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Neoadjuvant chemotherapy (NAC) is widely accepted as a primary treatment for inoperable or locally advanced breast cancer before definitive surgery. However, not all advanced breast cancers are sensitive to NAC. Contrast-enhanced ultrasonography (CEUS) has been considered to assess tumor response to NAC as it can effectively reflect the condition of blood perfusion and lesion size. Therefore, this study aimed to evaluate the diagnostic performance of CEUS to predict early response in different regions of interest in breast tumors under NAC treatment. This prospective study included 82 patients with advanced breast cancer. Parameters of TIC (time-intensive curve) between baseline and after the first cycle of NAC were calculated for the rate of relative change (Δ), including Δpeak, ΔTTP (time to peak), ΔRBV (regional blood volume), ΔRBF (regional blood flow) and ΔMTT (mean transit time). The responders and non-responders were distinguished by the Miller-Payne Grading (MPG) system and parameters from different regions of tumors were compared in these two groups. For ROI 1(the greatest enhancement area in the central region of the tumor), there were significant differences in Δpeak1, ΔRBV1 and ΔRBF1 between responders and non-responders. For ROI 2 (the greatest enhancement area on edge of the tumor), there were significant differences in Δpeak2 and ΔRBF2 between the groups. The Δpeak1 and ΔRBF2 showed good prediction (AUC 0.798-0.820, p ≤ 0.02) after the first cycle of NAC. When the cut-off value was 0.115, the ΔRBF2 had the highest diagnostic accuracy and the maximum NPV. Quantitative TIC parameters could be effectively used to evaluate early response to NAC in advanced breast cancer.
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Triple-negative breast cancer is a special type of breast cancer, characterized by younger onset age, shorter survival period, higher malignant degree, higher mortality, recurrence and metastasis. Triple-negative breast cancer is more harmful to women's life and health, compared with other types of breast cancer. This paper mainly studied the role of miR-585 in triple-negative breast cancer. Real-time quantitative PCR was used to detect the expression of miR-585 in triple-negative breast cancer cell lines and tissues. Kaplan-Meier curve and Cox proportional hazards model analysis were used to investigate the prognostic value of miR-585 in triple-negative breast cancer. CCK-8 and Transwell assays were used to detect cell proliferation, invasion and migration. miR-585 was significantly down-regulated in triple-negative breast cancer cells and tissues. The low expression of miR-585 has been shown to be significantly associated with poor prognosis in triple-negative breast cancer patients. Abnormally low expression of miR-585 can promote cell proliferation, migration and invasion. Overall, abnormally low expression of miR-585 is associated with prognosis and progression of triple-negative breast cancer. miR-585 may serve as a prognostic biomarker for patients with triple-negative breast cancer and it is expected to be a new method and strategy for the treatment of triple-negative breast cancer.
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MicroRNAs/genética , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Prognóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
With the great progress made recently in next generation sequencing (NGS) technology, sequencing accuracy and throughput have increased, while the cost for data has decreased. Various human leukocyte antigen (HLA) typing algorithms and assays have been developed and have begun to be used in clinical practice. In this study, we compared the HLA typing performance of three HLA assays and seven NGS-based HLA algorithms and assessed the impact of sequencing depth and length on HLA typing accuracy based on 24 benchmarked samples. The algorithms HISAT-genotype and HLA-HD showed the highest accuracy at both the first field and the second field resolution, followed by HLAscan. Our internal capture-based HLA assay showed comparable performance with whole exome sequencing (WES). We found that the minimal depth was 100X for HISAT-genotype and HLA-HD to obtain more than 90% accuracy at the third field level. The top three algorithms were quite robust to the change of read length. Thus, we recommend using HISAT-genotype and HLA-HD for NGS-based HLA genotyping because of their higher accuracy and robustness to read length. We propose that a minimal sequence depth for obtaining more than 90% HLA typing accuracy at the third field level is 100X. Besides, targeting capture-based NGS HLA typing may be more suitable than WES in clinical practice due to its lower sequencing cost and higher HLA sequencing depth.
