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1.
Genes Genomics ; 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38849705

RESUMO

BACKGROUND: Digital PCR (dPCR) technology allows absolute quantification and detection of disease-associated rare variants, and thus the use of dPCR technology has been increasing in clinical research and diagnostics. The high-resolution melting curve analysis (HRM) of qPCR is widely used to distinguish true positives from false positives and detect rare variants. In particular, qPCR-HRM is commonly used for methylation assessment in research and diagnostics due to its simplicity and high reproducibility. Most dPCR instruments have limited fluorescence channels available and separate heating and imaging systems. Therefore, it is difficult to perform HRM analysis using dPCR instruments. OBJECTIVE: A new digital real-time PCR instrument (LOAA) has been recently developed to integrate partitioning, thermocycling, and imaging in a single dPCR instrument. In addition, a new technique to perform HRM analysis is utilized in LOAA. The aim of the present study is to evaluate the efficiency and accuracy of LOAA dPCR on HRM analysis for the detection of methylation. METHODS: In this study, comprehensive comparison with Bio-Rad qRT-PCR and droplet-based dPCR equipment was performed to verify the HRM analysis-based methylation detection efficiency of the LOAA digital PCR equipment. Here, sodium bisulfite modification method was applied to detect methylated DNA sequences by each PCR method. RESULTS: Melting curve analysis detected four different Tm values using LOAA and qPCR, and found that LOAA, unlike qPCR, successfully distinguished between different Tm values when the Tm values were very similar. In addition, melting temperatures increased by each methylation were about 0.5℃ for qPCR and about 0.2 ~ 0.6℃ for LOAA. The melting temperature analyses of methylated and unmethylated DNA samples were conducted using LOAA dPCR with TaqMan probes and EvaGreen, and the result found that Tm values of methylated DNA samples are higher than those of unmethylated DNA samples. CONCLUSION: The present study shows that LOAA dPCR could detect different melting temperatures according to methylation status of target sequences, indicating that LOAA dPCR would be useful for diagnostic applications that require the accurate quantification and assessment of DNA methylation.

2.
Int J Radiat Biol ; 100(4): 541-549, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38227479

RESUMO

PURPOSE: In case of a nuclear accident, individuals with high-dose radiation exposure (>1-2 Gy) should be rapidly identified. While ferredoxin reductase (FDXR) was recently suggested as a radiation-responsive gene, the use of a single gene biomarker limits radiation dose assessment. To overcome this limitation, we sought to identify reliable radiation-responsive gene biomarkers. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from mice after total body irradiation, and gene expression was analyzed using a microarray approach to identify radiation-responsive genes. RESULTS: In light of the essential role of the immune response following radiation exposure, we selected several immune-related candidate genes upregulated by radiation exposure in both mouse and human PBMCs. In particular, the expression of ACOD1 and CXCL10 increased in a radiation dose-dependent manner, while remaining unchanged following lipopolysaccharide (LPS) stimulation in human PBMCs. The expression of both genes was further evaluated in the blood of cancer patients before and after radiotherapy. CXCL10 expression exhibited a distinct increase after radiotherapy and was positively correlated with FDXR expression. CONCLUSIONS: CXCL10 expression in irradiated PBMCs represents a potential biomarker for radiation exposure.


Assuntos
Leucócitos Mononucleares , Exposição à Radiação , Humanos , Camundongos , Animais , Leucócitos Mononucleares/efeitos da radiação , Relação Dose-Resposta à Radiação , Regulação para Cima , Triagem , Exposição à Radiação/efeitos adversos , Biomarcadores/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo
3.
EMBO Rep ; 20(10): e48058, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31468695

RESUMO

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinogênese/patologia , Quinases Ciclina-Dependentes/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Trastuzumab/uso terapêutico , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 17/genética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-3/metabolismo , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Via de Sinalização Wnt
4.
J Natl Cancer Inst ; 110(4)2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29028222

RESUMO

Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/fisiologia , Receptores de Estrogênio/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Análise de Variância , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Proteínas de Transporte/metabolismo , Estudos de Coortes , Colorimetria , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas , Proteínas Nucleares/metabolismo , Proteína 1 de Interação com Receptor Nuclear , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Tamoxifeno/uso terapêutico , Carga Tumoral
5.
EMBO Rep ; 16(10): 1288-98, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26303947

