Potential Biomarker For Breast Cancer Research Articles

Methylated PLK2 is a prognostic biomarker in taxane-treated breast cancers

Background: In search of potential biomarkers of drug responsiveness the tumour suppressor PLK2 has been identified as a mediator of taxane sensitivity in some tumour types, based on its role of G2M checkpoint regulation.Objective: The current study set out to evaluate PLK2 methylation in breast cancer treated with neo-adjuvant chemotherapy including a taxane, as a biomarker of disease progression.Methods: Silencing of PLK2 in MCF-7 cells followed by taxane treatment was assessed using apoptotic readout for proof of principle. DNA was extracted from 64 cases of diagnostic surgical FFPE sections. Using pyrosequencing, levels of PLK2 promoter methylation were measured.Results: Silencing of PLK2 resulted in a significantly reduced apoptotic response following paclitaxel treatment (compared with scramble transfected controls). An association with higher levels of CpG island promoter methylation was seen for those cases with a progression-free survival (PFS) of less than 12 months. Kaplan-Meier analysis showed there was an association between overall survival (OS) and level of methylation (p = .06).Conclusions: Thus, based on data obtained from this pilot study, further larger studies evaluating the utility of PLK2 methylation as a potential predictive biomarker in breast cancer are warranted.

LncRNA HOTAIR promotes breast cancer progression through regulating the miR-129-5p/FZD7 axis.

Breast cancer is the most common malignancies worldwide. LncRNA HOX transcript antisense intergenic RNA (HOTAIR) has been shown to promote progression and metastasis of various cancers, including breast cancer. This reasearch aimed to investigate the downstream regulatory pathways of HOTAIR in breast cancer. The levels of HOTAIR and miR-129-5p were examined in breast cancer tissues and SKBR3 and MCF7 cells by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined by Cell Counting Kit-8 (CCK-8) assay. Cell migration and invasion were estimated by transwell assay. Epithelial-to-mesenchymal transition (EMT)-related markers (E-cadherin, N-cadherin and Vimentin) were measured by Western blot assay. The expression of Frizzled 7 (FZD7) was detected using qRT-PCR or Western blot assay. Bioinformatics analysis, luciferase reporter assay or RNA Immunoprecipitation (RIP) assay was performed to explore the molecular mechanism of HOTAIR in breast cancer. Xenograft analysis was utilized to evaluate the tumor growth in vivo. HOTAIR and FZD7 were upregulated, while miR-129-5p was down-regulated in breast cancer tissues and cells. Knockdown of miR-129-5p reversed the effect of HOTAIR knockdown on cell proliferation, migration, invasion and EMT. FZD7 restored the inhibition of miR-129-5p on breast cancer progression. Furthermore, HOTAIR was a sponge of miR-129-5p and FZD7 was a target of miR-129-5p. Knockdown of HOTAIR inhibited the tumor growth in vivo. HOTAIR facilitated breast cancer progression by regulating the miR-129-5p/FZD7 axis, indicating that HOTAIR may be a potential biomarker and therapeutic target for breast cancer.

Elevated V-ATPase Activity Following PTEN Loss Is Required for Enhanced Oncogenic Signaling in Breast Cancer.

PTEN loss-of-function contributes to hyperactivation of the PI3K pathway and to drug resistance in breast cancer. Unchecked PI3K pathway signaling increases activation of the mechanistic target of rapamycin complex 1 (mTORC1), which promotes tumorigenicity. Several studies have suggested that vacuolar (H+)-ATPase (V-ATPase) complex activity is regulated by PI3K signaling. In this study, we showed that loss of PTEN elevated V-ATPase activity. Enhanced V-ATPase activity was mediated by increased expression of the ATPase H+ transporting accessory protein 2 (ATP6AP2), also known as the prorenin receptor (PRR). PRR is cleaved into a secreted extracellular fragment (sPRR) and an intracellular fragment (M8.9) that remains associated with the V-ATPase complex. Reduced PTEN expression increased V-ATPase complex activity in a PRR-dependent manner. Breast cancer cell lines with reduced PTEN expression demonstrated increased PRR expression. Similarly, PRR expression became elevated upon PTEN deletion in a mouse model of breast cancer. Interestingly, concentration of sPRR was elevated in the plasma of patients with breast cancer and correlated with tumor burden in HER2-enriched cancers. Moreover, PRR was essential for proper HER2 receptor expression, localization, and signaling. PRR knockdown attenuated HER2 signaling and resulted in reduced Akt and ERK 1/2 phosphorylation, and in lower mTORC1 activity. Overall, our study demonstrates a mechanism by which PTEN loss in breast cancer can potentiate multiple signaling pathways through upregulation of the V-ATPase complex. IMPLICATIONS: Our study contributed to the understanding of the role of the V-ATPase complex in breast cancer cell tumorigenesis and provided a potential biomarker in breast cancer.

