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1.
Artigo em Inglês | MEDLINE | ID: mdl-33822512

RESUMO

The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Xantonas/uso terapêutico , 9,10-Dimetil-1,2-benzantraceno , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinógenos , Proliferação de Células/efeitos dos fármacos , Feminino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Xantonas/farmacologia
2.
Nat Commun ; 12(1): 1502, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686070

RESUMO

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.


Assuntos
Proteína BRCA1/genética , Transformação Celular Neoplásica/genética , Neoplasias Mamárias Experimentais/genética , Fenobarbital/metabolismo , Análise de Célula Única/métodos , Células-Tronco/patologia , Animais , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Mutação , Células-Tronco/fisiologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
ACS Appl Mater Interfaces ; 13(5): 6034-6042, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33499584

RESUMO

MicroRNA (miRNA) represents a promising class of therapeutic nucleic acid drugs, while delivery challenges remain that impede the advancement of miRNA therapy, largely because of in vivo instability and low delivery efficiency. Herein, we discover the dual roles of metal-organic framework (MOF) nanoparticles (ZIF-8) as nanocarriers for miRNA delivery and adjuvants for chemodynamic therapy. The miR-34a-m@ZIF-8 complex demonstrated efficient cellular uptake and lysosomal stimuli-responsive miRNA release. Zn2+ triggered the generation of reactive oxygen species, which consequently induced apoptosis of tumor cells. Released miR-34a-m led to a remarkable decrease in expression of Bcl-2 at both mRNA and protein levels and enhanced cancer cell apoptosis. In vivo experiments showed high efficacy of using miR-34a-m@ZIF-8 to suppress tumor growth via synergistic gene/chemodynamic therapy in a mouse model of triple-negative breast cancer. Our work demonstrates MOFs as a promising nanoplatform for efficient synergetic gene/chemodynamic therapy.


Assuntos
Adjuvantes Farmacêuticos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Estruturas Metalorgânicas/química , MicroRNAs/farmacologia , Nanopartículas/química , Adjuvantes Farmacêuticos/química , Animais , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , MicroRNAs/química , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Zeolitas/química , Zeolitas/farmacologia
4.
J Mater Chem B ; 9(4): 1002-1008, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33399620

RESUMO

Single-component nanoplatforms combined with the second near-infrared optical window (NIR-II, 1000-1700 nm) fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) have received increasing attention owing to their capacity for precise diagnosis, noninvasive therapy, and real-time monitoring of the therapeutic effects. However, most of the PTT treatments are performed in the NIR-I window (700-900 nm). Moreover, the design and development of conjugated polymers (P1, P2, and P3) with both bright NIR-II fluorescence and superior NIR-II photothermal effect remained a huge challenge. Therefore, three double-acceptor conjugated polymers were designed and developed by adjusting the molar ratios of two acceptors, TTQ and DPP. Subsequently, their corresponding nanoparticles were fabricated, and finally, nanoparticles based on the conjugated polymer P1 (P1 NPs) with both high NIR-II fluorescence intensity and superior NIR-II photothermal efficiency were selected and applied for NIR-II FI and NIR-II PTT. Importantly, the experiments of in vivo NIR-II FI and NIR-II PTT demonstrated that P1 NPs exhibited not only high accumulation in the tumour sites and high sign-to-background ratio (SBR) of vascular imaging, but also superior NIR-II PTT efficiency for tumour treatment.


Assuntos
Corantes Fluorescentes/farmacologia , Imagem Óptica , Polímeros/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Hipertermia Induzida , Raios Infravermelhos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Estrutura Molecular , Tamanho da Partícula , Propriedades de Superfície
5.
J Mater Chem B ; 9(4): 1009-1017, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33427275

RESUMO

The design and synthesis of near-infrared (NIR) emissive fluorophores for the imaging of organelles and photodynamic therapy have received enormous attention. Hence, the development of NIR emissive fluorophores for high-fidelity lysosome targeting, two-photon fluorescence imaging, and the inducing of photo-triggered cancer-cell apoptosis is highly desirable. In this study, a novel lysosome-targeting two-photon fluorescent photosensitizer (TTRh-CN) is prepared and comprehensively investigated. TTRh-CN demonstrates near-infrared (NIR) emission, good biocompatibility, and superior photostability, and it can act as a two-photon fluorescent agent for the clear visualization of living cells and the vascular system within tissue, with deep-tissue penetration abilities. Furthermore, TTRh-CN can efficiently produce ROS in conjunction with lysosomes in situ upon light irradiation, which can damage lysosomes, up-regulate LC3 and Beclin1, increase BAX release, and induce cell apoptosis. The efficacy of TTRh-CN as a photosensitizer is explored in vivo. All these results confirm that TTRh-CN can serve as a potential platform for the two-photon fluorescence imaging of cells/tissue and for organelle-specific photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Imagem Óptica , Fotoquimioterapia , Fótons , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Raios Infravermelhos , Lisossomos/química , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Estrutura Molecular , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Células Tumorais Cultivadas
6.
Carbohydr Polym ; 255: 117490, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436250

