BRCA1: An Unrecognized Modulator of Lineage Plasticity in Basal-like Breast Cancer

Among breast cancer subtypes, basal-like breast cancer (BLBC) is a highly aggressive form characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor (HER2) expression and is associated with poor prognosis, leaving chemotherapy as the sole treatment option available. Loss-of-function mutations in BRCA1 are strongly associated with the development of BLBC. Patients with this subtype are more likely to have grade III tumors and larger average tumor sizes than those with other subtypes of breast cancer. It is not known whether BRCA1 loss of function affects all cell types equally within breast tissue or if it has a preferential malignant impact on specific cell types, leading to the progression of lineage-specific tumorigenesis in the breast epithelium of women carrying BRCA1 mutations. Lineage tracing experiments using genetically engineered mouse models have provided critical insights into how BRCA1 loss alters cellular hierarchy within the mammary gland. These studies have demonstrated that BRCA1-deficient luminal progenitors can aberrantly differentiate into basal-like cells, suggesting that BLBC may arise from a misregulated luminal compartment rather than pre-existing basal stem cells. Understanding the mechanisms underlying BRCA1-mediated lineage plasticity offers novel therapeutic avenues to target early-stage tumor initiation and progression in BRCA1-mutated breast cancer. This review perspective sheds light on the role of BRCA1 in lineage plasticity and highlights probable mechanisms by which BRCA1 could promote this lineage plasticity.