BARD1 and Breast Cancer: The Possibility of Creating Screening Tests and New Preventive and Therapeutic Pathways for Predisposed Women

Abstract

Current oncological developments are based on improved understanding of genetics, and especially the discovery of genes whose alterations affect cell functions with consequences for the whole body. Our work is focused on the one of these genes, BRCA1-associated RING domain protein 1 (BARD1), and its oncogenic role in breast cancer. Most importantly, the study points to new avenues in the treatment and prevention of the most frequent female cancer based on BARD1 research. The BARD1 and BRCA1 (BReast CAncer type 1) proteins have similar structures and functions, and they combine to form the new molecule BARD1-BRCA1 heterodimer. The BARD1-BRCA1 complex is involved in genetic stabilization at the cellular level. It allows to mark abnormal DNA fragments by attaching ubiquitin to them. In addition, it blocks (by ubiquitination of RNA polymerase II) the transcription of damaged DNA. Ubiquitination, as well as stabilizing chromatin, or regulating the number of centrosomes, confirms the protective cooperation of BARD1 and BRCA1 in the stabilization of the genome. The overexpression of the oncogenic isoforms BARD1β and BARD1δ permit cancer development. The introduction of routine tests, for instance, to identify the presence of the BARD1β isoform, would make it possible to detect patients at high risk of developing cancer. On the other hand, introducing BARD1δ isoform blocking therapy, which would reduce estrogen sensitivity, may be a new line of cancer therapy with potential to modulate responses to existing treatments. It is possible that the BARD 1 gene offers new hope for improving breast cancer therapy.

Keywords: BARD1; breast cancer; chemotherapy; genetic testing; management; neoadjuvant; predisposition; surveillance; susceptibility.

Figure 1

Schematic structures of BRCA1, BARD1, and isoforms: BARD1β, BARD1δ. RING finger domains enable to form a stable complex between BRCA1 and BARD1. NES are nuclear export signals which together with NLS (nuclear localization signals) are necessary for proper intracellular localization of BARD1. ANK (Ankyrin repeats) interacts with several proteins including p53 and NF-κB. BRCT (BRCA1 carboxy-terminal domain) motifs fold into a binding pocket with a key lysine residue (K619).