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Algoritmos , Antígenos HLA/genética , Antígenos HLA/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Alelos , Biologia Computacional/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/normas , Teste de Histocompatibilidade/normas , Humanos , Reprodutibilidade dos Testes , Análise de Sequência de DNA , SoftwareRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment. MATERIALS AND METHODS: We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model. RESULTS: Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060. CONCLUSION: RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.
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Biomarcadores Tumorais/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-met/genética , Receptores Proteína Tirosina Quinases/genética , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Circular RNAs (circRNAs), a novel class of non-coding RNAs, have been found to act as microRNA (miRNA) sponges and thus play key roles in biological processes and pathogenesis. However, studies regarding circRNAs in colorectal cancer (CRC) remain inadequate. RESULTS: By differential expression analysis, 10 candidate circRNAs (6 upregulated and 4 downregulated circRNAs) were chosen. 9 of 10 circRNAs were available on CSCD and their structure showed the binding potential of miRNA. Intersection analysis revealed that miR-145-5p, miR-3127-5p, miR-761, miR-4766-3p, miR-135a-5p, miR-135b-5p, miR-374a-3p and miR-330-3p were 8 miRNAs with the most potential in binding circRNAs. Further expression validation and correlation analysis demonstrated hsa_circ_0001955/miR-145-5p and hsa_circ_0000977/miR-135b-5p axes as key pathways in CRC. Subsequently, target gene prediction, differential expression analysis, intersection analysis and correlation analysis showed that CDK6, MMP12 and RAB3IP were the three potential downstream targets of hsa_circ_0001955/miR-145-5p axis and FOXO1, MBNL1, MEF2C, RECK, PPM1E, TTLL7 and PCP4L1 were the seven potential downstream targets of hsa_circ_0000977/miR-135b-5p axis in CRC. Finally, we also confirmed that expression of hsa_circ_0001955 or hsa_circ_0000977 was significantly positively correlated with their individual targets in CRC. CONCLUSIONS: In the present work, we constructed a potential hsa_circ_0001955/hsa_circ_0000977-mediated circRNA-miRNA-mRNA regulatory network in CRC by a series of in silico analysis and experimental validation. METHODS: Whole-transcriptome microarrays from CRC and matched normal samples were obtained from GEO. The structure of circRNA was identified by CSCD. starBase and miRNet were successively used to predict miRNA of circRNA and target gene of miRNA. Expression correlation between RNA-RNA interactions was assessed using GEO and TCGA data. Finally, a potential circRNA-miRNA-mRNA network was established based on competing endogenous RNA (ceRNA) hypothesis.
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Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Mensageiro/metabolismo , Regulação para Baixo , Proteínas Ligadas por GPI/metabolismo , Redes Reguladoras de Genes , Humanos , Transcriptoma , Regulação para CimaRESUMO
BACKGROUND: Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor, commonly occurring in distal extremities, such as fingers, hands and wrists. For oncologists and surgeons, a female patient with enlarged axillary lymph node on one side only is easily diagnosed with an occult breast carcinoma rather than ES. Besides, whole breast metastasis of ES has not been reported yet. CASE PRESENTATION: A 47-year-old Chinese woman came to the outpatient clinic of First Affiliated Hospital of Zhejiang University (FAHZU) with a complaint of an asymptomatic right axillary mass for 3 months. Then she received surgical resection of the right axillary lymph nodes and right supraclavicular lymph nodes. According to the clinical tumor site and routine immunohistochemistry (IHC), suspicion of metastatic epithelial sarcoma and metastatic breast cancer could not be ruled out. Subsequently, with more detailed medical history review and physical examination, a mass on the right forearm was found, which was considered as the primary lesion. Further IHC and Molecular Genetics revealed that all the neoplastic cells exhibited loss of INI1 protein and were negative for ERG gene rearrangement yet positive for epithelial membrane antigen (EMA), cytokeratin (CK) 8, CK19, Vimentin, CD34. The final diagnosis was ES. She received postoperative chemotherapy, without radiotherapy. Unexpectedly, an ipsilateral breast metastasis was developed at ten months after surgery. Regrettably, there was no positive result of the metastatic breast sample, based on a genome sequencing by a 381-cancer-gene panel in a lab. Therefore, she went through another round of chemotherapy and took Apatinib for maintenance treatment. During the last follow-up (26 months after diagnosis), the disease was under control. CONCLUSION: This rare but interesting case enables breast surgeons and pathologists to accumulate more experience of differential diagnosis of axillary mass for personalized treatment in clinical practice. Meanwhile, ipsilateral breast metastasis of ES we reported in the case urges that clinicians attach greater importance to the tumor metastasis mechanism.
