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Breast cancer is the most common malignancy in women. Metastatic breast cancer is incurable and is a major cause of shortened patient survival. The different molecular types of breast cancer make targeted therapy difficult and a complex challenge. Aryl hydrocarbon receptor (AhR) is an evolutionarily conserved transcription factor that has been implicated in the metabolism of xenobiotic ligands. AhR is activated by numerous exogenous and endogenous ligands and participates in multiple physiological processes, including proliferation, migration, invasion and apoptosis. AhR expression is upregulated in certain breast cancer subtypes, including estrogen receptor-positive breast cancer, and has been implicated in the development and progression of breast cancer. Over the last two decades, AhR and its ligands have emerged as novel biological targets for the treatment of breast cancer. Both AhR agonists and antagonists may be effective in inhibiting critical activities of breast cancer. The present review evaluates the role and underlying mechanisms of AhR and its ligands in breast cancer and demonstrates the potential of exploiting AhR as a novel target for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Recent studies have shown that microRNAs (miRs) play a key role in the regulation of cancer development. In the present study, reverse transcription-quantitative PCR was used to detect the expression of miR-1 in breast cancer and adjacent tissues, and survival analysis was performed to compare the low-expression groups with the Kaplan-Meier method. Overexpression of miR-1 was used to observe the effects on the proliferation, migration and invasion of breast cancer cells in vitro and in vivo. Moreover, Bcl-2 expression was measured by western blotting and luciferase assays after the overexpression of miR-1. The present study reported that miR-1 is expressed at low levels in breast cancer and that cell proliferation, migration and invasion are inhibited in miR-1-overexpressing cells. Enhanced miR-1 expression can also increase cell apoptosis. The present study also demonstrated that Bcl-2 is a potential target of miR-1. In vivo studies indicate that overexpression of miR-1 decreases tumor volume and weight in nude mice. The data from the present study demonstrated for the first time that overexpression of miR-1 increases the sensitivity of breast cancer cells to paclitaxel and cisplatin. The present study provided new evidence for the important role of miR-1 in the tumorigenesis and drug sensitivity of breast cancer. [ABSTRACT FROM AUTHOR]

Transgelin 2 (TAGLN2) is a cytoskeletal protein of the calponin family. Abnormal expression of TAGLN2 was observed in various types of cancer. Our previous study reported that TAGLN2 expression was reduced in lymph node-positive breast cancer patients; however, the role of TAGLN2 in breast cancer metastasis remains unknown. In the present study, the role of TAGLN2 in breast cancer metastasis was investigated in vitro and in vivo via Transwell migration, luciferase and flow cytometry assays, and a mouse xenograft model. Proteins interacting with TAGLN2 were identified via co-immunoprecipitation assays and liquid chromatography/mass spectrometry, and the signaling pathway associated with the effects of TAGLN2 was investigated. Additionally, western blotting and reverse transcription-quantitative polymerase chain reaction were performed to further explore the potential pathway in which TAGLN2 may be involved and the mechanism underlying its effects in breast cancer metastasis. The present study reported that TAGLN2 expression was increased by 11.4-fold in patients without distant metastasis compared with those positive for distant metastasis. Knockdown of TAGLN2 resulted in increased cell migration in vitro and promoted lung metastasis in vivo. Additionally, overexpression of TAGLN2 suppressed lung metastasis in a mouse model. Peroxiredoxin 1 (PRDX1), an important reactive oxygen species (ROS) regulator, was revealed to interact with TAGLN2. In addition, mitochondrial redistribution and PRDX1 downregulation were reported following TAGLN2 silencing, which promoted ROS production and nuclear factor (NF)-κB activation in breast cancer cells. This induced the expression of metastasis-associated genes, including C-X-C chemokine receptor 4, matrix metalloproteinase (MMP)1 and MMP2. The present study proposed TAGLN2 to function as a tumor suppressor and that loss of TAGLN2 may promote the metastasis of breast cancer by activating the ROS/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Benzyl isothiocyanate (BITC) has been reported to exhibit antitumor properties in various cancer types; however, the underlying mechanisms of its action remain unclear. In the present study, the efficacy of BITC on murine mammary carcinoma cells was evaluated in vitro and in vivo, revealing a potential mechanism for its action. In vivo bioluminescence imaging indicated dynamic inhibition of