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Background: In recent years, breast cancer has become the most common cancer in the world, increasing women's health risks. Approximately 60% of breast cancers are categorized as human epidermal growth factor receptor 2 (HER2)-low tumors. Recently, antibody-drug conjugates have been found to have positive anticancer efficacy in patients with HER2-low breast cancer, but more studies are required to comprehend their clinical and molecular characteristics., Methods: In this study, we retrospectively analyzed the data of 165 early breast cancer patients with pT1-2N1M0 who had undergone the RecurIndex testing. To better understand HER2-low tumors, we investigated the RecurIndex genomic profiles, clinicopathologic features, and survival outcomes of breast cancers according to HER2 status., Results: First, there were significantly more hormone receptor (HR)-positive tumors, luminal-type tumors, and low Ki67 levels in the HER2-low than in the HER2-zero. Second, RI-LR (P = .0294) and RI-DR (P = .001) scores for HER2-low and HER2-zero were statistically significant. Third, within HER2-negative disease, HR-positive/HER2-low tumors showed highest ESR1, NFATC2IP, PTI1, ERBB2, and OBSL1 expressions. Fourth, results of the survival analysis showed that lower expression of HER2 was associated with improved relapse-free survival for HR-positive tumors, but not for HR-negative tumors., Conclusions: The present study highlights the unique features of HER2-low tumors in terms of their clinical characteristics as well as their gene expression profiles. HR status may influence the prognosis of patients with HER2-low expression, and patients with HR-positive/HER2-low expression may have a favorable outcome., (© The Author(s) 2023. Published by Oxford University Press.)

Context: Although great progress has occurred in breast cancer (BC) treatment, including chemotherapy, chemoradiotherapy, and surgical resection, the rate of patients' survival is still unsatisfactory. Multiple genes and factors have proven to contribute to BC's occurrence. Thus, it's urgent to explore the molecular mechanisms in the development and progression of BC and find possible targets for therapy., Objective: The study intended to assess the mechanisms of miR-518a-5p's effect on BC by targeting the zinc finger E-box-binding homeobox 2 (ZEB2) gene., Design: The research team designed a laboratory study and retrospective analysis., Setting: The study took place in the Department of Breast Surgery at the Xingtai People's Hospital in Xingtai, Hebei, China., Outcome Measures: The study measured the miR-518a-5p expression in BC tissues and normal tissues using a real-time quantitative reverse transcription (qRT)-polymerase chain reaction (PCR) test. The research team purchased the BC cells MDA-MB-231 and MCF-7 and measured the effects of the miR-518a-5p on BC cell activity as well as epithelial-mesenchymal transition (EMT) ability, using cell scratch tests and Transwell assays. The team assessed the ZEB2 protein expression and verified the targeting relationship using a Dual-Luciferase Reporter assay., Results: The miR-518a-5p expressed was low in the BC tissues and cell lines compared with adjacent normal tissues (P < .05). Overexpressing the miR-518a-5p inhibited BC-cell migration and invasion (P < .05). Moreover, the ZEB2 was the target gene for the miR-518a-5p. The Luciferase assay verified that the miR-518a-5p directly targeted the ZEB2 in BC cells (P < .05). The Transwell invasion assay, western blot analysis, and wound healing assay also showed that the miR-518a-5p inhibited BC cells by targeting ZEB2 (P < .05)., Conclusions: The miR-518a-5p suppressed BC migration, invasion, and process of EMT by regulating ZEB2. In the future, this method may be a new option for BC diagnosis and treatment. An in-depth understanding of the role of the miR-518a-5p in BC can help clinicians to understand the pathogenic mechanism of breast cancer more accurately.

