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Accurate pathologic diagnosis and molecular classification of breast mass biopsy tissue is important for determining individualized therapy for (neo)adjuvant systemic therapies for invasive breast cancer. The CassiII rotational core biopsy system is a novel biopsy technique with a guide needle and a "stick-freeze" technology. The comprehensive assessments including the concordance rates of diagnosis and biomarker status between CassiII and core needle biopsy were evaluated in this study. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki67 were analyzed through immunohistochemistry. In total, 655 patients with breast cancer who underwent surgery after biopsy at Sir Run Run Shaw Hospital between January 2019 to December 2021 were evaluated. The concordance rates (CRs) of malignant surgical specimens with CassiII needle biopsy was significantly high compared with core needle biopsy. Moreover, CassiII needle biopsy had about 20% improvement in sensitivity and about 5% improvement in positive predictive value compared to Core needle biopsy. The characteristics including age and tumor size were identified the risk factors for pathological inconsistencies with core needle biopsies. However, CassiII needle biopsy was associated with tumor diameter only. The CRs of ER, PgR, HER2, and Ki67 using Cassi needle were 98.08% (kappa, 0.941; p<.001), 90.77% (kappa, 0.812; p<.001), 69.62% (kappa, 0.482; p<.001), and 86.92% (kappa, 0.552; p<.001), respectively. Post-biopsy complications with CassiII needle biopsy were also collected. The complications of CassiII needle biopsy including chest stuffiness, pain and subcutaneous ecchymosis are not rare. The underlying mechanism of subcutaneous congestion or hematoma after CassiII needle biopsy might be the larger needle diameter and the effect of temperature on coagulation function. In summary, CassiII needle biopsy is age-independent and has a better accuracy than CNB for distinguishing carcinoma in situ and invasive carcinoma.
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[This corrects the article DOI: 10.3389/fonc.2021.697950.].
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Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.
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BACKGROUND: Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. METHODS: The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. RESULTS: Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc- inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. CONCLUSIONS: This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.
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Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Metformina/administração & dosagem , Proteínas/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Ferroptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Metformina/farmacologia , Metilação , Camundongos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Drug resistance is a daunting challenge in the treatment of breast cancer, making it an urgent problem to solve in studies. Cell lines are important tools in basic and preclinical studies; however, few breast cell lines from drug-resistant patients are available. Herein, we established a novel HER2-positive breast cancer cell line from the pleural effusion of a drug-resistant metastatic breast cancer patient. This cell line has potent proliferative capability and tumorigenicity in nude mice but weak invasive and colony-forming capability. The molecular subtype of the cell line and its sensitivity to chemotherapeutics and HER2-targeting agents are different from those of its origin, suggesting that the phenotype changes between the primary and metastatic forms of breast cancer.
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Mastoscopic axillary lymph node dissection (MALND) is a currently used and safe surgical treatment option for breast cancer. However, the extensive application of MALND is still debatable because of the use of conventional axillary lymph node dissection (CALND). Therefore, in the current study, we aimed to compare the efficacy and safety of MALND and CALND for obtaining evidence-based conclusions about the short-term and long-term outcomes of MALND for patients with breast cancer. PubMed, Web of Science, Cochrane Library, and CNKI were comprehensively searched for articles published between January 1998 and January 2019. Then Newcastle-Ottawa scale was used for quality assessment. The Review Manager software version 5.0 was utilized for generating forest maps and funnel plots. Twelve studies including 2157 patients were selected for the meta-analysis. There were no significant differences in the number of lymph node dissections, tumor recurrence rate, axillary drainage, postoperative hospitalization time, and tumor size between the MALND and CALND groups (P > .05). In the MALND group, the surgery time was longer, while the incidence of intraoperative bleeding was lesser and the duration of drainage was shorter than those in the CALND group (P < .01). The complications in the MALND group were also fewer than those in the CALND group (P < .05). The results of the current study showed that MALND is reliable and feasible for breast cancer owing to the lesser incidence of intraoperative bleeding, shorter drainage duration, and lower incidence of complications compared to CALND.
