The transcription factor forkhead box C1 (FOXC1) has recently been proposed as a crucial regulator of triple‐negative breast cancer (TNBC) and associated with TNBC metastasis. However, the mechanism of FOXC1 in TNBC development and metastasis is elusive. In this study, overexpression of FOXC1 in MDA‐MB‐231 cells significantly enhanced, whereas knockdown of FOXC1 in BT549 cells significantly reduced, the capabilities of TNBC cell invasion and motility in vitro and metastasis to the lung in vivo, when compared to their respective control cells. Mechanistic studies revealed that FOXC1 increased the expression of CXC chemokine receptor‐4 (CXCR4), probably through transcriptional activation. AMD3100, an inhibitor of CXCR4, could block cell migration. In a zebrafish tumor model, AMD3100 could suppress cell invasion and metastasis. In addition, overexpressing CXCR4 in FOXC1‐knockdown BT549 cells increased the capabilities of TNBC cell invasion and motility. In contrast, inhibition of CXCR4 with either AMD3100 or siRNA in MDA‐MB‐231 cells overexpressing FOXC1 reduced the capabilities of invasion and motility. Taken together, our results reveal a potential mechanism for FOXC1‐induced TNBC metastasis.

BackgroundAldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle. Recently, a new role of ALDOA in several cancers has been proposed. However, the underlying mechanism remains obscure and inconsistent. In this study, we tried to investigate ALDOA-associated (AA) genes using available microarray datasets to help elucidating the role of ALDOA in cancer.ResultsIn the dataset of patients with non-small-cell lung cancer (NSCLC, E-GEOD-19188), 3448 differentially expressed genes (DEGs) including ALDOA were identified, in which 710 AA genes were found to be positively associated with ALDOA. Then according to correlation coefficients between each pair of AA genes, ALDOA-associated gene co-expression network (GCN) was constructed including 182 nodes and 1619 edges. 11 clusters out of GCN were detected by ClusterOne plugin in Cytoscape, and only 3 of them have more than three nodes. These three clusters were functionally enriched. A great number of genes (43/79, 54.4%) in the biggest cluster (Cluster 1) primarily involved in biological process like cell cycle process (P a = 6.76E-26), mitotic cell cycle (P a = 4.09E-19), DNA repair (P a = 1.13E-04), M phase of meiotic cell cycle (P a = 0.006), positive regulation of ubiquitin-protein ligase activity during mitotic cell cycle (P a = 0.014). AA genes with highest degree and betweenness were considered as hub genes of GCN, namely CDC20, MELK, PTTG1, CCNB2, CDC45, CCNB1, TK1 and PSMB2, which could distinguish cancer from normal controls with ALDOA. Their positive association with ALDOA remained after removing the effect of HK2 and PKM, the two rate limiting enzymes in glycolysis. Further, knocking down ALDOA blocked breast cancer cells in the G0/G1 phase under minimized glycolysis. All suggested that ALDOA might affect cell cycle progression independent of glycolysis. RT-qPCR detection confirmed the relationship of ALDOA with CDC45 and CCNB2 in breast tumors. High expression of the hub genes indicated poor outcome in NSCLC. ALDOA could improve their predictive power.ConclusionsALDOA could contribute to the progress of cancer, at least partially through its association with genes relevant to cell cycle independent of glycolysis. AA genes plus ALDOA represent a potential new signature for development and prognosis in several cancers.

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Objective: Invasive breast carcinoma (BRCA) is the most common cancer in women, and the prognosis of BRCA patients is poor. Lysine oxidase-like (LOXL) family genes have been demonstrated to be dysregulated in some malignancies and play crucial roles in tumor progression. However, the exact expression patterns and prognostic value of LOXL1-4 in BRCA remain unclear.Methods: Here, we investigated the expression levels, genetic variation, gene–gene interaction network, and prognostic value of LOXL1-4 in patients with BRCA using R and existing public bioinformatics databases. Gene ontology (GO) and KEGG pathway enrichment analyses were performed to explore biological functions via DAVID 6.8 and R. Moreover, GDSC and CTRP drug sensitivity data were analyzed to reveal that LOXL1-4 were correlated with the drug response across cancers. The relationship between LOXL1-4 expression and tumor immune infiltration was studied in the TIMER database.Results: The results revealed that LOXL1/2/4 were aberrantly expressed in BRCA. Moreover, LOXL1/2/4 expression was significantly associated with relapse-free survival (RFS), and LOXL4 expression was significantly associated with overall survival (OS). LOXL2 expression was associated with distant metastasis-free survival (DMFS). Immune score analysis showed that LOXL1-4 were significantly related to the tumor immune microenvironment and markedly correlated with immune cell infiltration. Further analysis demonstrated that copy number variations (CNVs) of LOXL1-4 were obviously associated with immune infiltration in BRCA and that CNV of LOXL2 was markedly associated with the OS and PFS of patients with BRCA.Conclusion: Our study reveals that LOXL1-4 expression is correlated with prognosis and immune infiltration levels, possibly providing new insights into immunotherapy for patients with breast cancer.

Purpose: Forkhead box C1 (FOXC1) may act as a therapeutic target for triple-negative breast cancer (TNBC) but without a comprehensive understanding of its regulations, especially at the upstream. L1 cell adhesion molecule (L1CAM) is a transmembrane glycoprotein that may involve in brain metastasis. Indicated by a positive correlation between FOXC1 and L1CAM transcripts, this study aims to further examine their relation in the process of TNBC. Methods: FOXC1 and L1CAM transcripts were downloaded fromtwo public datasets, and their proteins were examined in four TNBC cell lines. FOXC1 and L1CAM were separately knocked down in BT549 cells; L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell and wound healing assays were conducted in these cells, so was immunohistochemical staining in tumors. Results: L1CAM and FOXC1 transcripts were positively correlated in public datasets. BT549-shFOXC1 cells showed a decreased L1CAM expression both at the transcriptional and protein levels. Intriguingly, BT549-siL1CAM cells displayed decreased FOXC1 proteins, but exerted little effect on FOXC1 transcripts. Conversely, overexpression of L1CAM resulted in upregulation of FOXC1 protein without substantial change in FOXC1 mRNA, that consistently observedin BT549-shFOXC1, MDA-MB-231-L1CAM and HCC1937-L1CAM cells. Additionally, decreased or increased capacities of cell proliferation, migration, and invasion were seen along with down- or up-regulation of FOXC1 or L1CAM. Finally, a positive correlation between L1CAM and FOXC1 proteins was observed in human TNBC tumors. Conclusion:FOXC1 and L1CAM display coregulation at the protein level but not mRNA level to positively affect cell proliferation, migration and invasion in TNBC.