Background: A growing body of evidence indicates that abnormal expression of circular RNAs (circRNAs) plays a crucial role by acting as molecular sponges of microRNAs (miRNAs) in various diseases, including cancer. In this study, we explored whether circCCDC85A could function as a miR-550a-5p sponge and influence breast cancer progression., Methods: We detected the expression of circCCDC85A in breast cancer tissues and cells using fluorescence in situ hybridization (FISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). CCK-8 and colony formation assay were used to detect the proliferative ability of breast cancer cells. Wound healing assay and transwell migration and invasion assays were used to detect the migrative and invasive abilities of breast cancer cells. We also examined the interactions between circCCDC85A and miR-550a-5p using FISH, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. Moreover, we performed luciferase reporter assay, qRT-PCR, and Western blot to confirm the direct targeting of miR-550a-5p to MOB1A., Results: The expression of circCCDC85A in breast cancer tissues was obviously lower than that in normal breast tissues. Over-expression of circCCDC85A substantially inhibited the proliferative, migrative, and invasive ability of breast cancer cells, while knocking down of circCCDC85A enhanced the aforementioned properties of breast cancer cells. Moreover, enforced expression of circCCDC85A inhibits the oncogenic activity of miR-550a-5p and increases the expression of MOB1A targeted by miR-550a-5p. Further molecular mechanism research showed that circCCDC85A may act as a molecular sponge for miR-550a-5p, thus restoring miR-550a-5p-mediated targeting repression of tumor suppressor MOB1A in breast cancer cells., Conclusion: Our findings provide novel evidence that circCCDC85A inhibits the progression of breast cancer by functioning as a molecular sponge of miR-550a-5p to enhance MOB1A expression., (© 2021. The Author(s).)

The role of organic anion transporting polypeptide 1B3 (SLCO1B3) in breast cancer is still controversial. The clinical immunohistochemical results showed that a greater proportion of patients with negative lymph nodes, AJCC stage I, and histological grade 1 (P < 0.05) was positively correlated with stronger expression of SLCO1B3, and DFS and OS were also increased significantly in these patients (P = 0.041, P = 0.001). Further subgroup analysis showed that DFS and OS were significantly enhanced with the increased expression of SLCO1B3 in the ER positive subgroup. The cellular function assay showed that the ability of cell proliferation, migration and invasion was significantly enhanced after knockdown of SLCO1B3 expression in breast cancer cell lines. In contrast, the ability of cell proliferation, migration and invasion was significantly reduced after overexpress the SLCO1B3 in breast cancer cell lines (P < 0.05). Overexpression or knockdown of SLCO1B3 had no effect on the apoptotic ability of breast cancer cells. High level of SLCO1B3 expression can inhibit the proliferation, invasion and migration of breast cancer cells, leading to better prognosis of patients. The role of SLCO1B3 in breast cancer may be related to estrogen. SLCO1B3 will become a potential biomarker for breast cancer diagnosis and prognosis assessment.

The failure to treat and control the growth of metastases is the main cause of death in breast cancer (BC) patients. Compared to the traditional method of analyzing circulating tumor DNA (ctDNA), capturing intact circulating tumor cells (CTCs) allows us to more accurately characterize mutations and identify suitable targeted therapies. We used CellCollector to collect peripheral CTCs. Thirty metastatic breast cancer (MBC) patients were enrolled, and 17 were analyzed with next-generation sequencing (NGS) methods. Clinical characteristics were analyzed along with the CTCs enumeration and detection rates. Whole-genome amplification (WGA) was used to amplify the CTC genomic DNA of 127 genes. Patients younger than 45 years old, with brain metastasis, with three or more metastatic sites, or with HER2-positive had the highest number of CTCs collected. The CTCs detection rate was also correlated to the number of metastasis sites. Different metastasis sites such as the brain, viscus, bone, and soft tissue contained specific high-frequency gene mutations. AKT3, MYC, and NT5C2 mutations were only found in brain metastases. APC, BCL2L11, ESRP1, FLT3 mutations were only in the visceral metastases. KEAP1, KIT, MET were the specific mutation genes in patients with bone and soft tissue metastases. These findings provide evidence that we can detect gene mutation information for obtaining the biological characteristics by CTCs using CellCollector. Different metastasis sites contain specific high-frequency mutation genes, which provide guidance to the accurate gene therapy.

