Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth

Abstract

Introduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triplenegative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA. Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively. Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model. Conclusion:Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.

stMMR: accurate and robust spatial domain identification from spatially resolved transcriptomics with multi-modal feature representation

“…(regulated by NFKB1), and TRR01158 (regulated by RELA) -have also been confirmed in previous studies to play pivotal roles in the development and progression of breast cancer (64)(65)(66)(67)(68).…”

Subtype and cell type specific expression of lncRNAs provide insight into breast cancer

“…4f, Supplementary Data 6). On the other hand, promoters of the lncRNAs highly expressed in ER negative tumors were enriched for BATF3, MAF, and RELA, components of the NF-κB TF complex, shown to be constitutively active in triple negative breast cancer 33 (Fig. 4g, Supplementary Data 6).…”

“…ChIA-PET (ENCODE) and TF ChIP-seq (ReMap) data from MCF7, both used for Fig. 5e, h, can be obtained from ENCODE (ENCSR000CAA; https://www.encodeproject.org/experiments/) 33 , and ReMap 2018 72 database (ENCSR000BST.GATA3.MCF7, ERP000783.ESR1.MCF7, and GSE72249.FOXA1.MCF7). Source data for Fig.…”

Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells

“…NF-κB p65 expression (nuclear and cytoplasmic) and I-κB expression were higher and lower, respectively, in MDA-MB-231 and BT-549 cells than in MCF-10A cells. The expression of RELA is higher in patients with TNBC than in patients with other breast cancer subtypes (luminal A, luminal B, and HER2-positive) and in normal breast tissue [ 4 ]. In addition, NFKBIA deletion is associated with poor disease-specific survival, recurrence-free survival, and distant metastasis survival in patients with TNBC [ 15 ].…”

“…Recently, NF-κB p65 (RELA) gene expression was reported to be increased in TNBC compared to that in other subtypes, deeply involved in TNBC stem cell survival, and activated during the recurrence of breast cancers, including TNBC [ 4 , 5 , 6 ]. NF-κB, a transcription factor that promotes cell proliferation, differentiation, and survival, is involved in tumorigenesis and cancer survival in various solid tumors, including pancreatic, lung, cervical, prostate, breast, and gastric cancers [ 7 ].…”