Figure 2.

Model for role of ZNF423 and CTSO genes in controlling BRCA1 in ER+ breast cancer (BC). The results (12–15) show that E₂ can induce ZNF423 transcription critically requiring a region in the ZNF423 intron 2 near to four canonical, estrogen response element (ERE) sites. The calmodulin like 3 protein was found to act as a sensor to connect the single nucleotide polymorphism (SNP) DNA site with activated ERα. ZNF423 in turn induces the expression of BRCA1 acting through a region of the BRCA1 promoter, which has four ZNF423-binding sites. This process is modulated in variants that display SNPs in the ZNF423 intron 2, such that the normal estrogen response is reduced, whereas the response to selective estrogen receptor modulators (SERMs) can now have a reverse effect inducing ZNF423 and then BRCA1. This is compatible with the ZNF423 SNPs being associated with a decreased risk for BC during SERM therapy. The CTSO promoter has several SNPs from the genoma-wide association study with an increased risk for BC with SERM therapy (14). CTSO degrades specifically ZNF423 and BRCA1, consequently reducing dsDNA break repair and increasing proliferation. The response to SERMs treatment is ineffective as the variant SNP for CTSO interrupts an ERE site in the CTSO promoter (13). Cells with a deficit or low BRCA1 become being addicted to other DNA repair pathways and were more sensitive to PARP inhibitors. Additionally, ZNF423 has also been shown to co-activate Poly(ADP-ribose) polymerase 1 required for DNA break repair (44).