Breast cancer is the leading cause of cancer‑-associated deaths in women. Combination immunotherapy attracts great interest as a treatment for breast cancer. However, there are no studies on the use of cytotoxic T‑lymphocyte antigen 4 (CTLA‑4) monoclonal antibody in combination with the melanoma‑associated antigen A family (MAGE‑As) co‑antigen peptide (p248V9) for treating breast cancer, which should be explored. To this aim, in the present study, the samples of 115 patients with breast cancer were collected, and MAGE‑As and CTLA‑4 levels in breast cancer and adjacent normal tissues were assessed by immunohistochemical staining. The effect of 5‑aza‑2'‑deoxycytidine (5DC) on the expression of MAGE‑As in breast cancer cell lines was assessed by reverse transcription‑quantitative PCR and western blot assay. Cytotoxic T cells (CTLs) were induced by MAGE‑As co‑antigen peptide. The specific lytic rate and IFN‑γ level were examined by CCK‑8 assay and ELISA, respectively. It was found that MAGE‑As were highly expressed in breast cancer tissues. 5DC treatment promoted the expression of MAGE‑As in breast cancer cells. The upregulation of the expression of MAGE‑As specifically enhanced the ability of CTLs to kill breast cancer cells. CTLA‑4 was highly expressed in breast cancer tissues and cells, and patients with breast cancer exhibiting high expression of CTLA‑4 had low overall survival. CTLA‑4 promoted the lytic efficiency of CTLs in breast cancer cells, and the combination of an anti‑CTLA‑4 antibody and 10 µM 5DC exhibited the highest cell lysis ability of CTLs. The present study demonstrated that MAGE‑As co‑antigen peptide‑specific CTLs in combination with an anti‑CTLA‑4 monoclonal antibody and 5DC, have potent tumor cell‑killing effects. It provides a novel theory for the development of breast cancer therapies.

Background: Circular RNAs (circRNAs) have attracted lots of attention in tumorigenesis and progression. However, circRNAs as crucial regulators in epithelial-mesenchymal transition have not been systematically identified in breast cancer. The purpose of our research was to investigate the circRNA network associated with epithelial-mesenchymal transition in breast cancer., Methods: Expression profiling data of circRNAs were identified by circRNA microarray in transfected ZEB1 and control breast cancer cells. The differentially expressed circRNAs, miRNAs, and mRNAs were determined via fold change filtering. The competing endogenous RNAs (ceRNAs) network was established on the foundation of the relationship between circular RNAs, miRNAs and mRNAs. The CytoHubba was used to determine the hub genes from the protein-protein interaction (PPI) regulatory network. The GEPIA database was used to observe the expression of the hub genes mRNA between breast cancer tissues and normal tissues. The HPA database was applied to investigate the expression of six hub genes at the protein level. Morever, we further used Kaplan-Meier plotter to perform survival analysis of these hub genes., Results: The top three up-regulated differential expressed circRNAs were identified by circRNA microarray. Following the Real-time PCR validation of the three circRNAs, two circRNAs (hsa&#95;circRNA&#95;002082 and hsa&#95;circRNA&#95;400031) were selected for further analysis. After the predicted target miRNA, ten circRNA-miRNA interactions including two circRNAs and ten miRNAs were determined. Furthermore, the Venn diagram was used to intersect the predicted target genes and the differentially expressed genes, and screened 174 overlapped genes. Subsequently, we constructed a PPI network, and selecting six hub genes, containing KIF4A, CENPF, OIP5, ZWINT, DEPDC1, BUB1B. The mRNA expression levels of the six hub genes were obviously up-regulated in breast cancer. The protein expression levels of KIF4A, CENPF, OIP5, and DEPDC1 were significantly increased in breast cancer tissues. Moreover, the survival analysis results revealed that high expression of the six hub genes were obviously correlated with poor prognosis of breast cancer patients., Conclusions: Our study constructed and analyzed a circRNA-associated ceRNA regulatory network and discovered that hsa&#95;circRNA&#95;002082 and hsa&#95;circRNA&#95;400031 may mechanism as ceRNAs to serve key roles in breast cancer epithelial-mesenchymal transition., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Breast cancer is a malignant tumor that seriously threatens women's health, and luminal-like cancer subtypes account for the majority of the cases. The purpose of this study was to investigate the relationships among DNA methylation, gene expression profile, and the tumor-immune microenvironment of luminal-like breast cancer, and to identify the potential key genes that regulate immune cell infiltration in luminal-like breast cancer. The ESTIMATE algorithm was applied to calculate immune scores and stromal scores of patients with breast cancer. Kaplan-Meier curves were generated for survival analysis. The clusterProfile package was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software. Correlations between ADCY6 expression and immune cell infiltration-related pathways were analyzed by gene set variation analysis. R software was used for the statistical analysis and figure generation. Disease-free survival was higher in the immune score-high group than it was in the immune score-low group, while the stromal score had no correlation with prognosis. There were 515 genes that differed in both gene expression and DNA methylation levels, and these genes were mainly enriched in immune process-related pathways. ADCY6 was enriched in module A of the PPI network. Patients with downregulation and hypermethylation of ADCY6 associated with a better prognosis. ADCY6 expression was negatively correlated with the activation of immune process-related signaling pathways, immune checkpoint receptors, and ligands, except for CLEC4G. DNA methylation was found to be involved in the regulation of the key cellular pathways of luminal-like breast cancer immune cell infiltration. Additionally, ADCY6 was identified as a prognostic factor involved in the DNA methylation-regulated immune processes in luminal-like breast cancer., (© 2019 Wiley Periodicals, Inc.)