Identification of NUF2 and FAM83D as potential biomarkers in triple-negative breast cancer.

BackgroundBreast cancer is a heterogeneous disease. Compared with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is easy to metastasize and has a short survival time, less choice of treatment options. Here, we aimed to identify the potential biomarkers to TNBC diagnosis and prognosis.Material/MethodsThree independent data sets (GSE45827, GSE38959, GSE65194) were downloaded from the Gene Expression Omnibus (GEO). The R software packages were used to integrate the gene profiles and identify differentially expressed genes (DEGs). A variety of bioinformatics tools were used to explore the hub genes, including the DAVID database, STRING database and Cytoscape software. Reverse transcription quantitative PCR (RT-qPCR) was used to verify the hub genes in 14 pairs of TNBC paired tissues.ResultsIn this study, we screened out 161 DEGs between 222 non-TNBC and 126 TNBC samples, of which 105 genes were up-regulated and 56 were down-regulated. These DEGs were enriched for 27 GO terms and two pathways. GO analysis enriched mainly in “cell division”, “chromosome, centromeric region” and “microtubule motor activity”. KEGG pathway analysis enriched mostly in “Cell cycle” and “Oocyte meiosis”. PPI network was constructed and then 10 top hub genes were screened. According to the analysis results of the Kaplan-Meier survival curve, the expression levels of only NUF2, FAM83D and CENPH were associated with the recurrence-free survival in TNBC samples (P < 0.05). RT-qPCR confirmed that the expression levels of NUF2 and FAM83D in TNBC tissues were indeed up-regulated significantly.ConclusionsThe comprehensive analysis showed that NUF2 and FAM83D could be used as potential biomarkers for diagnosis and prognosis of TNBC.

MicroRNA analysis of NCI-60 human cancer cells indicates that miR-720 and miR-887 are potential therapeutic biomarkers for breast cancer.

MicroRNAs (miRNAs) play a vital role in many biological processes, including cell growth, differentiation, apoptosis, development, differentiation, and carcinogenesis. Since miRNAs might play a part in cancer initiation and progression, they comprise an original class of promising diagnostic and prognostic molecular markers. In order to systematically understand the regulation of miRNA expression in cancers, the current study analyzed the miRNA expression profile in NCI-60 human cancer cell lines. Over 300 miRNAs exhibited unique expression profiles in cell lines derived from the same lineage. This study identified 9 lineage-specific miRNA expression patterns. Moreover, results indicated that miR-720 and miR-887 are expressed at relatively high levels in breast cancer cell lines compared to other types of cancer. Ultimately, matching NCI-60 drug response data to miR-720 and miR-887 expression profiles revealed that several FDA-approved drugs were inversely related to miR-720 and miR-887. Furthermore, the anti-cancer effect of perifosine was significantly enhanced by inhibiting miR-720 and decreased by miR-720 precursor treatment in breast cancer cell lines. 5-Fu treatment was enhanced by inhibiting miR-887 and decreased by miR-887 precursor treatment. The current results offer insight into the relationship between miRNA expression and their lineage types, and the approach used here represents a potential cancer therapy with the help of miRNAs.