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Neoplasias da Mama/secundário , Sarcoma/secundário , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Excisão de Linfonodo/métodos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Mucina-1/metabolismo , Segunda Neoplasia Primária/patologia , Sarcoma/diagnósticoRESUMO
Aim: To identify novel competing endogenous RNA (ceRNA) network related to patients prognosis in breast cancer. Materials & methods: Dysregulated mRNA based on intersection of three Gene Expression Omnibus and The Cancer Genome Atlas datasets were analyzed by bioinformatics. Results: In total 72 upregulated and 208 downregulated genes were identified. Functional analysis showed that some pathways related to cancer were significantly enriched. By means of stepwise reverse prediction and validation from mRNA to lncRNA, 19 hub genes, nine key miRNA and four key lncRNAs were identified by expression and survival analysis. Ultimately, the coexpression analysis identified RRM2-let-7a-5p-SNHG16/MAL2 as key ceRNA subnetwork associated with prognosis of breast cancer. Conclusion: We successfully constructed a novel ceRNA network, among which each component was significantly associated with breast cancer prognosis.
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Neoplasias da Mama/mortalidade , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Mama/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Prognóstico , RNA Mensageiro/genética , Ribonucleosídeo Difosfato Redutase/genética , Análise de SobrevidaRESUMO
PURPOSE: Owing to the absence of any targeted therapies, triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, typically have a poorer outcome. In an attempt to find out the TNBCs' microenvironment, we ran into the endogenous expression of a newly discovered cytokine known as Interleukin (IL)-22. METHODS: Thirty TNBC patients were recruited and the levels of IL-22 producing (Th22) cells in tumor, paratumor and normal breast tissues were measured. Then we studied the role and mechanism of IL-22 in migration and paclitaxel resistance in TNBC cells MDA-MB 468 and MDA-MB 231. RESULTS: The prevalence of Th22 cells were gradually increased in normal, paratumor and tumor tissues. In vitro, IL-22 promotes TNBC cells migration and induces paclitaxel resistance. Importantly, IL-22 exposure of TNBC cells resulted in JAK-STAT3/MAPKs/AKT signaling pathways activated. CONCLUSION: IL-22 may play an accelerating role in the development of TNBC and may open a new therapeutic approach for TNBC.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucinas/metabolismo , Paclitaxel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Interleucina 22RESUMO
Though most patients with breast cancer are cured, there are still many patients progressed to metastatic breast cancer (MBC) and some are diagnosed as MBC. Human epidermal growth factor receptor 2 (HER2) is positive in about 20% all breast cancer patients and considered as a poor prognostic factor. The advent of ant-HER2 therapy has prominently prolonged the time of disease progression and survival for HER2-positive MBC patients. This review summarizes the advance in anti-HER2 therapy in HER2-positive MBC according to the phase III clinical trials, and briefly discusses some new agents and anti-HER2 therapy for HER2 low-or non-expression breast cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Oncologia/tendências , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Oncologia/métodos , Metástase Neoplásica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
Metastatic breast cancer is one of the major types of cancer in women. However, despite being the focus of considerable research efforts, its molecular mechanism remains to be fully elucidated. The B-cell lymphoma/leukemia gene-2 (Bcl-2) protein is well known for its role in inhibiting programmed cell death/apoptosis. However, little is known concerning its function in cell invasion and migration. In the present study, cell migration and invasion assays revealed that anti-apoptotic Bcl-2 protein induced migration and invasion without affecting cell proliferation in the BCap37 breast cancer cell line. In addition, it was found that the overexpression of Bcl-2 in BCap37 cells increased metastasis to the lung in a mouse model. Using western blotting and RT q-PCR analysis, it was demonstrated that the overexpression of Bcl-2 inhibited the expression of E-cadherin, an epithelial marker, whereas it increased the levels of mesenchymal markers N-cadherin and vimentin. Therefore, the results suggested that Bcl-2 may induce cellular metastasis in breast cancer via the epithelial-to-mesenchymal transition.
