Samenvatting

Hereditary Breast and Ovarian Cancer (HBOC) typically arises from mutations inherited in the germline. BRCA1 and BRCA2 mutaions are predominant contributors to HBOC, accounting for the majority of cases. These mutations are associated with 10% of ovarian cancer cases and 3-5% of breast cancer cases [4].

BRCA1 has crucial domains, including a zinc-binding RING domain, forming an ubiquitin ligase complex (E3) with BARD1. Ubiquitination, activated by ATP, removes damaged proteins and regulating cell functions. The RING finger enables substrate and ubiquitination-conjugating enzyme (E2) interaction, essential for BRCA1's function in tumor suppression. [4,5] The structure of the BRCA1/BARD1 heterodimer has revealed valuable insights into the function of the BRCA1 RING domain. Mutations in cysteine residues coordinating Zn2+ atoms in Site I and Site II can significantly impact function and increase cancer risk. Mutations in these sites alter the RING domain's folding, reduce Zn2+ binding, and decrease ubiquitin ligase activity and BRCA1/BARD1 interactions. These mutations are associated with an elevated risk of breast cancer [4].

BRCA1 proteins are vital for preserving genomic integrity by facilitating accurate DNA repair via homologous recombination. When BRCA1 function is lost, non-tumorigenic cells can transform into cancer stem cells (CSCs). Non-functional BRCA1 and mismatch repair genes contribute significantly to familial cancers. Defects in homologous recombination and mismatch repair pathways provide treatment options. Approximately 50% of hereditary cancer cases involve genes responsible for DNA repair and genome maintenance. In breast cancer, genetic factors like BRCA1 mutations increase the risk, although most genetic drivers remain unidentified. A deeper understanding of these risks can aid in personalized cancer prevention and screening strategies, as HBOC is often associated with BRCA1 and BRCA2 mutations, leading to elevated breast and ovarian cancer risks along with reduced risks of other cancer types [9,10,11]. The goal of this review is to underline how inherited BRCA1 gene mutations cause breast cancer.