Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Abstract

The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.

Keywords: Fanconi anemia; SNP; breast cancer; predisposition; susceptibility.

FIGURE 1

The schematic elucidation of the FA pathway mechanism used during DNA repair. In response to exogenous and/or endogenous damage, 8 FA genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) were assembled into the FA core complex, which functioned as a nuclear E3 ubiquitin ligase complex, to monoubiquitinate the I-D heterodimer. The monoubiquitinated I-D heterodimer was localized to the damaged chromatin, and interacted with DNA-repair proteins and other FA proteins (FANCD1, FANCDN, FANCJ, and FANCS) in the FA pathway, to conduct the repair process through homologous recombination (HR). After the damage was repaired, monoubiquitin was removed from the I-D complex by a de-ubiquitylation enzyme, Ubiquitin Specific Peptidase 1 (USP1), to “turn off” the network.

FIGURE 2

The mechanisms of tumorigenesis attributable to FA mutations. FA genes maintain genomic integrity through the different phases of the cell cycle, by participating in the DDR process, replication fork protection, normal centrosome function, and spindle assembly checkpoints. Mutations on different FA genes are involved in different mechanisms during the cell cycle, causing genomic instability, and causing a predisposition to cancer.

FIGURE 3

Functional domains of BRCA1/2 protein with pathogenic mutations. (A) The functional domains of the BRCA1 protein, mainly containing the RING-finger, SQ-cluster, and BRCT (middle) domains, functionally interacted with BARD1, RAD51C, and ATM (beneath), to orchestrate homologous recombination. The selected reported pathogenic mutations are indicated with black arrows, as shown. (B) BRCA2 was represented by a similar schematic figure with different functional domains (middle) and binding partners (beneath); confirmed pathogenic mutations are also shown above.