Background: Breast cancer is the most frequently diagnosed cancer in women worldwide. This study aimed to elucidate the potential key candidate genes and pathways in breast cancer., Methods: The gene expression profile dataset GSE65212 was downloaded from GEO database. Differentially expressed genes (DEGs) were obtained by the R Bioconductor packages. The Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were performed using DAVID database. The protein-protein interaction (PPI) network was then established by STRING and visualized by Cytoscape software. Module analysis of the PPI network was performed by the plug-in Molecular Complex Detection (MCODE). Then, the identified genes were verified by Kaplan-Meier plotter online database and quantitative real-time PCR (qPCR) in breast cancer tissue samples., Results: A total of 857 differential expressed genes were identified, of which, the upregulated genes were mainly enriched in the cell cycle, while the downregulated genes were mainly enriched in PPAR signaling pathway. Moreover, six hub genes with high degree were identified, including TOP2A, PCNA, CCNB1, CDC20, BIRC5 and CCNA2. Lastly, the Kaplan-Meier plotter online database confirmed that higher expression levels of these hub genes were related to lower overall survival. Experimental validation showed that all six hub genes had the same expression trend as predicted., Conclusion: These results identified key genes, which could be used as a new biomarker for breast cancer diagnosis and treatment., (Copyright © 2019. Published by Elsevier GmbH.)

BACKGROUND The purpose of the present study was to evaluate the effect of leptin and leptin receptor (LEPR) expression on the efficacy of neoadjuvant chemotherapy in breast cancer. MATERIAL AND METHODS There were 325 breast cancer patients with complete data enrolled in this study. Patients were categorized into 3 groups: pathological complete response group, non-pathological complete response group, and progressive disease group. Immunohistochemistry was performed to determine leptin and its receptor LEPR expression levels that were compared among the 3 groups. RESULTS Compared with the non-pathological complete response group, patients in the pathological complete response group had increased leptin and LEPR expression, although the difference was not statistically significant (P=0.194, P=0.110). In addition, the expression of leptin and LEPR in the pathological complete response group was also higher than that in the progressive disease group, and the difference of LEPR expression was statistically significant (P=0.008) while the leptin expression was not (P=0.065). There were more HER2+ breast cancer patients in the pathological complete response group categorized into strong positive, and positive expression of leptin and LEPR compared with the progressive disease group (P<0.05). There were significant differences of leptin and LEPR expression among breast cancer patients under different molecular subtypes HER2+, HR+, and triple negative, in which the triple negative patients had the highest expression of leptin and LEPR. In addition, patients in the progressive disease group had high and low expression of leptin and LEPR: 13.25% versus 11.32% and 13.1% versus 10.42% respectively. CONCLUSIONS Overexpression of leptin and LEPR improved the therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer, especially for those with HER2+ subtype. Overexpression of leptin and LEPR was distinct among the different molecular subtypes of breast cancer, suggesting a certain predictive value for breast cancer prognosis.

MicroRNAs (miRs) are a small non-coding RNA family with a length of 18-22 nucleotides. They are able to regulate gene expression by either triggering target messenger RNA degradation or by inhibiting mRNA translation. Enhancer of zeste homolog 2 (EZH2) is the core enzymatic subunit of polycomb repressor complex 2 and is responsible for the trimethylation of histone 3 on lysine 27 (H3K27me3); it is also able to silence a bundle of tumor suppressor genes through promoter binding. However, little is known regarding the effect of miR‑92b on cell autophagy, viability and invasion as well as how it interacts with EZH2. The present study investigated the major role of miR‑92b in the autophagy, viability and invasion of breast cancer. It was revealed that in MCF‑7 and MDA‑MB‑453 cells, the expression of miR‑92b promoted autophagy induced by starvation and rapamycin treatment. The results of in vitro experiments results demonstrated that miR‑92b inhibited breast cancer cell viability, invasion and migration. To further elucidate the regulatory mechanisms of miR‑92b in autophagy, a dual luciferase reporter assay was performed to determine whether miR‑92b targeted the EZH2 gene. The expression of miR‑92b was negatively correlated to EZH2 mRNA expression in breast cancer. Depletion of EZH2 induced phenocopied effects on miR‑92b overexpression, thereby demonstrating its importance in autophagy. These results indicated that miR‑92b may serve an important role in breast cancer in controlling autophagy, viability and invasion. The present study indicated that miR‑92b and EZH2 may serve as potential biomarkers for cancer detection and highlighted their possible therapeutic implications.

Melanoma-associated antigen-A11 (MAGE-A11) is frequently expressed in breast cancer and is associated with poor prognosis. Therefore, MAGE-A11 is a potential immunotherapy target in breast cancer. MAGE-A11 expression, however, is downregulated in many patients, thus constraining the application of immunotherapy. The induction of MAGE-A11 expression is crucial for the recognition and killing of breast cancer cells by cytotoxic T lymphocytes (CTL). In this study, a series of HLA-A2-restricted candidate MAGE-A11 peptides were predicted, synthesized, and tested. Of the selected peptides, p350 (FLFGEPKRL) elicited peptide-specific CTLs from healthy HLA-A*0201-positive donors. The induced CTLs can lyse MAGE-A11-expressing breast cancer cells but not MAGE-A11-negative tumor cells. To improve antitumor immune response, zebularine, a DNA methyltransferase inhibitor, was used to induce MAGE-A11 expression and upregulate the cytotoxicity of antigen-specific T cells in breast cancer cell lines and primary breast cancer cells. The present findings suggested that peptide p350 induces peptide-specific cytolytic activity and is thus a potential candidate for tumor vaccination or T-cell therapy. Epigenetic modulation by zebularine can induce MAGE-A11 expression in breast cancer cells and facilitate cytotoxicity via MAGE-A11-specific CTL.