murine mammary carcinoma cell growth and metastasis by BITC. A terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay demonstrated that BITC also induced apoptosis. BITC further exhibited antitumorigenic activity in 4T1-Luc cells in vitro via the inhibition of cell proliferation, induction of apoptosis and cell cycle arrest, and inhibition of cell migration and invasion. Furthermore, the activity of key molecules of the adenomatous polyposis coli (APC)/β-catenin complex was altered following treatment with BITC, which suggested a potential role for the APC/β-catenin complex in the BITC-mediated induction of apoptosis and inhibition of metastasis in murine mammary carcinoma. BITC upregulated the activity of glycogen synthase kinase-3β and APC proteins, whereas it downregulated β-catenin expression. The inhibition of metastasis was accompanied with the downregulation of vimentin and upregulation of E-cadherin. Conversely, BITC did not exhibit toxicity or side effects in the normal mammary epithelial cell line MCF-10A. The present study indicated that BITC exhibited anticancer properties due to the induction of breast cancer cell apoptosis and inhibition of breast cancer cell metastasis mediated by the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the feature genes in metastatic breast cancer samples. A total of 5 expression profiles of metastatic breast cancer samples were downloaded from the Gene Expression Omnibus database, which were then analyzed using the MetaQC and MetaDE packages in R language. The feature genes between metastasis and non‑metastasis samples were screened under the threshold of P<0.05. Based on the protein‑protein interactions (PPIs) in the Biological General Repository for Interaction Datasets, Human Protein Reference Database and Biomolecular Interaction Network Database, the PPI network of the feature genes was constructed. The feature genes identified by topological characteristics were then used for support vector machine (SVM) classifier training and verification. The accuracy of the SVM classifier was then evaluated using another independent dataset from The Cancer Genome Atlas database. Finally, function and pathway enrichment analyses for genes in the SVM classifier were performed. A total of 541 feature genes were identified between metastatic and non‑metastatic samples. The top 10 genes with the highest betweenness centrality values in the PPI network of feature genes were Nuclear RNA Export Factor 1, cyclin‑dependent kinase 2 (CDK2), myelocytomatosis proto‑oncogene protein (MYC), Cullin 5, SHC Adaptor Protein 1, Clathrin heavy chain, Nucleolin, WD repeat domain 1, proteasome 26S subunit non‑ATPase 2 and telomeric repeat binding factor 2. The cyclin‑dependent kinase inhibitor 1A (CDKN1A), E2F transcription factor 1 (E2F1), and MYC interacted with CDK2. The SVM classifier constructed by the top 30 feature genes was able to distinguish metastatic samples from non‑metastatic samples [correct rate, specificity, positive predictive value and negative predictive value >0.89; sensitivity >0.84; area under the receiver operating characteristic curve (AUROC) >0.96]. The verification of the SVM classifier in an independent dataset (35 metastatic samples and 143 non‑metastatic samples) revealed an accuracy of 94.38% and AUROC of 0.958. Cell cycle associated functions and pathways were the most significant terms of the 30 feature genes. A SVM classifier was constructed to assess the possibility of breast cancer metastasis, which presented high accuracy in several independent datasets. CDK2, CDKN1A, E2F1 and MYC were indicated as the potential feature genes in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to screen the prognostic targets for breast cancer based on a co‑expression modules analysis. The microarray dataset GSE73383 was downloaded from the Gene Expression Omnibus (GEO) database, including 15 breast cancer samples with good prognosis and 9 breast cancer samples with poor prognosis. The differentially expressed genes (DEGs) were identified with the limma package. The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, the co‑expression analysis of DEGs was conducted with weighted correlation analysis. The interaction associations were analyzed with the Human Protein Reference Database and BioGRID. The protein‑protein interactions (PPI) network was constructed and visualized by Cytoscape software. A total of 491 DEGs were identified in breast cancer samples with poor prognosis compared with those with good prognosis, and they were enriched in 85 GO terms and 4 KEGG pathways. 