The vast majority of breast cancers has been shown to display aberrant constitutive expression of NF-kB subunits, which enhances their mobility and promotes their survival and malignancy. Recently, we demonstrated that the RelB NF-kB subunit promotes migration of breast cancer cells, in part via repression of estrogen receptor (ER)α transcription. Furthemore, we showed that inhibition of the ERα promoter was mediated by the zinc finger transcriptional repressor B lymphocyte-induced maturation protein (Blimp-1), transcribed from the PRDM1 gene, which is induced by RelB-mediated activation of a Bcl-2/Ras pathway. Indeed, we showed for the first time that Blimp-1 is present in breast cancer and is more highly expressed in ERα negative breast cancer cells where it plays an essential role in their migratory and invasive abilities. Blimp-1 is a well-known zinc finger repressor, which is critical for terminal differentiation of B and T cells and for migration of primordial germ cells. Here we have examined the mechanism of activation of Blimp-1 expression in breast cancer cells. Given the role of Ras to c-Raf signaling in migration of cancer cells, we tested the role of this downstream mediator. A constitutively active c-Raf led to induction of Blimp-1 in breast cancer lines while a dominant negative variant reduced its levels. RelB/p52 NF-kB complexes induced c-Jun, c-Fos, Fra-1 and Fra-2 Activator Protein-1 (AP-1) subunits, which activated the PRDM1 gene promoter. The transforming growth factor (TGF)-β induces a more mesenchymal phenotype of breast cancer cells. Treatment of NMuMG breast epithelial cells with TGF-β led to Blimp-1 activation through AP-1 and epithelial-to-mesenchymal transition (EMT). Importantly, Blimp-1 knockdown counteracted TGF-mediated EMT and wound healing in both NMuMG and MDA-MB-231 breast cells. Thus, activation of AP-1 complexes via a Ras/Raf/Erk signaling pathway mediates induction of PRDM1 gene transcription and Blimp-1 expression in ERα negative breast cancer cells, which is essential for TGF-β-induced mesenchymal phenotype. Therefore, downstream mediators of Blimp-1 activity might emerge as new therapeutic targets for treatment of patients with ERα negative breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-14.