Overexpression of miR-331 Indicates Poor Prognosis and Promotes Progression of Breast Cancer

Background: With the increasing number of cases of breast cancer every year, the exploration of novel biomarkers has drawn attention. miR-331 has been demonstrated to play a role in various cancers, but its role in breast cancer is still unknown. Methods: In this study, we included 121 patients with breast cancer treated at Affiliated Hospital of Weifang Medical University. Breast cancer tissues and adjacent normal tissues were collected during the surgery. The expression of miR-331 in breast cancer tissues and cell lines was detected by qRT-PCR assay. Then, with the help of Kaplan-Meier survival and Cox regression analyses, the role of miR-331 in the prognosis of breast cancer was analyzed. Finally, the effect of miR-331 on cell proliferation, migration, and invasion was investigated with CCK-8 assay and transwell assay. Results: miR-331 was significantly upregulated in breast cancer tissues compared with normal tissues. The overexpression of miR-331 was associated with lymph node metastasis, TNM stage, and poor prognosis. From the results of Cox regression analyses, it was found that miR-331 served as an independent indicator in the prognosis of breast cancer. In addition, miR-331 was also found to be upregulated in breast cancer cells, which promoted cell proliferation, migration, and invasion of breast cancer. Conclusion: As shown from our data, miR-331 may be a potential prognostic biomarker in breast cancer. Moreover, the development and progression of breast cancer may involve miR-331. These findings suggest a novel therapeutic target for the treatment of breast cancer.

ZEB1-Mediated Transcriptional Upregulation of circWWC3 Promotes Breast Cancer Progression through Activating Ras Signaling Pathway

Zinc finger E-box binding homeobox 1 (ZEB1) has been widely recognized as an important driver of tumor growth and metastasis. However, nothing is known about ZEB1-regulated circular (circ)RNAs in cancer. In the current study, we evaluated the function of a novel ZEB1-regulated circRNA derived from the WWC3 gene locus, circWWC3 in breast cancer progression. We found that ZEB1 upregulated circWWC3 expression but not the linear WWC3 mRNA expression. circWWC3 is highly expressed in breast cancer tissues and is associated with the poor prognosis of breast cancer patients. Silencing of circWWC3 significantly suppresses the proliferation, migration, and invasion of breast cancer cells. Mechanically, circWWC3 upregulates multiple oncogenes’ expression of the Ras signaling pathway through acting as the sponge of microRNA (miR)-26b-3p and miR-660-3p. Moreover, short hairpin (sh)RNA-mediated knockdown of circWWC3 partially antagonized ZEB1-mediated breast cancer growth and metastasis in vivo. Our findings reveal that ZEB1-mediated upregulation of circWWC3 promotes breast cancer progression through activating Ras signaling pathway, which provides a potential therapeutic target and prognostic biomarker for breast cancer.

Identification of SCARA5 Gene as a Potential Immune-Related Biomarker for Triple-Negative Breast Cancer by Integrated Analysis.

Triple-negative breast cancer (TNBC) refers to breast cancer without significant expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2. We sought to identify the hub genes and find the potential progression mechanism of TNBC as well as immunotherapeutic targets. First, we screened the overlapped hub genes of Immune and Stromal, and the tumor mutation burden gene sets, as well as the The Cancer Genome Atlas (TCGA)-TNBC data set. Among these hub genes, we performed gene set enrichment analysis (GSEA) and gene set variation analysis analyses to recognize and evaluate the hub genes. Moreover, immune cell infiltration was evaluated by the CIBERSORT algorithm and single-sample GSEA. In addition, the expression and methylation of scavenger receptor class A member 5 (SCARA5) in TNBC were verified by quantitative PCR and methylation-specific PCR. Also, MTT and transwell assays were used to assess the biological function of SCARA5 in TNBC. SCARA5 and CMA1 were listed, and they mainly participated in cancer-related signaling pathways and immune-related signaling pathways. Interestingly, SCARA5 was closely associated with tumor purity and immune cell infiltration. Moreover, we found that SCARA5 was significantly downregulated and hypermethylation was in the promoter of SCARA5 in TNBC tissues. Our study showed the role of SCARA5 in proliferation and migration of TNBC, and suggested that SCARA5 can potentially serve as a candidate immunotherapy target for TNBC.

Identification of plasma hsa_circ_0008673 expression as a potential biomarker and tumor regulator of breast cancer.