368 DEGs were co‑expressed with others, and they were clustered into 10 modules. Module 6 was the most relevant to the clinical features, and 21 genes and 273 interaction pairs were selected out. Abnormal expression levels of required for meiotic nuclear division 5 homolog A (RMND5A) and angiopoietin‑like protein 1 (ANGPTL1) were associated with a poor prognosis. It was indicated that SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, dihydropyrimidinase‑like 2, RMND5A and ANGPTL1 were potential prognostic markers in breast cancer, and the cell cycle may be involved in the regulation of breast cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) pathway in circulating tumor cells (CTCs) and corresponding cancerous tissues. Stemness-like circulating tumor cells (slCTCs) and CTCs in epithelial-mesenchymal transition (EMT) have been implicated as the active source of metastatic spread in breast cancer (BC). In this regard, the PI3KCA-AKT signaling pathway was demonstrated to be implicated in and to be frequently mutated in BC. The present study compared this pathway in slCTCs/CTCs in EMT and the corresponding tumor tissues of 90 metastatic BC patients (pts). slCTCs and CTCs in EMT were isolated using the AdnaTest EMT-1/StemCell for the detection of aldehyde dehydrogenase 1 family member A1 (ALDH1) (singleplex PCR) and PI3KCA, AKT2 and twist family bHLH transcription factor 1 (multiplex PCR). Tumor tissue was investigated for PI3KCA hotspot mutations using Sanger sequencing of genomic DNA from micro-dissected formalin-fixed paraffin-embedded tissue, and for the expression of ALDH1 and phosphorylated AKT (pAKT), and phosphatase and tensin homolog (PTEN) loss, by immunohistochemistry. slCTCs were identified in 23% of pts (21/90 pts) and CTCs in EMT in 56% (50/90 pts) of pts. pAKT and ALDH1 positivity in tumor tissue was identified in 47 and 9% of cases, respectively, and a PTEN loss was observed in 18% of pts. A significant association was detected between pAKT expression in cancerous tissue and AKT2 expression in CTCs (P=0.037). PI3KCA mutations were detected in 32% of pts, most frequently on exons 21 (55%) and 10 (45%). Pts with PI3KCA mutations in tumor tissue had a significantly longer overall survival than pts with wild-type PI3KCA expression (P=0.007). Similar results were obtained for pts with aberrant PI3KCA signaling in CTCs and/or aberrant signaling in cancerous tissue (P=0.009). Therapy-resistant CTCs, potentially derived from the primary tumor or metastatic tissue, may be eliminated with specific PI3K pathway inhibitors, alone or in combination, to improve the prognosis of metastatic BC pts. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the expression status and clinical implications of DEK in breast cancer, in order to contribute to developments in breast cancer management. DEK expression status was detected in 628 breast cancer specimens by western blot analysis and immunohistochemistry staining, and the correlation between DEK protein and clinico-pathological parameters and prognosis of breast cancer was subsequently determined. In comparison to para-carcinoma tissues, DEK protein was highly expressed in breast cancer specimens and was correlated with chemotherapy resistance. In total, 61.94% (389/628) of breast cancer cases exhibited high expression of DEK. According to universal analysis, it was observed that age, tumor size, histological grade, metastatic nodes and distant metastasis (P=0.024, 0.001, 0.001, 0.001 and 0.001 respectively) are key factors associated with DEK. Furthermore, compared with samples with no or low DEK protein expression, high DEK expression resulted in a significantly increased distant metastasis rate and poor disease-specific survival (P=0.001). In addition, DEK protein was detected as an independent prognostic factor (P=0.001) in the Cox regression analysis. DEK was correlated with chemotherapy resistance and may be an independent prognostic factor for breast cancer, as well as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Checkpoint with FHA and RING finger domains (CHFR) is a G2 phase/mitosis checkpoint. Several studies have reported that CHFR is downregulated in multiple cancer types and serves a tumor suppressor role. However, the biological function of CHFR in breast cancer (BRCA), particularly regarding metastasis, are yet to be elucidated. In the present study, it was revealed that CHFR is upregulated in BRCA compared with normal tissues, according to The Cancer Genome Atlas database. In addition, subgroup analysis of BRCA revealed that CHFR was upregulated in both human epidermal growth factor receptor 2-positive and triple-negative BRCA. Meanwhile, patients with high expression levels of CHFR exhibited poorer overall survival rates. Furthermore, the present data revealed that the overexpression of CHFR in SKBR3 cells resulted in enhanced cell migration and invasiveness, and also significantly upregulated mesenchymal markers, such as N-cadherin, vimentin, transcription factor Slug and tight junction protein claudin-1. Furthermore, knockdown of CHFR in MDA-MB-231 cells significantly inhibited cell migration and invasiveness, and also downregulated mesenchymal markers, such as N-cadherin, vimentin and tight junction protein claudin-1. In conclusion, the current results indicated that CHFR expression was associated with cell metastasis in BRCA by mediating epithelial-to-mesenchymal transition. [ABSTRACT FROM AUTHOR]