Effect of BRWD3 on lymph node metastasis in breast cancer / 解放军医学杂志

ABSTRACT

Objective: To explore the effect of the bromodomain and WD repeat domain containing 3 (BRWD3) on lymph node metastasis in breast cancer and its mechanism. Methods: In vitro cell invasion experiments were used to explore the effect of BRWD3 on the invasion phenotype of breast cancer cell lines. Mouse lymph node metastasis model and lung metastasis model were used to investigate the role of BRWD3 in regulating breast cancer lymph node metastasis and lung metastasis in BALB/c nude mice. The BRWD3 co-expressed genes were searched through cBioPortal databases to analyze the biological functions and pathways of BRWD3, constructed a BRWD3 molecular regulatory network, which is examined with Western blotting analysis partly. The public breast cancer dataset and the KMPLOT analysis platform was used to analyze the expression of BRWD3 in breast cancer and the relationship between the expression of BRWD3 and breast cancer prognosis. Results: In vitro experiments showed that knockdown of BRWD3 significantly enhanced the invasion and migration of breast cancer cells (P<0.01), but did not promote their proliferation. The lymph node metastasis model demonstrated that knockdown of BRWD3 dramatically enhanced lymph node metastasis of breast cancer. Interestingly, the lung metastasis model showed that BRWD3 did not affect the mouse lung metastasis ability. Further functional clustering GO analysis of the co-expressed genes of BRWD3 suggested that they are mainly involved in gene expression regulation, DNA damage repair, chromosome organization and modification, ubiquitination, etc. Meanwhile, KEGG enrichment analysis showed that they were involved in signaling pathways such as ubiquitination, oxidative phosphorylation, MAPK, etc. Besides, via the Western blotting experiment, it was found that knockdown of BRWD3 increased the phosphorylation of ERK1/2. Moreover, BRWD3 expression in breast cancer with lymph node metastasis is significantly lower than in patients without lymph node metastasis. Further, the survival analysis in KMPLOT found that the prognosis of patients with low expression of BRWD3 was poor, which was significantly lower than that of patients with high expression of BRWD3. Conclusions: BRWD3 can regulate breast cancer invasion in vitro and lymph node metastasis in vivo. Afterward, the prognosis of patients with low expression of BRWD3 is poor. Meanwhile, ubiquination, oxidative phosphorylation, MAPK pathway, etc. were the possible regulation pathways of BRWD3, which provide a new theoretical basis for the research and application of molecular markers related to breast cancer lymph node metastasis.