ObjectiveCell‐free circular RNAs (circRNAs) are stable and abundantly exist in body fluids. In this study, we aimed to investigate plasma cell‐free circRNAs as a novel class of biomarkers for the diagnosis of breast cancer (BC).MethodsDifferentially expressed circRNAs from 6 normal and 6 BC plasma samples were detected by microarray. Hsa_circ_0008673 was then screened and validated in the plasma of 102 normal and 378 BC samples. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. The correlations between hsa_circ_0008673 expression and demographic characteristics, tumor features, and prognosis were analyzed. The effects of hsa_circ_0008673 on BC cell proliferation and metastasis were also measured.ResultsOf the top ten up‐regulated (hsa_circ_0008673, hsa_circ_0008500, hsa_circ_0005260, hsa_circ_0003423, hsa_circ_0119881, hsa_circ_0000987, hsa_circ_0007386, hsa_circ_0000091, hsa_circ_0016601, and hsa_circ_0008549) and top ten down‐regulated (hsa_circ_0000826, hsa_circ_0072697, hsa_circ_0004587, hsa_circ_0000471, hsa_circ_0007786, hsa_circ_0001417, hsa_circ_0005982, hsa_circ_0001566, hsa_circ_0003823, and hsa_circ_0003823) circRNAs from microarray, hsa_circ_0008673 was the most significantly up‐regulated circRNA in BC, and represented a good diagnostic value. Hsa_circ_0008673 was remarkably down‐regulated after breast mastectomy. Hsa_circ_0008673 expression was associated with larger tumor size, distant metastasis, positive estrogen receptor (ER) status, and positive progesterone receptor (PR) status. Additionally, hsa_circ_0008673 could serve as a prognostic predicator of overall survival (OS) and disease‐specific survival (DSS). Cell assays proved that hsa_circ_0008673 knockdown contributed to inhibition of tumor cell proliferation and migration.ConclusionPlasma cell‐free hsa_circ_0008673 was up‐regulated in BC, which was associated with poorer prognosis and promoted tumor proliferation and metastasis. Hsa_circ_0008673 is a promising biomarker for tumor diagnosis and prognostic assessment of BC patients.

The proteomic analysis of breast cell line exosomes reveals disease patterns and potential biomarkers

Cancer cells release small extracellular vesicles, exosomes, that have been shown to contribute to various aspects of cancer development and progression. Differential analysis of exosomal proteomes from cancerous and non-tumorigenic breast cell lines can provide valuable information related to breast cancer progression and metastasis. Moreover, such a comparison can be explored to find potentially new protein biomarkers for early disease detection. In this study, exosomal proteomes of MDA-MB-231, a metastatic breast cancer cell line, and MCF-10A, a non-cancerous epithelial breast cell line, were identified by nano-liquid chromatography coupled to tandem mass spectrometry. We also tested three exosomes isolation methods (ExoQuick, Ultracentrifugation (UC), and Ultrafiltration–Ultracentrifugation) and detergents (n-dodecyl β-d-maltoside, Triton X-100, and Digitonin) for solubilization of exosomal proteins and enhanced detection by mass spectrometry. A total of 1,107 exosomal proteins were identified in both cell lines, 726 of which were unique to the MDA-MB-231 breast cancer cell line. Among them, 87 proteins were predicted to be relevant to breast cancer and 16 proteins to cancer metastasis. Three exosomal membrane/surface proteins, glucose transporter 1 (GLUT-1), glypican 1 (GPC-1), and disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), were identified as potential breast cancer biomarkers and validated with Western blotting and high-resolution flow cytometry. We demonstrated that exosomes are a rich source of breast cancer-related proteins and surface biomarkers that may be used for disease diagnosis and prognosis.

Construction and Comprehensive Analysis of a ceRNA Network to Reveal Potential Novel Biomarkers for Triple-Negative Breast Cancer.