RESUMO

The histone H3K27 demethylase, UTX, is a known component of the H3K4 methyltransferase MLL complex, but its functional association with H3K4 methylation in human cancers remains largely unknown. Here we demonstrate that UTX loss induces epithelial-mesenchymal transition (EMT)-mediated breast cancer stem cell (CSC) properties by increasing the expression of the SNAIL, ZEB1 and ZEB2 EMT transcription factors (EMT-TFs) and of the transcriptional repressor CDH1. UTX facilitates the epigenetic silencing of EMT-TFs by inducing competition between MLL4 and the H3K4 demethylase LSD1. EMT-TF promoters are occupied by c-Myc and MLL4, and UTX recognizes these proteins, interrupting their transcriptional activation function. UTX decreases H3K4me2 and H3 acetylation at these promoters by forming a transcriptional repressive complex with LSD1, HDAC1 and DNMT1. Taken together, our findings indicate that UTX is a prominent tumour suppressor that functions as a negative regulator of EMT-induced CSC-like properties by epigenetically repressing EMT-TFs.


Assuntos
Repressão Epigenética , Transição Epitelial-Mesenquimal , Histona Desmetilases/genética , Células-Tronco Neoplásicas/fisiologia , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Neoplasias da Mama , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/genética , Histona Desacetilase 1/fisiologia , Histona Desmetilases/fisiologia , Humanos , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Nat Commun ; 6: 7821, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26199140

RESUMO

DOT1L has emerged as an anticancer target for MLL-associated leukaemias; however, its functional role in solid tumours is largely unknown. Here we identify that DOT1L cooperates with c-Myc and p300 acetyltransferase to epigenetically activate epithelial-mesenchymal transition (EMT) regulators in breast cancer progression. DOT1L recognizes SNAIL, ZEB1 and ZEB2 promoters via interacting with the c-Myc-p300 complex and facilitates lysine-79 methylation and acetylation towards histone H3, leading to the dissociation of HDAC1 and DNMT1 in the regions. The upregulation of these EMT regulators by the DOT1L-c-Myc-p300 complex enhances EMT-induced breast cancer stem cell (CSC)-like properties. Furthermore, in vivo orthotopic xenograft models show that DOT1L is required for malignant transformation of breast epithelial cells and breast tumour initiation and metastasis. Clinically, DOT1L expression is associated with poorer survival and aggressiveness of breast cancers. Collectively, we suggest that cooperative effect of DOT1L and c-Myc-p300 is critical for acquisition of aggressive phenotype of breast cancer by promoting EMT/CSC.


Assuntos
Neoplasias da Mama/etiologia , Proteína p300 Associada a E1A/metabolismo , Epigênese Genética , Transição Epitelial-Mesenquimal , Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo
7.
Oncotarget ; 6(19): 17276-90, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25938540

RESUMO

Inhibitor of differentiation/DNA binding (Id)1 is a crucial regulator of mammary development and breast cancer progression. However, its effect on stemness and tumorigenesis in mammary epithelial cells remains undefined. Herein, we demonstrate that Id1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities in transgenic mice. MaSC-enriched basal cell expansion and increased self-renewal and in vivo regenerative capacity of MaSCs are observed in the mammary glands of MMTV-Id1 transgenic mice. Furthermore, MMTV-Id1 mice develop ductal hyperplasia and mammary tumors with highly expressed basal markers. Id1 also increases breast cancer stem cell (CSC) population and activity in human breast cancer lines. Moreover, the effects of Id1 on normal and malignant stem cell activities are mediated by the Wnt/c-Myc pathway. Collectively, these findings provide in vivo genetic evidence of Id1 functions as an oncogene in breast cancer and indicate that Id1 regulates mammary basal stem cells by activating the Wnt/c-Myc pathway, thereby contributing to breast tumor development.