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Chemoresistance often leads to the failure of breast cancer treatment. MicroRNAs (miRNAs) play an important role in the progression and chemoresistance of cancer. However, because of the complexity of the mechanisms of chemoresistance and the specificity of miRNA regulation in different cell types, the function of miR-20a in breast cancer chemoresistance is still unclear. Here, by using miRNA microarray and high-content screening techniques, we found that miR-20a/b were significantly downregulated in breast cancer tissues compared with normal breast tissues, and low miR-20a/b expression was correlated with poor survival in breast cancer patients. Ectopic overexpression of miR-20a sensitized breast cancer cells to a broad spectrum of chemotherapy drugs and suppress their proliferation both in vitro and in vivo. Further study demonstrated that miR-20a directly targeted the 3'untranslated region of MAPK1, and thus downregulated the expression of P-gp and c-Myc by inhibiting the MAPK/ERK signaling pathway, whereas c-Myc can bind to the promoter region of the miR-20a gene to promote the expression of miR-20a. Together, our study identified a novel miR-20a/MAPK1/c-Myc feedback loop that regulates breast cancer growth and chemoresistance. These findings suggest that miR-20a synergizing with anticancer drugs will be a promising treatment strategy, especially for chemoresistant patients.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Células Tumorais CultivadasRESUMO
Major histocompatibility complex class I chain-related proteins A and B (MICA and MICB) are important ligands for recognition of tumor cells by immune effector cells. Here, we report that resveratrol upregulated the protein and mRNA expression of MICA and MICB in breast cancer cells, which in turn promoted breast cancer cell lysis by natural killer (NK) cells in vitro and in vivo. Antibodies against NK group 2 member D blocked this effect. The 3'-untranslated regions of MICA and MICB were found to be direct binding targets of miR-17. MICA and MICB expression increased or decreased in breast cancer cells transfected with a miR-17 inhibitor or mimic, respectively. C-Myc overexpression/knockdown increased/decreased transcription of the miR-17-92 cluster host gene. Resveratrol suppressed c-Myc expression, which inhibited the transcription of miR-17-92 cluster, thereby downregulating miR-17. MiR-17 expression correlated inversely with MICA and MICB expression and overall survival in two sets of breast cancer specimens. Resveratrol thus upregulates MICA and MICB by suppressing the c-Myc/miR-17 pathway in breast cancer cells, and increases the cytolysis of breast cancer cells by NK cells. This suggests resveratrol has the potential to promote antitumor immune responses in breast cancer patients.
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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy due to its broad resistance to chemotherapy. Gemcitabine is used as a standard chemotherapeutic drug for PDAC treatment, either alone or in combination with other chemotherapeutics. However, in patients with advanced disease, survival is rarely improved. This study aimed to investigate the therapeutic efficacy of N1-guanyl-1, 7-diaminoheptane (GC7) combined with gemcitabine in PDAC therapy. We measured eukaryotic translation initiation factor 5A2 (eIF5A2) expression and gemcitabine sensitivity in different PDAC cell lines (Panc-1, BxPC-3, and T3-M4). The synergistic cytotoxic effects of gemcitabine combined with GC7 were measured using Cell Counting Kit-8 assays. Western blots were performed to measure eIF5A2 and multi-drug resistance 1 (MDR1) protein expression in PDAC cells. The present findings demonstrated that combined treatment with GC7 and gemcitabine significantly inhibited PDAC cell line viability (P<0.05). EdU incorporation assays also indicated that GC7 co-treatment remarkably enhanced gemcitabine sensitivity in PDAC cells. Furthermore, downregulation of eIF5A2 diminished the regulatory role of GC7 in gemcitabine cytotoxicity. Western blotting data indicated that GC7 downregulated the expression of MDR1 while gemcitabine induced MDR1 upregulation. These findings showed that GC7 combination therapy may enhance the therapeutic efficacy of gemcitabine in PDAC by downregulating MDR1 expression.