BackgroundTriple-negative breast cancer (TNBC) is the most common and aggressive type of breast cancer with an unfavourable outcome worldwide. Novel therapeutic targets are urgently required to explore this malignancy. This study explored the ceRNA network and the important genes for predicting the therapeutic targets.MethodsIt identified the differentially expressed genes of mRNAs, lncRNAs and miRNAs between TNBC and non-TNBC samples in four cohorts (TCGA, GSE38959, GSE45827 and GSE65194) to explore the novel therapeutic targets for TNBC. Downstream analyses, including functional enrichment analysis, ceRNA network, protein–protein interaction and survival analysis, were then conducted by bioinformatics analysis. Finally, the potential core protein of the ceRNA network in TNBC was validated by immunohistochemistry.ResultsA total of 1,045 lncRNAs and 28 miRNAs were differentially expressed in the TCGA TNBC samples, and the intersections of 282 mRNAs (176 upregulations and 106 downregulations) between the GEO and TCGA databases were identified. A ceRNA network composed of 7 lncRNAs, 62 mRNAs, 12 miRNAs and 244 edges specific to TNBC was established. The functional assay showed dysregulated genes, and GO, DO and KEGG enrichment analysis were performed. Survival analysis showed that mRNA LIFR and lncRNA AC124312.3 were significantly correlated with the overall survival of patients with TNBC in the TCGA databases (P < 0.05). Finally, the LIFR protein was validated, and immunohistochemical results showed the upregulated expression of LIFR in TNBC tissues.ConclusionThus, our study presents an enhanced understanding of the ceRNA network in TNBC, where the key gene LIFR may be a new promising potential therapeutic target for patients with TNBC.

Identification of Potential Prognostic Biomarkers for Breast Cancer Based on lncRNA-TF-Associated ceRNA Network and Functional Module.

Breast cancer leads to most of cancer deaths among women worldwide. Systematically analyzing the competing endogenous RNA (ceRNA) network and their functional modules may provide valuable insight into the pathogenesis of breast cancer. In this study, we constructed a lncRNA-TF-associated ceRNA network via combining all the significant lncRNA-TF ceRNA pairs and TF-TF PPI pairs. We computed important topological features of the network, such as degree and average path length. Hub nodes in the lncRNA-TF-associated ceRNA network were extracted to detect differential expression in different subtypes and tumor stages of breast cancer. MCODE was used for identifying the closely connected modules from the ceRNA network. Survival analysis was further used for evaluating whether the modules had prognosis effects on breast cancer. TF motif searching analysis was performed for investigating the binding potentials between lncRNAs and TFs. As a result, a lncRNA-TF-associated ceRNA network in breast cancer was constructed, which had a scale-free property. Hub nodes such as MDM4, ZNF410, AC0842-19, and CTB-89H12 were differentially expressed between cancer and normal sample in different subtypes and tumor stages. Two closely connected modules were identified to significantly classify patients into a low-risk group and high-risk group with different clinical outcomes. TF motif searching analysis suggested that TFs, such as NFAT5, might bind to the promoter and enhancer regions of hub lncRNAs and function in breast cancer biology. The results demonstrated that the synergistic, competitive lncRNA-TF ceRNA network and their functional modules played important roles in the biological processes and molecular functions of breast cancer.

MAM domain containing 2 is a potential breast cancer biomarker that exhibits tumour-suppressive activity.

ObjectivesThe aim of this study was to discover new potential biomarkers of breast cancer and investigate their cellular functions.Materials and methodsWe analysed the gene expression profiles of matched pairs of breast tumour and normal tissues from 24 breast cancer patients. Tetracycline‐inducible MAMDC2 expression system was established and used to evaluate cell proliferation in vitro and in vivo. MAMDC2‐mediated signalling was determined using immunoblot analysis.ResultsWe identified MAMDC2 as a down‐regulated gene showing significant prognostic capability. Overexpression of MAMDC2 or treatment with MAMDC2‐containing culture medium significantly inhibited the cell proliferation of T‐47D cells. Furthermore, MAMDC2 expression reduced in vivo growth of T‐47D xenograft tumours. MAMDC2 may exert its growth‐inhibitory functions by attenuating the MAPK signalling pathway.ConclusionWe report that MAMDC2 has a tumour‐suppressive role and, as a secretory protein, it might be useful as a biomarker for breast cancer treatment.

