZNF350 promoter variants in intermediate BC risk has been suggested [16,17]. Other BRCA1/2 interactors were also studied, many having no effect on BC predisposition [18,19].…”