Abstract PD09-01: BRCA1 inactivation induces NF-κB in human breast cancer cells and in murine and human mammary glands

Abstract Understanding the biological mechanisms underlying the initiation and progression of breast cancer it is an important step for its prevention and treatment. In 2011 in the United States, approximately 230,000 women were diagnosed with breast cancer and 40,000 died. Individuals with mutations in breast cancer-associated gene 1 (BRCA1) have a lifetime risk of developing breast cancer up to 85%. It is well known that BRCA1 participates in DNA damage repair and cell cycle checkpoint control, serving as a tumor suppressor gene to maintain the global genomic stability. 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 NF-κB activity is increased in both mammary carcinoma cell lines and primary human breast cancer tissue. Indeed, in a previous study it has been demonstrated that NF-κB inducible kinase (NIK), p100/p52 and RelB (all components of the alternative NF-κB pathways) were increased in BRCA1-mutated tumors. Here we show that BRCA1-loss or -mutation is responsible for activation of the alternative NF-κB pathway evidenced by NIK and IκB kinase-α (IKKα) phosphorylation, processing of p100 to p52 and p52/RelB nuclear localization. Moreover, increased p52 was also observed after BRCA1 inhibition. A BRCA1-mutated human breast cancer cell line (HCC1937) was also used to understand the role played by NIK in NF-κB alternative pathway activation. Indeed, NIK inhibition in HCC1937 cell line resulted in a decrease in p52 formation. Moreover, a decrease in NIK mRNA level was also observed when wild-type BRCA1 was reconstituted in HCC1937 cells. BRCA1 inactivation in MCF-7 cells also induced NIK phosphorylation and nuclear localization of RelB and p52. Overall, these data show that inactivation of BRCA1 increases NIK mRNA level, associated with induction of the NF-κB alternative pathway. Stem/progenitors cells sorted using the CD24/CD49f immunophenotype derived from BRCA1 knockout mouse mammary glands showed alternative NF-κB pathway activation. Inhibition of IKKα/β using BMS-345541 completely blocked mammary colony formation in a Matrigel assay. Moreover, increased p52 formation was found in mammary stem/progenitor cells and mammary gland paraffin sections obtained from BRCA1 knockout mice. 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. Our data show that BRCA1 inactivation induces alternative NF-κB activation which ultimately promotes the expansion of the 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-κB pathway could be of benefit in the prevention of BRCA1-associated breast cancer by limiting progenitor cell expansion. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-01.

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