Assuntos
Transformação Celular Neoplásica/genética , Proteína 1 Inibidora de Diferenciação/biossíntese , Neoplasias Mamárias Experimentais/patologia , Células-Tronco Neoplásicas/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos , Imuno-Histoquímica , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Transgênicos , Oncogenes/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
J Clin Invest ; 125(5): 1801-14, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25822021

RESUMO

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Receptor alfa de Estrogênio/biossíntese , Estrogênios , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/metabolismo , Complexo Repressor Polycomb 1/fisiologia , Progesterona , Receptores de Progesterona/biossíntese , Aminopiridinas/administração & dosagem , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Cisteína Endopeptidases , Resistencia a Medicamentos Antineoplásicos , Endopeptidases/metabolismo , Receptor alfa de Estrogênio/análise , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Morfolinas/administração & dosagem , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Complexo Repressor Polycomb 1/deficiência , Complexo Repressor Polycomb 1/genética , Modelos de Riscos Proporcionais , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptor ErbB-2/análise , Receptores de Progesterona/análise , Receptores de Progesterona/genética , Fator de Transcrição Sp1/metabolismo , Sumoilação/efeitos dos fármacos , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
9.
FASEB J ; 29(1): 300-13, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25351982

RESUMO

Polycomb protein chromobox homolog 7 (CBX7) is involved in several biologic processes including stem cell regulation and cancer development, but its roles in breast cancer remain unknown. Here, we demonstrate that CBX7 negatively regulates breast tumor initiation. CD44(+)/CD24(-)/ESA(+) breast stem-like cells showed diminished CBX7 expression. Furthermore, small hairpin RNA-mediated CBX7 knockdown in breast epithelial and cancer cells increased the CD44(+)/CD24(-)/ESA(+) cell population and reinforced in vitro self-renewal and in vivo tumor-initiating ability. Similarly, CBX7 overexpression repressed these effects. We also found that CBX7 inhibits the Wnt/ß-catenin/T cell factor pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist. In particular, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of the DKK-1 promoter. Furthermore, pharmacologic inhibition of DKK-1 in CBX7-overexpressing cells showed recovery of Wnt signaling and consequent rescue of the CD44(+)/CD24(-)/ESA(+) cell population. Taken together, these findings indicate that CBX7-mediated epigenetic induction of DKK-1 is crucial for the inhibition of breast tumorigenicity, suggesting that CBX7 could be a potential tumor suppressor in human breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epigênese Genética , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Fatores de Transcrição TCF/metabolismo , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
10.
FASEB J ; 26(12): 5002-13, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22954590

RESUMO

Mel-18 has been proposed as a negative regulator of Bmi-1, a cancer stem cell (CSC) marker, but it is still unclear whether Mel-18 is involved in CSC regulation. Here, we examined the effect of Mel-18 on the stemness of human breast CSCs. In Mel-18 small hairpin RNA (shRNA)-transduced MCF-7 cells, side population (SP) cells and breast CSC surface marker (CD44(+)/CD24(-)/ESA(+))-expressing cells, which imply a CSC population, were enriched. Moreover, the self-renewal of CSCs was enhanced by Mel-18 knockdown, as measured by the ability for tumorsphere formation in vitro and tumor-initiating capacity in vivo. Similarly, Mel-18 overexpression inhibited the number and self-renewal activity of breast CSCs in SK-BR-3 cells. Furthermore, our data showed that Mel-18 blockade up-regulated the expression of the Wnt/TCF target Jagged-1, a Notch ligand, and consequently activated the Notch pathway. Pharmacologic inhibition of the Notch and Wnt pathways abrogated Mel-18 knockdown-mediated tumorsphere formation ability. Taken together, our findings suggest that Mel-18 is a novel negative regulator of breast CSCs that inhibits the stem cell population and in vitro and in vivo self-renewal through the inactivation of Wnt-mediated Notch signaling.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Receptor Notch1/genética , Fatores de Transcrição TCF/genética , Proteínas Wnt/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Immunoblotting , Células MCF-7 , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Genéticos , Células-Tronco Neoplásicas/patologia , Complexo Repressor Polycomb 1/metabolismo , Interferência de RNA , Receptor Notch1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células da Side Population/metabolismo , Células da Side Population/patologia , Transdução de Sinais/genética , Transplante Heterólogo , Via de Sinalização Wnt/genética
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