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Neoplasias da Mama/cirurgia , Endoscopia/métodos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Recidiva Local de Neoplasia/cirurgia , Biópsia de Linfonodo Sentinela/métodos , Axila , Neoplasias da Mama/patologia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Recidiva Local de Neoplasia/patologia , Resultado do TratamentoRESUMO
Purpose: FKBP4 is a member of the immunophilin protein family, which plays a role in immunoregulation and basic cellular processes involving protein folding and trafficking associated with HSP90. However, the relationship between abnormal expression of FKBP4 and clinical outcome in luminal A subtype breast cancer (LABC) patients remains to be elucidated. Methods: Oncomine, bc-GenExMiner and HPA database were used for data mining and analyzing FKBP4 and its co-expressed genes. GEPIA database was used for screening co-expressed genes of FKBP4. Results: For the first time, we found that higher FKBP4 expression correlated with LABC patients and worse survival. Moreover, the upregulated co-expressed genes of FKBP4 were assessed to be significantly correlated with worse survival in LABC, and might be involved in the biological role of FKBP4. Conclusion: The expression status of FKBP4 is a significant prognostic indicator and a potential drug target for LABC.
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Long noncoding RNA (lncRNA) H19 and Lin28 protein have been shown to participate in various pathophysiological processes, including cellular proliferation, autophagy and epithelialmesenchymal transition (EMT). A number of studies have investigated lncRNAs, microRNAs and mRNAs, and their roles in the initiation and progression of cancer, in doing so identifying competitive endogenous RNA (ceRNA) networks, including the H19/let7/Lin28 network. However, whether the H19/let7/Lin28 ceRNA network is involved in autophagy and EMT in breast cancer (BC) remains unclear. The present study demonstrated that the H19/let7/Lin28 loop was required for the downregulation of autophagy in BC cells via western blot analysis, reverse transcriptionquantitative PCR and autophagy flux monitoring. Using wound healing, migration and invasion assays, and morphological assays, the H19/let7/Lin28 loop was revealed to promote EMT in BC cells. Moreover, the H19/let7/Lin28 network was found to contribute to autophagy by inhibiting EMT in BC cells. To the best of our knowledge, the present study is the first to suggest the important roles of the H19/let7/Lin28 ceRNA network in BC autophagy and EMT, thus providing insight for the use of these molecules as prognostic biomarkers and therapeutic targets in BC metastasis.
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Neoplasias da Mama/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Autofagia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7RESUMO
PURPOSE: In this study, we aimed to investigate the viability of utilizing CytoSorter® system to detect circulating tumor cells (CTCs) and to evaluate the diagnostic value of CTCs in breast cancer (BC). METHODS: A total of 366 females patients suspected of having BC and 30 healthy female volunteers were enrolled in this study. CTCs were enriched by CytoSorter® , a microfluidic-based CTCs capturing platform. CTC detection was performed before operation or biopsy. Based on the biopsy results, patients were divided into two groups, namely patients with BC and patients with benign breast diseases (BBD). Patients with BBD and healthy volunteers were serving as controls. The correlation between CTC enumeration and patients' clinicopathological characteristics was evaluated. The receiver operating characteristic (ROC) curve was plotted to assess the diagnostic potency of CytoSorter® system in BC. RESULTS: Based on the biopsy results, 130 BC patients at different cancer stages and 236 patients with BBD were enrolled in the study. Seven subjects were dropped out from the study. CTCs were detected in 109 of 128 BC patients, in one of 29 healthy volunteers, and in 37 of 232 patients with BBD. Maximum CTC counts detected in BC patients, healthy volunteers, and patients with BBD were 8, 1, and 4, respectively. Statistical analysis showed CTCs could be used to distinguish BC patients from healthy volunteers and patients with BBD (P < .0001). Circulating tumor cells were statistically associated with patients' cancer stage (P = .0126), tumor size (tumor node metastasis [TNM] T stage, P = .0253), cancer type (invasive vs noninvasive, P = .0141), and lymph node metastasis (P = .0436). More CTCs were found in patients at advanced cancer stage or TNM T stage and in patients with invasive tumor or lymph node metastasis. Furthermore, CTC detection rates in BC patients at Tis and T1-4 stages were 50%, 81.67%, 91.07%, 100%, and 100%, respectively. When the CTC cut-off value was set to 2, the ROC curve gave an area under the curve (AUC) of 0.86 with a specificity and sensitivity of 95.4% and 76.56%, respectively. Taken together, CTCs could be used as a diagnostic aid in assistance of cancer screening and staging. CONCLUSION: Circulating tumor cells were successfully isolated in BC patients using CytoSorter® system. CTCs can be used to differentiate BC patients from the patients with BBD or healthy volunteers, and as a diagnostic aid for early cancer diagnosis and cancer staging.