The Emerging Role of MicroRNAs in Breast Cancer.

Breast cancer (BC) is the most common malignancy in women. Due to BC heterogeneity, complexity, and metastasis, many BC patients do not successfully respond to therapies. The effective management of BC depends on early diagnosis and monitoring of drug response. Therefore, identifying new biomarkers for the diagnosis, prognosis, and development of new drugs is urgently required. Dysregulation of microRNAs (miRNAs) participates in the tumorigenesis and progression of cancers, especially breast cancer (BC). Several studies demonstrated that miRNAs could perform their function as oncogenes or tumor suppressors. This review describes recent progress on the role of microRNAs in the diagnosis, prognosis, hallmark, and treatment of BC. According to a recent literature survey, miRNAs play a pivotal role in the regulation of hallmarks of cancer, such as proliferation, apoptosis, invasion, metastasis, and tumor stemness. Many miRNAs are potential biomarkers for BC for diagnosis, and some are indicators of prognosis. Moreover, circulating miRNA profiles, as minimally invasive, diagnostic, and prognostic markers, are broadly used in BC therapy, and some miRNAs are good predictors of therapeutic outcomes. Other miRNAs are involved in overcoming chemoresistance and in increasing BC drug sensitivity.

Identifying potential serum biomarkers of breast cancer through targeted free fatty acid profiles screening based on a GC-MS platform.

Recent advances suggest that abnormal fatty acid metabolism highly correlates with breast cancer, which provide clues to discover potential biomarkers of breast cancer. This study aims to identify serum free fatty acid (FFA) metabolic profiles and screen potential biomarkers for breast cancer diagnosis. Gas chromatography-mass spectrometry and our in-house fatty acid methyl ester standard substances library were combined to accurately identify FFA profiles in serum samples of breast cancer patients and breast adenosis patients (as controls). Potential biomarkers were screened by applying statistical analysis. A total of 18 FFAs were accurately identified in serum sample. Two groups of patients were correctly discriminated by the orthogonal partial least squares-discriminant analysis model based on FFA profiles. Seven FFA levels were significantly higher in serum from breast cancer patients than that in controls, and exhibited positive correlation with malignant degrees of disease. Furthermore, five candidates (palmitic acid, oleic acid, cis-8,11,14-eicosatrienoic acid, docosanoic acid and the ratio of oleic acid to stearic acid) were selected as potential serum biomarkers for differential diagnosis of breast cancer. Our study will help to reveal the metabolic signature of FFAs in breast cancer patients, and provides valuable information for facilitating clinical noninvasive diagnosis.

MiR-140 and miR-196a as Potential Biomarkers in Breast Cancer Patients.

Objective: MiR-140 and miR-196a were known to be correlated with cancer diagnosis and prognosis. The current study aimed at the analysis of miR-140 and miR-196a expression patterns and their clinical significance for breast cancer (BC) patients. Methods:Differentially expressed miR-140 and miR-196a were examined via quantitative PCR in 110 cases of BC and their adjacent non-tumor (ANT) tissues. Results:The results indicated that miR-140 and miR-196a, respectively, notably decreased and increased expression in BC samples in comparison with ANT (p<0.001). Reduced miR-140 expression was also related to Lymph node metastasis (LNM, P= 0.023) and stage (P = 0.009). Additionally, Receiver Operating Characteristics (ROC) analysis illustrated that miR-140 had a significant diagnostic accuracy for stage and LNM of BC patients. We also discovered a strong negative correlation between miR-196a expression with histological grade (P = 0.038), LNM (P = 0.012) and stage (P = 0.001). Conclusion:Overall, exploring the miR-140 and miR-196a profiles not only can statistically different among BC and ANT samples, but it is also expected to become potential BC biomarkers.

Gene Pair Correlation Coefficients in Sphingolipid Metabolic Pathway as a Potential Prognostic Biomarker for Breast Cancer.

