100P - BRCA1 Inactivation Induces Alternative NF-κB Pathway Activation in Human Breast Cancer Cells and Mammary Glands

Abstract

Understanding the biological mechanisms underlying the initiation and progression of breast cancer it is an important step for prevention and treatment. Individuals with mutations in breast cancer-associated gene 1 (BRCA1) have up to an 85% increased risk of developing breast cancer during their lifetime. It is well known that BRCA1 participates in DNA damage repair and cell cycle checkpoint control. However, BRCA1 has also been shown to play a key role in maturation of mammary stem/progenitor cells, which are the targets for carcinogenesis in individuals who have undergone loss of heterozygosity (LOH) for BRCA1. Recently, it has also been shown that p100/p52 and RelB (all components of the alternative NF-kB pathways) were increased in BRCA1-mutated tumors. Here we show that BRCA1-loss or -mutation is responsible for activation of the alternative NF-kB pathway evidenced by I&kgr;B kinase-α (IKKa) phosphorylation, processing of p100 to p52 and p52/RelB nuclear localization. Stem/progenitors cells derived from BRCA1 knockout mouse mammary glands showed alternative NF-kB pathway activation. Inhibition of IKKα/β using BMS-345541 completely blocked mammary colony formation in a Matrigel assay. Remarkably, RelB and p100/p52 were highly expressed in 20-50% of the lobular structures in histologically normal breast tissue obtained from human BRCA1 mutation carriers while no staining was evident in normal tissue from non-carrier mastectomy samples. We also demonstrated that BRCA1 inhibition induces an increase of SLUG protein levels while p100 knock down through shRNA decreases SLUG and c-myc protein levels in the HCC1937 basal breast cancer cell line. Our data show that BRCA1 inactivation induces alternative NF-kB activation, an increase in SLUG protein levels and ultimately an expansion of aberrant mammary progenitor population. These novel findings provide a new basis for functional classification of BRCA1 mutations and a potential method for predicting breast cancer in BRCA1 mutation carriers. Lastly our results suggest that targeting the alternative NF-&kgr;B pathway could be of benefit in the prevention of BRCA1-associated breast cancer by limiting the expansion of aberrant progenitor cell populations. Disclosure: All authors have declared no conflicts of interest.