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Approximately 30% of all breast cancers are caused by a lack of estrogen receptor (ER), which renders the cancer resistant to endocrine-based therapy. Many studies suggest that ubiquitin-specific peptidase 9, X-linked (usp9x) regulates multiple cellular behaviors, such as tumor growth, invasion, and resistance to chemotherapeutic agents. This study aimed to evaluate the anti-tumor effects of WP1130, a partially selective inhibitor of deubiquitinating enzymes, in breast cancer cells. We found that WP1130 enhanced cisplatin cytotoxicity in ER-negative tumor cells (MDA-MB-231 and MDA-MB-468), but had little effect in ER-positive Bcap-37 cells. Western blot analysis revealed that usp9x expression was dramatically lower in ER-positive cells compared to that in ER-negative cells. Furthermore, WP1130 treatment suppressed the expression of usp9x and Mcl-1 in ER-negative cells, but not in ER-positive cells. In addition, we found that knockdown of usp9x diminished the chemosensitization activity of WP1130 on breast cancer cells in the presence of cisplatin. Taken together, these results demonstrated that combined treatment with WP1130 could increase the cisplatin sensitivity in a usp9x-dependent manner in estrogen receptor-negative breast cancer cells.
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NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DLs). NKG2DLs are expressed on malignant cells and sensitize them to early elimination by cytotoxic lymphocytes. We investigated the clinical importance of NKG2DLs and the mechanism of NKG2DL regulation in breast cancer (BC). Among the NKG2DLs MICA/B and ULBP1/2/3, the expression levels of MICA/B in BC tissues were inversely associated with the Tumor Node Metastasis stage. We first found that the high expression of MICB, but not MICA, was an independent prognostic factor for overall survival in patients with BC. Investigation into the mechanism revealed that a group of microRNAs (miRNAs) belonging to the miR-17-92 cluster, especially miR-20a, decreased the expression of ULBP2 and MICA/B. These miRNAs downregulated the expression of MICA/B by targeting the MICA/B 3'-untranslated region and downregulated ULBP2 by inhibiting the MAPK/ERK signaling pathway. Functional analysis showed that the silencing of NKG2DL-targeting miRNAs in BC cells increased NK cell-mediated cytotoxicity in vitro and inhibited immune escape in vivo. In addition, histone deacetylase inhibitors (HDACis) increased NKG2DL expression in BC cells by inhibiting members of the miR-17-92 cluster. Thus, targeting miRNAs with antisense inhibitors or HDACis may represent a novel approach for increasing the immunogenicity of BC.
Assuntos
Neoplasias da Mama/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , MicroRNAs/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , RNA Neoplásico/imunologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células Matadoras Naturais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Masculino , Camundongos , MicroRNAs/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , RNA Neoplásico/genéticaRESUMO
Breast cancer (BC) is the most common female malignancy within the spectrum of human cancer. One promising way to reduce the mortality and morbidity of BC is to explore novel diagnostic markers for early diagnosis and prognostication. The neutrophil lymphocyte ratio (NLR) is a good reflection of inflammation, which plays an important role in tumor progression and metastasis. However, the association between NLR and BC prognosis remains unclear. The aim of this meta-analysis is to explore the prognostic value of NLR in BC. Among the screened references in the database, 12 eligible studies were identified in this study. Patients with a higher NLR had a shorter disease-free survival (hazard ratio =1.46, 95% confidence interval: 1.12-1.90, P=0.044) and overall survival (hazard ratio =2.03, 95% confidence interval: 1.41-2.93, P<0.001). In the subgroup analysis of NLR and disease-free survival, the studies from Eastern countries had a positive result with perfect homogeneity (I (2)=0); however, this homogeneity has not been achieved in studies from Western countries. In the subgroup analysis of the NLR and overall survival, the results of the univariate and multivariate analyses were completely different, with different heterogeneity. In the luminal A and luminal B subtypes, we found that there was no association between the NLR and overall survival in the BC patients. Positive results were obtained in the analyses of the human epidermal growth factor receptor 2 (HER2)-positive and triple-negative BC subtypes. In conclusion, this meta-analysis suggests that NLR is a good prognostic marker for BC, and patients with a higher NLR have poorer prognoses. Future studies should perform more detailed investigations to decrease heterogeneity and determine the appropriate cut-off values for different races.
