Abstract
BackgroundThe activation of the NF-κB pathway plays a crucial role in the progression of breast cancer (BCa) and also involved in endocrine therapy resistance. On the contrary to the canonical NF-κB pathway, the effect of the noncanonical NF-κB pathway in BCa progression remains elusive.MethodsBCa tumor tissues and the corresponding cell lines were examined to determine the correlation between RelB and the aggressiveness of BCa. RelB was manipulated in BCa cells to examine whether RelB promotes cell proliferation and motility by quantitation of apoptosis, cell cycle, migration, and invasion. RNA-Seq was performed to identify the critical RelB-regulated genes involved in BCa metastasis. Particularly, RelB-regulated MMP1 transcription was verified using luciferase reporter and ChIP assay. Subsequently, the effect of RelB on BCa progression was further validated using BCa mice xenograft models.ResultsRelB uniquely expresses at a high level in aggressive BCa tissues, particularly in triple-negative breast cancer (TNBC). RelB promotes BCa cell proliferation through increasing G1/S transition and/or decreasing apoptosis by upregulation of Cyclin D1 and Bcl-2. Additionally, RelB enhances cell mobility by activating EMT. Importantly, RelB upregulates bone metastatic protein MMP1 expression through binding to an NF-κB enhancer element located at the 5′-flanking region. Accordingly, in vivo functional validation confirmed that RelB deficiency impairs tumor growth in nude mice and inhibits lung metastasis in SCID mice.DZN_5Vqa81wW39kH5tnWrvVideo abstract
Highlights
The activation of the Nuclear factor-κb (NF-κB) pathway plays a crucial role in the progression of breast cancer (BCa) and involved in endocrine therapy resistance
RelB upregulates bone metastatic protein Matrix metalloproteinase-1 (MMP1) expression through binding to an NF-κB enhancer element located at the 5′-flanking region
RelB is correlated with BCa aggressiveness We analyzed the BCa cohort in The Cancer Genome Atlas (TCGA) database to examine whether the expression level of RelB is correlated to BCa progression and patient survival
Summary
The activation of the NF-κB pathway plays a crucial role in the progression of breast cancer (BCa) and involved in endocrine therapy resistance. Owing to improved early diagnosis and advanced therapy strategies, the current death rates of BCa have appreciatively decreased in the Western developed countries, including the United States. Distant-organ metastasis associated with endocrine therapy resistance still remains as a large obstacle to successful control of advanced BCa [3, 4]. BCa patients with distant metastasis at the time of diagnosis appeared to be worse prognosis with a 5-year survival rate of 23.4% [5]. Since metastasis is the main cause of death of BCa patients, the key for improving the BCa survival rate is to accurately evaluate the metastatic potential for the
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