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Neoplasias da Mama/diagnóstico , Separação Celular/instrumentação , Detecção Precoce de Câncer/instrumentação , Células Neoplásicas Circulantes/patologia , Adolescente , Adulto , Idoso , Biópsia , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Casos e Controles , Contagem de Células , Linhagem Celular Tumoral , Diagnóstico Diferencial , Detecção Precoce de Câncer/métodos , Estudos de Viabilidade , Feminino , Voluntários Saudáveis , Humanos , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Adulto JovemRESUMO
BACKGROUND: Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. METHODS: Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. RESULTS: In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. CONCLUSIONS: Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , RNA Longo não Codificante/genética , Tamoxifeno/farmacologia , Adenosil-Homocisteinase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , DNA Metiltransferase 3A , Doxiciclina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Distribuição Aleatória , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Nicotinamide N-methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear. METHODS: NNMT expression in breast carcinoma was examined by immunohistochemistry, and then, its relationship with patient clinicopathological characteristics was analyzed. The effects of NNMT on chemoresistance in breast cancer cells were assessed by cell viability, colony formation, and apoptosis assay. The NNMT, SIRT1, p53, and acetyl-p53 proteins, which are involved in NNMT-related chemoresistance, were examined by Western blotting. The SIRT1 mRNA was examined by real-time PCR, and its activity was measured by using the SIRT1 deacetylase fluorometric reagent kit. RESULTS: NNMT expression was significantly higher (53.9%) in breast carcinoma than in paracancerous tissues (10.0%) and breast hyperplasia (13.3%). A high level of NNMT expression correlated with poor survival and chemotherapy response in breast cancer patients who received chemotherapy. Ectopic overexpression of NNMT significantly inhibited the apoptotic cell death and suppression of colony formation induced by adriamycin and paclitaxel. Mechanistic studies revealed that NNMT overexpression increased SIRT1 expression and promoted its activity. Either inhibition of SIRT1 by EX527 or knockdown of SIRT1 by siRNA could reverse NNMT-mediated resistance to adriamycin and paclitaxel, which suggests that SIRT1 plays a critical role in NNMT-related chemoresistance in breast cancer. CONCLUSIONS: The results of this study demonstrate a novel correlation between the NNMT expression level and patient survival, suggesting that NNMT has the potential to become a new prognostic biomarker to predict the treatment outcomes of the clinical chemotherapy in breast cancer. Moreover, targeting NNMT or downstream SIRT1 may represent a new therapeutic approach to improve the efficacy of breast cancer chemotherapy.
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Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Nicotinamida N-Metiltransferase/metabolismo , Sirtuína 1/metabolismo , Adulto , Idoso , Antineoplásicos/farmacologia , Apoptose/genética , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hiperplasia , Imuno-Histoquímica , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nicotinamida N-Metiltransferase/genética , Estabilidade Proteica , Interferência de RNA , RNA Interferente Pequeno/genética , Sirtuína 1/genéticaRESUMO
BACKGROUND: Basal/human epidermal growth factor receptor (HER)2-positive (HER2+) breast cancer is resistant to monoclonal antibody (herceptin) treatment. There are currently only three basal/HER2+ breast cancer cell lines available, but they are not from Chinese populations. METHODS: Three immortalized cell lines (ZJU-0327, ZJU-0725, and ZJU-1127) were established from invasive ductal breast carcinoma tissue of two patients treated by surgical resection at our center. The cell lines were characterized in terms of histology, therapeutic response, and biomarker expression. Their tumorigenic potential was evaluated in an athymic nude (BALB/C nu) mouse xenograft model. Cell authentication testing by the techniques of short tandem repeat. RESULTS: ZJU-0327, ZJU-0725, and ZJU-1127 cell lines were maintained for more than 110 passages in vitro. The cells grew as monolayers; showed typical epithelial morphology and ultrastructure; were polyploid; had doubling times of 18, 57.5, and 18 h, respectively; had a near-tetraploid (ZJU-0327 and ZJU-1127) or aneuploid (ZJU-0725) karyotype with structural aberrations and tumor protein 53 mutation; insensitive to chemotherapeutic drugs and/or radiation; show high invasiveness and tumorigenicity in mice; and had no mycoplasma contamination. The cell lines were basal/HER2+, expressed cluster of differentiation, and were associated with poor prognosis. Cell authentication testing by the American Type Culture Collection confirmed the human origin of the cell lines, which did not match those in existing databases. CONCLUSIONS: The three novel basal/HER2+ breast cancer cell lines recapitulating the malignant characteristics of the parent tumor's, and can be useful for clarifying the molecular pathogenesis of basal/HER2+ breast cancer.
