BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality.

The discovery of and as tumor susceptibility genes and their role in genome maintenance has transformed our understanding of hereditary breast and ovarian cancer. This review traces the evolution of BRCA1/2 research over the past 30 years, highlighting key discoveries in the field and their contributions to tumor development. Additionally, we discuss current preventive measures for mutation carriers and targeted treatment options based on the concept of synthetic lethality.

Mechanisms that clear mutations drive field cancerization in mammary tissue.

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1;Trp53 cells, and find that both follow a similar pattern of loss and spread within ducts.

Transcriptomic Analysis of Pubertal and Adult Virgin Mouse Mammary Epithelial and Stromal Cell Populations.

Conflicting data exist as to how mammary epithelial cell proliferation changes during the reproductive cycle. To study the effect of endogenous hormone fluctuations on gene expression in the mouse mammary gland, we performed bulk RNAseq analyses of epithelial and stromal cell populations that were isolated either during puberty or at different stages of the adult virgin estrous cycle. Our data confirm prior findings that proliferative changes do not occur in every mouse in every cycle.

Rat Models of Hormone Receptor-Positive Breast Cancer.

Hormone receptor-positive (HR) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70-80% of all invasive cases. Patients with HR BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy.

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation.