Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.405
Filtrar
1.
Life Sci ; 284: 119885, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34384830

RESUMO

AIMS: Pyruvate dehydrogenase E1A (PDH-E1A) is one of the key regulators of metabolic pathways that determines pyruvate entry into the citric acid cycle or glycolysis. When PDH-E1A is phosphorylated (P-PDH-E1A), it loses its activity, shifting the metabolism towards glycolysis. Breast cancer (BC) is a highly heterogeneous disease by which different breast cancer subtypes acquire distinct metabolic profiles. Assessing PDH-E1A and P-PDH-E1A expressions among BC subtypes might reveal their association with the distinct molecular profiles of BCs. METHODS: The expressions of PDH-E1A and P-PDH-E1A were investigated in BC cell lines and 115 BC tissues using Western blot and immunohistochemistry, respectively. Besides, PDHE1A mRNA expression was assessed in 1084 BCE patients' transcriptomics data retrieved from Cancer Genome Atlas database. Statistical analyses were performed to assess the correlation of PDH-E1A and P-PDH-E1A expressions with patients' clinicopathological characteristics. Kaplan-Meier method was used to evaluate their prognostic value. KEY FINDINGS: Multivariate analysis revealed a significant association between PDH-E1A/P-PDH-E1A expressions and the molecular subtype, histological type, and tumor size of breast cancer tissues. The hormonal receptors (ER and PR), HER-2, and Ki67 protein expressions were significantly associated with PDH-E1A and P-PDH-E1A protein expressions. Similar findings were observed when PDHA1 mRNA expression was assessed. The increased protein expression of PDH-E1A could be an independent prognostic factor for unfavorable overall survival (OS). In contrast, high PDHA1 mRNA expression had better OS. SIGNIFICANCE: This study revealed the differential expression of PDH-E1A and P-PDH-E1A among breast cancer subtypes and suggested PDH-E1A expression as a prognostic factor for BC patients' OS.


Assuntos
Neoplasias da Mama/enzimologia , Piruvato Desidrogenase (Lipoamida)/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/metabolismo , Transcriptoma/genética
2.
Nat Commun ; 12(1): 5112, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433817

RESUMO

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Feminino , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/genética
3.
Aging (Albany NY) ; 13(17): 20886-20895, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413267

RESUMO

The potential role of abnormal ACE2 expression after SARS-CoV-2 infection in the prognosis of breast cancer is still ambiguous. In this study, we analyzed ACE2 changes in breast cancer and studied the correlation between ACE2 and the prognosis and further analyzed the relationship between immune infiltration and the prognosis of different breast cancer subtypes. Finally, we inferred the prognosis of breast cancer patients after SARS-CoV-2 infection. We found that ACE2 expression decreased significantly in breast cancer, except for basal-like subtype. Decreased ACE2 expression level was correlated with abnormal immune infiltration and poorer prognosis of luminal B breast cancer (RFS: HR 0.76, 95%CI=0.63-0.92, p=0.005; DMFS: HR 0.70, 95%CI=0.49-1.00, p=0.046). The expression of ACE2 was strongly positively correlated with the immune infiltration level of CD8+ T cell (r=0.184, p<0.001), CD4+ T cell (r=0.104, p=0.02) and neutrophils (r=0.101, p=0.02). ACE2 expression level in the luminal subtype was positively correlated with CD8A and CD8B markers in CD8+ T cells, and CEACAM3, S100A12 in neutrophils. In conclusion, breast tumor tissues might undergo a further decrease in the expression level of ACE2 after SARS-CoV-2 infection, which could contribute to further deterioration of immune infiltration and worsen the prognosis of luminal B breast cancer after SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/virologia , COVID-19/enzimologia , COVID-19/imunologia , Linfócitos do Interstício Tumoral/imunologia , SARS-CoV-2/fisiologia , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Chlorocebus aethiops , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Prognóstico , Células Vero
4.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360649

RESUMO

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Humanos
5.
Cell Death Dis ; 12(7): 690, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244472

RESUMO

Emerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Neoplasias da Mama/enzimologia , Proteínas de Membrana/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Complexo de Endopeptidases do Proteassoma/genética , Regulação para Cima
6.
Biomed Res Int ; 2021: 5516078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307654

RESUMO

Background: Despite recent advances in scientific knowledge and clinical practice, management, and treatment of breast cancer, as one of the leading causes of female mortality, breast cancer remains a major burden. Recently, methods employing stem cells and their derivatives, i.e., exosomes, in gene-based therapies hold great promise. Since these natural nanovesicles are able to transmit crucial cellular information which can be engineered to have robust delivery and targeting capacity, they are considered one of the modes of intercellular communication. miR-145, one of the downregulated microRNAs (miRNAs) in various cancers, can regulate tumor cell invasion, metastasis, apoptosis, and proliferation and stem cell differentiation. Objectives: The aim of this study was to investigate the role of exosomes secreted from adipose tissue-derived mesenchymal stem cells (MSCs) for miR-145 transfection into breast cancer cells in order to weaken their expansion and metastasis. Methods: Here, we exploited the exosomes from adipose tissue-derived mesenchymal stem cells (MSC-Exo) to deliver miR-145 in the T-47D breast cancer cell line. Lentiviral vectors of miR-145-pLenti-III-enhanced green fluorescent protein (eGFP) and empty pLenti-III-eGFP as the backbone were used to transfect MSCs and T-47D cells. In order to find the efficiency of exosomes as a delivery vehicle, the expression level of some miR-145 target genes, including Rho-Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Matrix Metalloproteinase 9 (MMP9), and Tumor Protein p53 (TP53), was compared in all treatment groups (T-47D cells treated by miR-145-transfected MSCs and their derivatives or their backbone) and control group (untransfected T-47D cells) using real-time PCR. Results: The obtained data represented the inhibitory effect of miR-145 on apoptosis induction and metastasis in both direct miR-treated groups. However, exosome-mediated delivery caused an improved anticancer property of miR-145. Conclusion: Restoration of miR-145 using MSC-Exo can be considered a potential novel therapeutic strategy in breast cancer in the future.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Transfecção , Tecido Adiposo/citologia , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Exossomos/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/genética , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
7.
J Enzyme Inhib Med Chem ; 36(1): 1454-1471, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34210212

RESUMO

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC50 values (0.002 - 0.004 µM) comparing to Staurosporine of IC50; 0.005 µM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC50 range 0.0149 - 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-ß, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-ß of IC50 values 0.17 × 10-3, 0.07 × 10-3 µM in comparison with the reference drug sorafenib of IC50; 0.28 × 10-3, 0.13 × 10-3 µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.


Assuntos
Neoplasias da Mama/prevenção & controle , Química Verde , Quinolonas/química , Quinolonas/farmacologia , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/síntese química , Análise Espectral/métodos
8.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200807

RESUMO

Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC50 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC50 values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Benzimidazóis/química , Neoplasias da Mama/tratamento farmacológico , Caseína Quinase II/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Células MCF-7 , Relação Estrutura-Atividade
9.
Bull Cancer ; 108(9): 843-854, 2021 Sep.
Artigo em Francês | MEDLINE | ID: mdl-34154797

RESUMO

The historical median survival of advanced luminal breast cancer does not exceed four years. The deciphering of the mechanisms of resistance to hormone therapy has led to the development of inhibitors of cyclin D dependent kinases (CDK4 and 6). Three drugs, palbociclib, ribociclib and abemaciclib, very similar pharmacologically, have been evaluated in the context of pivotal, randomized phase III trials. Strikingly and regardless of the endocrine therapy backbone, and in both hormone-sensitive and hormone-resistant patients, the addition of a CDK4 / 6 inhibitor doubles progression-free survival with a hazard ratio always around 0.55. The benefit in overall survival begins to be demonstrated. This review presents all published results, as well as the main safety data.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclo Celular , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Purinas/uso terapêutico , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
10.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066541

RESUMO

Breast cancer is one of the major causes of deaths due to cancer, especially in women. The crucial barrier for breast cancer treatment is resistance to radiation therapy, one of the important local regional therapies. We previously established and characterized radio-resistant MDA-MB-231 breast cancer cells (RT-R-MDA-MB-231 cells) that harbor a high expression of cancer stem cells (CSCs) and the EMT phenotype. In this study, we performed antibody array analysis to identify the hub signaling mechanism for the radiation resistance of RT-R-MDA-MB-231 cells by comparing parental MDA-MB-231 (p-MDA-MB-231) and RT-R-MDA-MB-231 cells. Antibody array analysis unveiled that the MAPK1 protein was the most upregulated protein in RT-R-MDA-MB-231 cells compared to in p-MDA-MB-231 cells. The pathway enrichment analysis also revealed the presence of MAPK1 in almost all enriched pathways. Thus, we used an MEK/ERK inhibitor, PD98059, to block the MEK/ERK pathway and to identify the role of MAPK1 in the radio-resistance of RT-R-MDA-MB-231 cells. MEK/ERK inhibition induced cell death in both p-MDA-MB-231 and RT-R-MDA-MB-231 cells, but the death mechanism for each cell was different; p-MDA-MB-231 cells underwent apoptosis, showing cell shrinkage and PARP-1 cleavage, while RT-R-MDA-MB-231 cells underwent necroptosis, showing mitochondrial dissipation, nuclear swelling, and an increase in the expressions of CypA and AIF. In addition, MEK/ERK inhibition reversed the radio-resistance of RT-R-MDA-MB-231 cells and suppressed the increased expression of CSC markers (CD44 and OCT3/4) and the EMT phenotype (ß-catenin and N-cadherin/E-cadherin). Taken together, this study suggests that activated ERK signaling is one of the major hub signals related to the radio-resistance of MDA-MB-231 breast cancer cells.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/radioterapia , Sistema de Sinalização das MAP Quinases , Tolerância a Radiação , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Ciclofilina A/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Poli(ADP-Ribose) Polimerases/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteômica , Tolerância a Radiação/efeitos dos fármacos
11.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188567, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34015411

RESUMO

Giant obscurins (720-870 kDa), encoded by OBSCN, were originally discovered in striated muscles as cytoskeletal proteins with scaffolding and regulatory roles. Recently though, they have risen to the spotlight as key players in cancer development and progression. Herein, we provide a timely prudent synopsis of the expanse of OBSCN mutations across 16 cancer types. Given the extensive work on OBSCN's role in breast epithelium, we summarize functional studies implicating obscurins as potent tumor suppressors in breast cancer and delve into an in silico analysis of its mutational profile and epigenetic (de)regulation using different dataset platforms and sophisticated computational tools. Lastly, we formally describe the OBSCN-Antisense-RNA-1 gene, which belongs to the long non-coding RNA family and discuss its potential role in modulating OBSCN expression in breast cancer. Collectively, we highlight the escalating involvement of obscurins in cancer biology and outline novel potential mechanisms of OBSCN (de)regulation that warrant further investigation.


Assuntos
Genes Supressores de Tumor , Mutação , Neoplasias/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA , Epigênese Genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/enzimologia , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/genética , RNA Antissenso/genética , RNA Antissenso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Transdução de Sinais
12.
Biochem Pharmacol ; 188: 114579, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895161

RESUMO

Osteolytic diseases, including breast cancer-induced osteolysis and postmenopausal osteoporosis, are attributed to excessive bone resorption by osteoclasts. Spleen tyrosine kinase (SYK) is involved in osteoclastogenesis and bone resorption, whose role in breast cancer though remains controversial. Effects of PRT062607 (PRT), a highly specific inhibitor of SYK, on the osteoclast and breast cancer functionalities are yet to be clarified. This study demonstrated the in vitro inhibitory actions of PRT on the osteoclast-specific gene expression, bone resorption, and osteoclastogenesis caused by receptor activator of nuclear factor kappa B ligand (RANKL), as well as its in vitro suppressive effects on the growth, migration and invasion of breast carcinoma cell line MDA-MB-231, which were achieved through PLCγ2 and PI3K-AKT-mTOR pathways. Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts.


Assuntos
Neoplasias da Mama/enzimologia , Cicloexilaminas/uso terapêutico , Osteólise/enzimologia , Ovariectomia/efeitos adversos , Pirimidinas/uso terapêutico , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Animais , Reabsorção Óssea/enzimologia , Reabsorção Óssea/patologia , Reabsorção Óssea/prevenção & controle , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Linhagem Celular Tumoral , Cicloexilaminas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Osteólise/patologia , Osteólise/prevenção & controle , Pirimidinas/farmacologia
13.
J Cell Biochem ; 122(8): 897-910, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33829554

RESUMO

Cyclin-dependent kinase 6 (CDK6) is a member of serine/threonine kinase family, and its overexpression is associated with cancer development. Thus, it is considered as a potential drug target for anticancer therapies. This study showed the CDK6 inhibitory potential of vanillin using combined experimental and computational methods. Structure-based docking and 200 ns molecular dynamics simulation studies revealed that the binding of vanillin stabilizes the CDK6 structure and provides mechanistic insights into the binding mechanism. Enzyme inhibition and fluorescence-binding studies showed that vanillin inhibits CDK6 with an half maximal inhibitory concentration = 4.99 µM and a binding constant (K) 4.1 × 107 M-1 . Isothermal titration calorimetry measurements further complemented our observations. Studies on human cancer cell lines (MCF-7 and A549) showed that vanillin decreases cell viability and colonization properties. The protein expression studies have further revealed that vanillin reduces the CDK6 expression and induces apoptosis in the cancer cells. In conclusion, our study presents the CDK6-mediated therapeutic implications of vanillin for anticancer therapies.


Assuntos
Benzaldeídos , Neoplasias da Mama , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina , Neoplasias Pulmonares , Simulação de Dinâmica Molecular , Proteínas de Neoplasias , Células A549 , Benzaldeídos/química , Benzaldeídos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Células MCF-7 , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo
14.
BMC Cancer ; 21(1): 409, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858374

RESUMO

BACKGROUND: Carnitine palmitoyl transferase 1A (CPT1A), the key regulator of fatty acid oxidation, contributes to tumor metastasis and therapeutic resistance. We aimed to identify its clinical significance as a biomarker for the diagnosis and prediction of breast cancer. METHODS: Western blot, ELISA and in silico analysis were used to confirm CPT1A levels in breast cancer cell lines, cell culture medium and breast cancer tissues. Four hundred thirty breast cancer patients, 200 patients with benign breast disease, and 400 healthy controls were enrolled and randomly divided into a training set and a test set with a 7:3 ratio. Training set was used to build diagnostic models and 10-fold cross validation was used to demonstrate the performance of the models. Then test set was aimed to validate the effectiveness of the diagnostic models. ELISA was conducted to detect individual serum CPT1A levels. Receiver operating characteristic (ROC) curves were generated, and binary logistic regression analyses were performed to evaluate the effectiveness of CPT1A as a biomarker in breast cancer diagnosis. CPT1A levels between post-operative and pre-operative samples were also compared. RESULTS: CPT1A was overexpressed in breast cancer tissues, cell lines and cell culture medium. Serum CPT1A levels were higher in breast cancer patients than in controls and were significantly associated with metastasis, TNM stage, histological grading and molecular subtype. CPT1A levels were decreased in post-operative samples compared with paired pre-operative samples. Moreover, CPT1A exhibited a higher efficacy in differentiating breast cancer patients from healthy controls (training set: area under the curve, AUC, 0.892, 95% CI, 0.872-0.920; test set, AUC, 0.904, 95% CI, 0.869-0.939) than did CA15-3, CEA, or CA125. CONCLUSION: CPT1A is overexpressed in breast cancer and can be secreted out of breast cancer cell. Serum CPT1A is positively associated with breast cancer progression and could serve as an indicator for disease monitoring. Serum CPT1A displayed a remarkably high diagnostic efficiency for breast cancer and could be a novel biomarker for the diagnosis of breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/enzimologia , Carnitina O-Palmitoiltransferase/metabolismo , Adulto , Idoso , Doenças Mamárias/diagnóstico , Doenças Mamárias/enzimologia , Neoplasias da Mama/mortalidade , Carnitina O-Palmitoiltransferase/sangue , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Reprodutibilidade dos Testes
15.
Mar Drugs ; 19(5)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925873

RESUMO

In this study, the anti-proliferative effect of ilimaquinone, a sesquiterpene derivative from the marine sponge, in breast cancer cells was investigated. Ilimaquinone inhibited the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 10.6 µM and 13.5 µM, respectively. Non-tumorigenic human breast epithelial cells were less sensitive to ilimaquinone than breast cancer cells. Flow cytometric and Western blot analysis showed that ilimaquinone induced S-phase arrest by modulating the expression of p-CDC-2 and p21. Ilimaquinone induces apoptosis, which is accompanied by multiple biological biomarkers, including the downregulation of Akt, ERK, and Bax, upregulation of p38, loss of mitochondrial membrane potential, increased reactive oxygen species generation, and induced autophagy. Collectively, these findings suggest that ilimaquinone causes cell cycle arrest as well as induces apoptosis and autophagy in breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Poríferos/metabolismo , Quinonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinonas/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Sesquiterpenos/isolamento & purificação , Transdução de Sinais
16.
Anticancer Res ; 41(4): 1793-1802, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813384

RESUMO

BACKGROUND/AIM: Human epidermal growth factor receptor 2 (HER2) P95-isoform could be involved in trastuzumab resistance in HER2 metastatic breast cancer. MATERIALS AND METHODS: A total of 114 metastatic breast cancer patients treated with trastuzumab were evaluated retrospectively. HER2 was centrally reviewed. P95 was evaluated along with other markers possibly affecting trastuzumab efficacy in regards to progression-free survival and overall survival. RESULTS: HER2 was centrally negative in 54 cases. P95 expression was significantly higher in HER2-positive tumors. High p95 was associated with gain of HER2 copy number variations (CNVs), high pHER2Tyr877, Ki67 and HER2 mRNA. P95 as a continuous variable was positively correlated with mRNA expression of HER2 and negatively correlated with HER4 and IGF1. HER2-negative p95-high patients had a marginally higher risk for death (HR=2.15, p=0.055). CONCLUSION: p95 was associated with higher HER2 CNVs and mRNA expression, pHER2Tyr877 expression and high Ki67, indicating a more aggressive phenotype.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Isoenzimas , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
17.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802237

RESUMO

Breast cancer is the most frequent cancer in the female population worldwide. The role of germline genetic variability in cytochromes P450 (CYP) in breast cancer prognosis and individualized therapy awaits detailed elucidation. In the present study, we used the next-generation sequencing to assess associations of germline variants in the coding and regulatory sequences of all human CYP genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 22 prioritized variants associating with a response or survival in the above evaluation phase were then analyzed by allelic discrimination in the large confirmation set (n = 802). Associations of variants in CYP1B1, CYP4F12, CYP4X1, and TBXAS1 with the response to the neoadjuvant cytotoxic chemotherapy were replicated by the confirmation phase. However, just association of variant rs17102977 in CYP4X1 passed the correction for multiple testing and can be considered clinically and statistically validated. Replicated associations for variants in CYP4X1, CYP24A1, and CYP26B1 with disease-free survival of all patients or patients stratified to subgroups according to therapy type have not passed a false discovery rate test. Although statistically not confirmed by the present study, the role of CYP genes in breast cancer prognosis should not be ruled out. In conclusion, the present study brings replicated association of variant rs17102977 in CYP4X1 with the response of patients to the neoadjuvant cytotoxic chemotherapy and warrants further research of genetic variation CYPs in breast cancer.


Assuntos
Neoplasias da Mama , Sistema Enzimático do Citocromo P-450 , Variação Genética , Terapia Neoadjuvante , Proteínas de Neoplasias , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Taxa de Sobrevida
18.
Commun Biol ; 4(1): 312, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750924

RESUMO

Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group, NOTCH alterations are frequent, and also associate with decreased PTEN expression. We show that repression of PTEN occurs through the combined action of NOTCH (NOTCH1 or NOTCH2) and EZH2 alterations in a subset of breast cancers. In fact, in cases harboring NOTCH1 mutation or a NOTCH2 fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress PTEN transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.


Assuntos
Neoplasias da Mama/enzimologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Humanos , Mutação , PTEN Fosfo-Hidrolase/genética , Receptor Notch1/genética , Receptor Notch2/genética , Transcrição Genética
19.
Mol Biol Rep ; 48(3): 2315-2324, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788053

RESUMO

Matrix-metalloproteinase-2 (MMP2) is a foremost MMP, governing invasion of breast cancer cells during metastasis. miR-20a was reported to induce mesenchymal to epithelial transition in MDA-MB-231 cells and its endogenous expression varies directly with invasiveness of breast cancer cells. The inverse and direct correlation of invasiveness with miR-20a and Nucleolin respectively led us to study the post-transcriptional regulation of MMP2 by miR-20a and mRNA stabilizing protein, Nucleolin. Thus, understanding the mechanism of its regulation will enable modification of the invasion potential. MMP2 was found to be higher in MDA-MB-231 than MCF-7 cells both at RNA and protein levels. RNA-protein co-immunoprecipitation assay with Argonaute 2 revealed that MMP2 undergoes miRNA-mediated post-transcriptional regulation. miR-20a decreased MMP2 expression as well as its enzymatic activity as found by zymogram assay. Reporter assay showed that miR-20a directly binds to its putative binding site in MMP2 3'-UTR as per in silico prediction. miR-20a additionally impeded MMP2 mRNA stability, and binding of stabilizing trans-factor Nucleolin to its 3'-UTR was confirmed by RNA-protein co-immunoprecipitation assay. Partial down-regulation of Nucleolin by Si-RNA resulted in the downregulation of MMP2 and Nucleolin over-expression rescued the inhibitory effect of miR-20a on MMP2 expression. Delineating the mechanism of post-transcriptional regulation of MMP2, two of its potent regulators, miR-20a and Nucleolin were identified. It was established for the first time that MMP2 is a direct target of miR-20a. The results also elucidated that Nucleolin binds to MMP2 3' UTR and its abundance affects MMP2 expression.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 2 da Matriz/genética , MicroRNAs/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regiões 3' não Traduzidas/genética , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular Tumoral , Simulação por Computador , Regulação para Baixo/genética , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/genética , Ligação Proteica , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
Aging (Albany NY) ; 13(6): 8095-8114, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686962

RESUMO

The expression and prognostic significance of transcription-associated cyclin-dependent kinases (TA-CDKs) in breast cancer have not been systematically investigated. Using Oncomine, GEPIA2, the Human Protein Atlas, the Kaplan-Meier Plotter, cBioPortal, Metascape, and DAVID 6.8, we profiled the expression of TA-CDKs in breast cancer, inferred their biological functions, and assessed their effect on prognosis. The expression of CDK7/10/13/19 mRNAs in breast cancer tissues was significantly higher than in normal breast tissues. Survival analysis of breast cancer patients revealed that increased CDK8 expression was associated with inferior overall survival (OS), higher expression of CDK7 or CDK8 was associated with inferior relapse-free survival (RFS), but higher expression of CDK13 was associated with favorable RFS and OS. In addition, a high genetic alteration rate (56%) in TA-CDKs was associated with shorter OS. On functional enrichment analysis, top GO enrichment items for TA-CDKs and their neighboring genes included cyclin-dependent protein serine/threonine kinase activity and transferase complex. The top KEGG pathways included cell cycle and mismatch repair. These results suggest that CDK7/8/13 are potential prognostic biomarkers for breast cancer patients and provide novel insight for future studies examining their usefulness as therapeutic targets.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Proteína Quinase CDC2/metabolismo , Quinase 8 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Prognóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...