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PURPOSE: Cancer stem cell-tumor microenvironment ecosystem is proposed to drive tumor heterogeneity. Tumor-infiltrating lymphocytes (TILs) in breast cancer ecosystem were demonstrated to indicate better prognosis and benefit from chemotherapy. This study sought to detect the association between breast cancer stem cells and TILs. METHODS: 92 patients with breast cancer were enrolled. Matched cancerous and paracancerous tissues were assembled in a tissue microarray and immunohistochemistry was employed to test expression of breast cancer stem cells (BCSCs) markers. TILs counts were estimated with global hematoxylin-eosin staining. The association between TILs and BCSCs phenotypes was analysed by multivariate analysis. RESULTS: Although it was unable to find direct significant association between BCSCs phenotypes and TILs, the BCSCs phenotype with CD44(+)CD24(-)ALDH1A1(+)EpCAM(+)CD49f(+) was proved to be associated with worse DFS and OS (P=0.037 and 0.001). This result was confirmed by cox proportional-hazards regression model (for DFS and OS respectively, HR=2.438 and 3.383, P=0.019 [95%CI 1.418-3.457] and 0.025 [95%CI 1.162-9.843]). Additionally, in results of TILs, plasma cell-predominant breast cancer (PPBC) was unexpectedly found to indicate worse OS and HR was 2.686 (P=0.038 [95%CI 1.582-3.789]). CONCLUSIONS: The BCSCs phenotype and PPBC may be helpful stratified factors in future clinical trials. The underlying mechanism needs further research.
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Neoplasias da Mama/patologia , Linfócitos do Interstício Tumoral/patologia , Células-Tronco Neoplásicas/patologia , Plasmócitos/patologia , Microambiente Tumoral , Adulto , Idoso , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de TecidosRESUMO
BACKGROUND: Approximately 30% of breast cancer does not express the estrogen receptor (ER), which is necessary for endocrine-based therapy approaches. Many studies demonstrated that eukaryotic translation initiation factor 5A2 (eIF5A2) serves as a proliferation-related oncogene in tumorigenic processes. METHODS: The present study used cell viability assays, EdU incorporation assays, western blot, and immunofluorescence to explore whether N1-guanyl-1,7-diaminoheptane (GC7), which inhibits eIF5A2 activation, exerts synergistic cytotoxicity with doxorubicin in breast cancer. RESULTS: We found that GC7 enhanced doxorubicin cytotoxicity in ER-negative HCC1937 cells but had little effect in ER-positive MCF-7 and Bcap-37 cells. Administration of GC7 reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in ER-negative breast cancer cells. Knockdown of eIF5A2 by siRNA inhibited the doxorubicin-induced EMT in ER-negative HCC1937 cells. CONCLUSION: These data demonstrated that GC7 combination therapy may enhance the therapeutic efficacy of doxorubicin in estrogen negative breast cancer cells by preventing EMT through inhibition of eIF5A2 activation.
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Neoplasias da Mama/metabolismo , Diaminas/farmacologia , Doxorrubicina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores de Estrogênio/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Técnicas de Silenciamento de Genes , Humanos , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
Resistance to single or multiple chemotherapeutic drugs is a major obstacle in breast cancer therapy. Recent studies have suggested that GPR30 is implicated in mediating cancer cell proliferation. The aim of this study was to examine the anti-tumor effects of the GPR30 antagonist G15 in breast cancer. We found that low concentrations of G15 had little effect on breast cancer cell viability, but could enhance doxorubicin sensitivity in MDA-MB-231 and MCF-7 cells with epithelial phenotypes. In addition, G15 prevented epithelial breast cancer cells undergoing epithelial-mesenchymal transition (EMT) after doxorubicin induction. Moreover, downregulation of GPR30 suppressed the EMT in breast cancer cells. These results support that G15 enhanced doxorubicin sensitivity and prevented the EMT in epithelial breast cancer cells by inhibiting GPR30 expression.