Progenitor cell origins of breast cancers arising in BRCA1 and BRCA2 mutation carriers: Role of NF-κB signaling
The mature mammary gland contains a stem/progenitor epithelial cell hierarchy which gives rise to the basal and luminal epithelia. In humans and mice this consists of rare stem/basal cell progenitors, luminal progenitors (LPs) and differentiated cells derived from each to form ducts, alveoli and myoepithelium. This cellular hierarchy can be FACS-enriched based on established surface markers. There are three main subtypes of breast cancer based on genomic signatures including claudin-low, basal and luminal, which derive from progenitor cells. Basal cancers are thought to arise from the RANK+/ER– LP subset of LPs while luminal cancers may arise from a different fraction of the LP population.
The transcription factor NF-κB has a central role in mammary epithelial cell proliferation. Progesterone (P4) regulates the expansion of Receptor Activator of NF-κB (RANK)pos LPs by inducing soluble RANK ligand (RANKL) expression in a subset of P4-receptor+ mature LPs thereby activating NF-κB through RANK in a paracrine manner. The FACS-enriched LP population can be further subdivided into RANKpos and RANKneg cells. NF-κB activity is also induced in an atypical manner by activation of the DNA damage response. We recently demonstrated that NF-κB is differentially and persistently activated in BRCA1-deficient mammary LPs associated with DNA damage. This is critical to the expansion of an aberrant LP population since it provides extended proliferative capacity even in the absence of hormonal signaling in the premalignant gland. Aberrant progenitor proliferation in vitro and the accumulation of these cells in vivo can be markedly inhibited by an NF-κB inhibitor. In contrast to BRCA1mut tumors, BRCA2mut tumors are RANKneg and the majority of these are classified with a luminal B (ER+) genomic signature. The RANKpos LP population is abnormally expanded in the mammary glands of BRCA1 mutation carriers (BRCA1mut/+). However the RANKpos LP population is not expanded in BRCA2mut/+ glands relative to normal controls. In new data we demonstrate that BRCA2-deficiency induces NF-κB and show that mammary glands harbor an expanded LP population that is RANKneg. We provide a functional and genetic mechanism underlying the marked differences in LP cell expansion in BRCA1mut/+ and BRCA2mut/+ mammary glands and the breast cancers derived from each.