Complex diseases such as cancer are usually governed by dynamic and simultaneous modifications of multiple genes. Since sphingolipids are potent bioactive molecules and regulate many important pathophysiological processes such as carcinogenesis, we studied the gene pair correlations of 36 genes (31 genes in the sphingolipid metabolic pathway and 5 genes encoding the sphingosine-1-phosphate receptors) between breast cancer patients and healthy controls. It is remarkable to observe that the gene expressions were widely and strongly correlated in healthy controls but in general lost in breast cancer patients. This study suggests that gene pair correlation coefficients could be applied as a systematic and novel method for the diagnosis and prognosis of breast cancer.

CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation

Endocrine therapy is a systemic therapy and has become the main treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, tamoxifen resistance has become an insurmountable clinical challenge, and the underlying mechanisms are still poorly understood. In this study, we explored the roles of CXC chemokine receptor type 4 (CXCR4) in tamoxifen-treated breast cancer and tamoxifen resistance. Based on the Gene Expression Omnibus (GEO) database, high expression of CXCR4 was found to be associated with worse overall survival (hazard ratio [HR] = 4.646, p < 0.001) and cancer-specific survival (HR = 4.480, p < 0.001) in tamoxifen-treated breast cancer. CXCR4 was also positively correlated with the level of AKT phosphorylation and the resistance to tamoxifen in breast cancer. AMD3100 is a CXCR4 antagonist and was found to decrease phosphorylated (p)-AKT levels of tamoxifen-resistant cells. The reversal effect of AMD3100 on tamoxifen resistance was also confirmed in vitro and in vivo. Taken together, our study demonstrated that CXCR4 could be a potential prognostic biomarker for tamoxifen-treated breast cancer, and the combination of AMD3100 with tamoxifen could be a more efficacious therapeutic strategy for the treatment of tamoxifen resistance.

Development and validation of a hypoxia-related prognostic signature for breast cancer.

Hypoxia, an important component of the tumor microenvironment, plays a crucial role in the occurrence and progression of cancer. However, to the best of our knowledge, a systematic analysis of a hypoxia-related prognostic signature for breast cancer is lacking and is urgently required. Therefore, in the present study, RNA-seq data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and served as a discovery cohort. Cox proportional hazards regression analysis was performed to construct a 14-gene prognostic signature (PFKL, P4HA2, GRHPR, SDC3, PPP1R15A, SIAH2, NDRG1, BTG1, TPD52, MAFF, ISG20, LALBA, ERRFI1 and VHL). The hypoxia-related signature successfully predicted survival outcomes of the discovery cohort (P<0.001 for the TCGA dataset). Three independent Gene Expression Omnibus databases (GSE10886, GSE20685 and GSE96058) were used as validation cohorts to verify the value of the predictive signature (P=0.007 for GSE10886, P=0.021 for GSE20685, P<0.001 for GSE96058). In the present study, a robust predictive signature was developed for patients with breast cancer, and the findings revealed that the 14-gene hypoxia-related signature could serve as a potential prognostic biomarker for breast cancer.

Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer.

Endocrine therapy is the mainstay of adjuvant treatment for patients with luminal breast cancer. Despite ongoing advances in endocrine therapy to date, a proportion of patients ultimately develop endocrine resistance, resulting in failure of therapy and poor prognosis. Therefore, as part of the growing concept of personalised medicine, the need for identification of predictive markers of endocrine therapy response at an early stage, is recognised. The METABRIC series was used to identify differentially expressed genes (DEGs) in term of response to adjuvant endocrine therapy. Drebrin 1 (DBN1) was identified as a key DEG associated with response to hormone treatment. Next, large, well-characterised cohorts of primary luminal breast cancer with long-term follow-up were assessed at the mRNA and protein levels for the value of DBN1 as a prognostic marker in luminal breast cancer, as well as its potential for predicting the benefit of endocrine therapy. DBN1 positivity was associated with aggressive clinicopathological variables and poor patient outcomes. Importantly, high DBN1 expression predicted relapse patients who were subject to adjuvant endocrine treatment. Our results further demonstrate that DBN1 is an independent prognostic marker in luminal breast cancer. Its association with the response to endocrine therapy and outcome provides evidence for DBN1 as a potential biomarker in luminal breast cancer, particularly for the benefit of endocrine treatment. Further functional investigations into the mechanisms underlying sensitivity to endocrine therapy is required.