Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 May 18:9:255.
doi: 10.3389/fendo.2018.00255. eCollection 2018.

ZNF423: A New Player in Estrogen Receptor-Positive Breast Cancer

Heather M Bond  1 , Stefania Scicchitano  1 , Emanuela Chiarella  1 , Nicola Amodio  2 , Valeria Lucchino  1 , Annamaria Aloisio  1 , Ylenia Montalcini  1 , Maria Mesuraca  1 , Giovanni Morrone  1
Affiliations
Review

ZNF423: A New Player in Estrogen Receptor-Positive Breast Cancer

Heather M Bond et al. Front Endocrinol (Lausanne). .

Abstract

Preventive therapy can target hormone-responsive breast cancer (BC) by treatment with selective estrogen receptor modulators (SERMs) and reduce the incidence of BC. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) with relevant predictive values, SNPs in the ZNF423 gene were associated with decreased risk of BC during SERM therapy, and SNPs in the Cathepsin O gene with an increased risk. ZNF423, which was not previously associated with BC is a multifunctional transcription factor known to have a role in development, neurogenesis, and adipogenesis and is implicated in other types of cancer. ZNF423 is transcriptionally controlled by the homolog ZNF521, early B cell factor transcription factor, epigenetic silencing of the promoter by CpG island hyper-methylation, and also by ZNF423 itself in an auto-regulatory loop. In BC cells, ZNF423 expression is found to be induced by estrogen, dependent on the binding of the estrogen receptor and calmodulin-like 3 to SNPs in ZNP423 intronic sites in proximity to consensus estrogen response elements. ZNF423 has also been shown to play a mechanistic role by trans-activating the tumor suppressor BRCA1 and thus modulating the DNA damage response. Even though recent extensive trial studies did not classify these SNPs with the highest predictive values, for inclusion in polygenic SNP analysis, the mechanism unveiled in these studies has introduced ZNF423 as a factor important in the control of the estrogen response. Here, we aim at providing an overview of ZNF423 expression and functional role in human malignancies, with a specific focus on its implication in hormone-responsive BC.

Keywords: ZNF423; ZNF521; breast cancer; calmodulin like 3; cathepsin O; estrogen receptors; selective estrogen receptor modulators; single nucleotide polymorphisms.

PubMed Disclaimer

Figures

Figure 1
Figure 1
ZNF423 gene regulation. Diagram to illustrate the structure for the ZNF423 human (NG_032972.2, 377, 389 bp) gene, which comprises 8 exons and introns with the major part of the protein being coded by exon 4. Two alternative promoters have been described (21, 59), and these are subject to regulation by demethylation and methylation of the CpG islands controlled by GADD45-inhibitor of growth protein 1 (ING1) or retinoic acid induced RAR–ING1 complexes (68). Epigenetic reprogramming is also associated with histone methylation (H3K9me3) and acetylation (H3K9ac), controlled by PCR2 and EHZ2 (56) as well as by ZNF521 (33). BMP4 can result in the demethylation of specific CpG dinucleotides resulting in activation of transcription (40). Consensus conserved across species sites for ZNF423, early B cell factor (EBF), and small mother against decapentaplegic have been found in introns 3 and 5. The enhancer site in intron 5 was found to be occupied by Zfp423 or Zfp521 together with EBF1 resulting in autoregulation by Zfp423 (34) or repression by Zfp521 (33). In ER+ breast cancers, single nucleotide polymorphisms in intron 2 (12) and in intron 5 (15) have been found, which are sufficiently close to ERα canonical consensus-binding sites [estrogen response element (ERE)] such that the response to E2 and selective estrogen receptor modulators is affected. Additionally, the 3′UTR of the ZNF423 mRNA contains sites for miR195 (35, 53) and miR23a (36), which control expression.
Figure 2
Figure 2
Model for role of ZNF423 and CTSO genes in controlling BRCA1 in ER+ breast cancer (BC). The results (–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).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: convergence of incidence rates between black and white women. CA Cancer J Clin (2016) 66(1):31–42.10.3322/caac.21320 - DOI - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin (2018) 68:7–30.10.3322/caac.21442 - DOI - PubMed
    1. Mirkin S, Pickar JH. Selective estrogen receptor modulators (SERMs): a review of clinical data. Maturitas (2015) 80(1):52–7.10.1016/j.maturitas.2014.10.010 - DOI - PubMed
    1. Li F, Dou J, Wei L, Li S, Liu J. The selective estrogen receptor modulators in breast cancer prevention. Cancer Chemother Pharmacol (2016) 77(5):895–903.10.1007/s00280-016-2959-0 - DOI - PubMed
    1. Cuzick J. Preventive therapy for cancer. Lancet Oncol (2017) 18(8):e472–82.10.1016/S1470-2045(17)30536-3 - DOI - PubMed

LinkOut - more resources