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BACKGROUND: Gastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer. RESULTS: Among 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival (P log-rank=0.001) and progress-free survival (P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways. METHODS: Tumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms. CONCLUSION: Both tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.
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Biomarcadores Tumorais/metabolismo , Neoplasias Gástricas/diagnóstico , gama-Glutamiltransferase/metabolismo , Carcinogênese , Feminino , Glutationa/metabolismo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , gama-Glutamiltransferase/genéticaRESUMO
AIMS: To determine whether circulating multiple miRNAs can be used as novel biomarkers for the diagnosis in breast cancer, we performed a systematic review and meta-analysis. MATERIALS & METHODS: After searching the databases of PubMed, EMBASE and Web of Science, we used the bivariate meta-analysis model to summarize the diagnostic indices and plot the summary receiver operator characteristic curve. RESULTS: The summary estimates revealed that the pooled sensitivity was 88% (95% CI: 82-93%); specificity was 84% (95% CI: 74-91%); positive likelihood ratio was 4.69 (95% CI: 2.93-7.51); negative likelihood ratio was 0.15 (95% CI: 0.09-0.25); diagnostic odds ratio was 38.21 (95% CI: 13.41-108.85); and the area under the curve was 0.93 (95% CI: 0.90-0.95). CONCLUSION: These results suggested that circulating multiple miRNAs might serve as novel biomarkers for breast cancer, with a relatively high level of accuracy.
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Neoplasias da Mama/diagnóstico , MicroRNAs/sangue , Área Sob a Curva , Neoplasias da Mama/genética , Bases de Dados Factuais , Feminino , Humanos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e EspecificidadeRESUMO
The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (p<0.05 for each). Kaplan-Meier analysis illustrated that both Lin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, p<0.01). Multivariate Cox analysis showed that Lin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.
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Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Western Blotting , Proliferação de Células , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Chemotherapy resistance is one of the major obstacles limiting the success of cancer drug treatment. Among the mechanisms of resistance to chemotherapy treatment, there are those closely related to P-Glycoprotein, multidrug resistance-related protein, glutathione S-transferase pi and topoisomerase-II. Lin28 is a highly conserved RNA-binding protein, it consists of a cold shock domain and retroviral-type (CCHC) zinc finger motifs. In previous preclinical and clinical studies, positive Lin28 expression in cancer cells was correlated with decreased sensitivity to chemotherapy. And Lin28 could mediate cancer chemotherapy resistance via regulation of miR107 and Let-7 MiRNA. This article reviews current knowledge on predictive value of Lin28 in response to chemotherapy. Better understanding of its role may facilitate patient's selection of therapeutic regimen and lead to optimal clinical outcome.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas de Ligação a RNA/genética , Resultado do TratamentoRESUMO
Current endocrine therapies for females with estrogen receptor-positive breast cancer have facilitated substantial improvements in outcomes. The effectiveness of endocrine therapy is limited by either initial de novo resistance or acquired endocrine resistance. Multiple mechanisms responsible for endocrine resistance have been proposed, including deregulation of various components of the estrogen receptor (ER) pathway, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways. Dysregulation of miRNA expression has been associated with experimental and clinical endocrine therapy resistance. miRNAs are pivotal to understanding the complex biological mechanism of endocrine resistance, and may serve as novel candidate predictive and prognostic surrogates and therapeutic targets. This review focuses on current progress concerning the roles of miRNAs in endocrine resistance, and discusses the challenges and opportunities for implementing miRNA-based assays and treatment for patients with endocrine-resistant breast cancer.
