DNA Damage Signalling in BRCA1-Deficient Mammary Progenitor Cells Activates Autologous p52/RelB NF-κB

Abstract

Understanding the biological mechanisms underlying the initiation and progression of breast cancer is an important step for its prevention and treatment. We used an in vitro and in vivo model to demonstrate that p100/p52 and RelB are strongly activated in BRCA1-deficient mouse mammary progenitor cells and human BRCA1-mutation carriers. We found that NF-κB activation induces stem and progenitor cell expansion and inhibits differentiation. Knockdown and pharmacological inhibition showed that the progesterone-independent growth of BRCA1-deficient progenitor cells requires the alternative NF-κB activation mediated by ATM. Remarkably, treatment of mice with the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) resulted in prolonged repression of BRCA1-deficient progenitor cell proliferation, revealing a possible approach to cyclic chemoprevention.