Background: Our study aims to analyze the expression pattern, mechanism, and prognostic significance of melanoma-associated antigen MAGE-C1 and MAGE-C2 in breast cancer., Methods: Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to investigate the expressions of MAGE-C1 and MAGE-C2 in breast benign disease specimens, tumor-free breast specimens, and breast cancer specimens; their correlation with clinicopathologic parameters and recurrence-free survival was elucidated. We examined the influence of DNA methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) together with histone deacetylase inhibitor trichostatin A on the expression of MAGE-C1 and MAGE-C2 in breast cancer cell lines., Result: Proteins for MAGE-C1 and MAGE-C2 expressions were 38.3% and 58.3% in breast cancer specimens, messenger RNA for MAGE-C1 and MAGE-C2 expressions were 43.3% and 61.7%, respectively. MAGE-C1 and MAGE-C2 expressions were positively associated with high tumor grade and reduced recurrence-free survival; MAGE-C2 expression was also associated with tumor embolus and histologic type. 5-aza-CdR treatment alone could induce expression of MAGE-C2, whereas trichostatin A was able to synergistically enhance 5-aza-CdR-mediated MAGE-C2 transcription., Conclusions: MAGE-C1 and MAGE-C2 maybe potential targets for tumor immunotherapy, and their expressions are associated with advanced breast cancer and poor outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: The LIM domain only proteins (LMOs) which consist of four members (LMO1-LMO4) are a family of nuclear transcription coregulators that are characterized by the exclusive presence of two tandem LIM domains and no other functional domains. They regulate gene transcription by functioning as "linker" or "scaffolding" proteins by virtue of their LIM domains and are involved in the formation of multiprotein complexes with several DNA-binding factors and transcriptional regulatory proteins. In the present study, we tried to find the physical interaction between p53 and LMO4, and the effect of LMO4 on p53-mediated proliferative inhibition of breast cancer cells., Main Methods: FCM analysis was developed to detect the apoptosis of breast cancer cells after adriamycin (ADR) treatment. RT-PCR and Western blot analysis were performed to detect the expression of LMO4 and p53-related genes and proteins. Immunoprecipitation assay was used to detect the interaction between LMO4 and p53. Colony formation assay was developed to detect the proliferation of breast cancer cells., Key Findings: We found that p53 was induced, but LMO4 was down-regulated in response to ADR. We also found that enforced expression of p53 inhibited the expression of LMO4, suggesting that LMO4 is a direct transcriptional target of p53. Furthermore, LMO4 can interact with p53 and inhibit p53-mediated inhibition of colony formation of breast cancer MDA-MB-453 cells., Significance: The present study showed that LMO4 is a direct target of p53 and inhibits p53-mediated proliferative inhibition of breast cancer cells through interacting p53., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Melanoma-associated antigens-A (MAGE-A) family is a group of well-characterized cancer/testis antigens (CTA), because they are strictly tumor specific and are shared by many kinds of tumors. However, the expression pattern of MAGE-A10 and MAGE-A11 in breast cancer patients is still unclear. The purpose of our study is to investigate the expression pattern and prognostic significance of MAGE-A10 and MAGE-A11 in breast cancer patients., Methods: Formalin-fixed and paraffin-embedded tissues and the clinicopathological parameters from 75 primary breast cancer patients were collected. The expressions of MAGE-A10 and MAGE-A11 proteins were immunohistochemically detected, and the association of MAGE-A10 and MAGE-A11 expressions with the clinicopathological parameters and the survival of breast cancer patients were analyzed., Results: The expression rates of MAGE-A10 and MAGE-A11 in breast cancer specimens were 73.3 and 52.0%, respectively. MAGE-A11 expression was more frequent in estrogen-receptor (ER)-positive breast carcinomas compared with ER-negative breast carcinomas (P = 0.004). MAGE-A11 expression was positively associated with HER-2 expression (P = 0.003). Overall survival of patients with MAGE-A11-negative expression was significantly longer than those patients with positive MAGE-A11 expression (P = 0.030), but no difference of overall survival was found between patients with MAGE-A10-negative and -positive expression (P = 0.881)., Conclusions: MAGE-A10 and MAGE-A11 are tumor-specific antigens, and MAGE-A11 expression probably is a potential poor prognostic factor for breast cancer patients.

It has been well documented that tumor suppressor p53 is mutated in about 50% of all human tumors. p53 status might be one of the critical determinants for the chemo-sensitivity of human tumors. In the present study, we have found that p53 family member p73 as well as 14-3-3sigma is down-regulated in response to adriamycin (ADR) in ADR-resistant human breast cancer-derived MBA-MD-436 cells which carry p53 mutation. Like p53, 14-3-3sigma was transactivated by p73 and, in turn, stabilized p73. Luciferase reporter analysis and colony formation assays demonstrated that 14-3-3sigma has an ability to enhance the p73-mediated transcriptional activity as well as its pro-apoptotic function. Furthermore, enforced expression of 14-3-3sigma increased the ADR sensitivity of MBA-MD-436 cells. Taken together, our present results strongly suggest that p73-dependent induction of 14-3-3sigma plays an important role in the regulation of chemo-sensitivity of breast cancers bearing p53 mutation.