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Resistance to radiation therapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to breast tumorigenesis; however, the relationship between Lin28 and radioresistance remains unknown. In this study, we investigated the association of Lin28 with radiation resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines. The results showed that the expression level of Lin28 was closely associated with resistance to radiation treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to radiation than MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which have low-level Lin28 expression. Transfection with Lin28 siRNA significantly led to an increase of sensitivity to radiation. By contrast, stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to radiation treatment. Stable expression of Lin28 also significantly inhibited radiation-induced apoptosis. Moreover, further studies have shown that caspases, H2A.X and Let-7 miRNA were the molecular targets of Lin28. Stable expression of Lin28 and treatment with radiation induced H2AX expression, while inhibited p21 and γ-H2A.X. Overexpression of Let-7 enhanced the sensitivities to radiation in breast cancer cells. Taken together, these results indicate that Lin28 might be one mechanism underlying radiation resistance, and Lin28 could be a potential target for overcoming radiation resistance in breast cancer.
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Histonas/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/fisiologia , Apoptose/efeitos da radiação , Neoplasias da Mama , Sobrevivência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Células MCF-7 , Tolerância a Radiação , Transdução de SinaisRESUMO
The relationship between estrogen receptor (ER)α and patient prognosis has been identified in gastric cancer; however, the definite role of ERα in gastric cancer remains to be fully elucidated. The aim of the present in vitro study was to investigate the impact of ERα on cell proliferation, migration and invasion in gastric cancer cell lines. We investigated the biological effect of ERα overexpression on gastric carcinoma cells. An MKN28 gastric cancer cell line stably overexpressing ERα was established. The effect of ERα overexpression on cell growth was assessed by evaluating cell survival, colony formation, cell cycle progression and apoptosis. Cell migration and invasion were detected by Transwell migration/invasion assays. The protein levels of several potentially involved genes were determined by western blotting to elucidate the underlying molecular mechanisms. The Student's t-test was used to determine the statistical differences between various experimental and control groups, and one-way ANOVA test was used to determine the difference between three or more groups. The results showed that ERα overexpression significantly inhibited cell growth and proliferation, blocked cell entry into the G1/G0 phase and promoted cell apoptosis. In addition, ERα reduced the motility and invasion of gastric cancer cells. These phenotypes may partly be explained by a decrease in ß-catenin expression caused by ERα overexpression. ERα overexpression effectively inhibited cell growth and cancer progression by suppressing ß-catenin in gastric cancer, identifying ERα as a promising target with therapeutic potential for development of new approaches to treat gastric cancer.
Assuntos
Adenocarcinoma/patologia , Receptor alfa de Estrogênio/metabolismo , Neoplasias Gástricas/patologia , beta Catenina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Receptor alfa de Estrogênio/biossíntese , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , beta Catenina/antagonistas & inibidoresRESUMO
The purpose of this study was to investigate the expression of Lin28 in gastric carcinoma and to assess its clinical significance. The expression level of Lin28 was assessed by reverse-transcriptase polymerase chain reaction in 10 surgically resected gastric carcinoma and corresponding normal tissues, and by immunohistochemical staining in surgically resected gastric carcinoma tissues of 229 patients, including 215 curative resection patients and 14 palliative resection patients. The expression level of Lin28 mRNA in gastric carcinoma tissues and corresponding normal tissues had no statistically significant difference. In curative resection patients, Lin28 protein expression was positive in 99 of 215 (46.0 %) gastric carcinoma tissues. In palliative resection patients, Lin28 protein expression was positive in 4 of 14 (28.6 %) gastric carcinoma tissues. In R0 patients, Lin28 protein positive expression was correlated with poor outcome (P = 0.017). In multivariate analysis, the Lin28 protein positive expression was a significant independent prognostic factor for overall survival (P = 0.024; HR, 1,768; 95 % CI 1.077-2.903). Our results indicate that Lin28 was expressed in both gastric carcinoma and corresponding normal tissues. Lin28 protein positive expression served as an independent prognostic factor.