Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

Abstract

Approximately 5-10% of all breast cancer (BC) cases are caused by germline pathogenic variants (GPVs) in various cancer predisposition genes (CPGs). The most common contributors to hereditary BC are BRCA1 and BRCA2, which are associated with hereditary breast and ovarian cancer (HBOC). ATM, BARD1, CHEK2, PALB2, RAD51C, and RAD51D have also been recognized as CPGs with a high to moderate risk of BC. Primary and secondary cancer prevention strategies have been established for HBOC patients; however, optimal preventive strategies for most hereditary BCs have not yet been established. Most BC-associated CPGs participate in DNA damage repair pathways and cell cycle checkpoint mechanisms, and function jointly in such cascades; therefore, a fundamental understanding of the disease drivers in such cascades can facilitate the accurate estimation of the genetic risk of developing BC and the selection of appropriate preventive and therapeutic strategies to manage hereditary BCs. Herein, we review the functions of key BC-associated CPGs and strategies for the clinical management in individuals harboring the GPVs of such genes.

Keywords: BRCA; cancer predisposition gene; cancer prevention; function; hereditary breast cancer.

Figure 1

Timeline reflecting the identification of 12 breast cancer predisposition genes.

Figure 2

Frequency of protein-truncating variants in 12 breast cancer predisposition genes in the population-based study reported by Dorling et al. [12].

Figure 3

Distinct functions of BRCA1 and BRCA2 in (a) homologous recombination (HR) repair, (b) DNA damage cell cycle checkpoint, (c) R-loop processing and transcription, and (d) DNA replication fork protection.

Figure 3

Distinct functions of BRCA1 and BRCA2 in (a) homologous recombination (HR) repair, (b) DNA damage cell cycle checkpoint, (c) R-loop processing and transcription, and (d) DNA replication fork protection.

Figure 4

Binding of estrogens (E2s) to estrogen receptor (ERα) transiently induces DNA double-strand breaks via topoisomerase II (TOP2). BRCA1 ensures genome integrity by removing the pathological TOP2–DNA complexes induced by estrogen. Abbreviations: ERE, estrogen responsive element; CoA, co-activator; NHEJ, non-homologous end-joining.

Figure 5

Carcinogenic mechanism of basal-like breast cancer (BC). Dysregulation of ESR1 transcription due to BRCA1 dysfunction inhibits luminal progenitor cell differentiation. RANK/RANK-L-mediated proliferation of BRCA1-deficient cells leads to the generation of driver mutations, resulting in the development of basal-like BC.