RESUMO

To deliver photosensitizers with PEGylated heparin (HP) into tumor cells for photodynamic therapy, we prepared two polyethylene glycol (PEG)-functionalized HP-based polymers conjugated with pyropheophorbide-a (Ppa): a non-GSH-responsive nanoagent (HP-Ppa-mPEG) with the mPEG moiety chemically attached to HP directly; and a GSH-responsive nanoagent (HP-Ppa-SS-mPEG) with the mPEG moiety conjugated to HP via a disulfide linkage. The Ppa-functionalized HP without PEGylation (HP-Ppa) was designed as another control. These amphiphilic polymers could aggregate into nanoparticles. Cellular uptake of three nanoparticles by 4T1 cells led to abundant production of reactive oxygen species after irradiation by a 660 nm laser, inducing cell apoptosis. HP-Ppa-SS-mPEG was found to achieve the highest tumor accumulation, the longest retention time and the best penetration into tumor tissues, resulting in the highest in vivo anticancer efficacy with 94.3 % tumor growth inhibition rate, suggesting that tumor microenvironment-responsive PEGylated HP-based nanomedicines may act as efficient anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Clorofila/análogos & derivados , Heparina/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/química , Feminino , Lasers , Luz , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanoconjugados/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
7.
Am J Pathol ; 191(3): 515-526, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33345997

RESUMO

Nerve infiltration into the tumor is a common feature of the tumor microenvironment. The mechanisms of axonogenesis in breast cancer remain unclear. We hypothesized that vascular endothelial growth factor (VEGF), as well as nerve growth factor (NGF), is involved in the axonogenesis of breast cancer. A N-methyl-N-nitrosourea (MNU)-induced rat model of breast cancer was used to explore the presence of axonogenesis in breast tumor and the involvement of VEGF, as well as NGF, in the axonogenesis of breast tumor. Nerve infiltration into the tumor was found in MNU-induced rat model of breast cancer including the sensory and sympathetic nerve fibers. Nerve density was increased following the growth of tumor. The sensory neurons innervating the thoracic and abdominal mammary tumors peaked at T5 to T6 and L1 to L2 dorsal root ganglions, respectively. Either VEGF receptor inhibitor or antibody against VEGF receptor 2, as well as NGF receptor inhibitor, apparently decreased both the nerve density and vascular density of breast tumor. The reduced nerve density was correlated with the decreased vascular density induced by these treatments. In cultured dorsal root ganglion neurons, phosphatidylinositol 3 (PI3K)/Akt, extracellular signal-regulated protein kinase (ERK), and p38 inhibitors significantly attenuated VEGF-induced neurite elongation. These findings provide direct evidence that VEGF, as well as NGF, may control the axonogenesis of breast cancer.


Assuntos
Axônios/patologia , Neoplasias Mamárias Experimentais/patologia , Neuritos/patologia , Neurogênese , Fator A de Crescimento do Endotélio Vascular/metabolismo , Alquilantes/toxicidade , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Sistema de Sinalização das MAP Quinases , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Metilnitrosoureia/toxicidade , Neuritos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética
8.
Mol Cell ; 81(2): 386-397.e7, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33340488

RESUMO

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosfoglicerato Desidrogenase/genética , Serina/biossíntese , Animais , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
9.
Carbohydr Polym ; 254: 117476, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357929

RESUMO

Herein the nucleic acid aptamers were attached to the polydeoxyadenylic acid (poly(dA)) tail for improving the tumor-targetability and cellular internalization of s-LNT/poly(dA) composite composed of two single chains of triple helical ß-glucan lentinan (s-LNT) and one poly(dA) chain. The in vitro results demonstrate that the cellular uptake of s-LNT/poly(dA) composites in MCF-7 cancer cells was enhanced effectively after attaching the aptamer. The as-prepared fluorescin isothiocyanate (FITC)-labelled LNT (LNT-FITC) through grafting was used for tracing the enhanced tumor-targetability of the composites. As a result, the cellular internalization of the LNT-FITC into MCF-7 and 4T1 cancer cells was further increased by the aptamer conjugated to poly(dA). Meanwhile, the in vivo experiments further demonstrate more s-LNT/poly(dA)-aptamer composites were effectively accumulated at the tumor site compared with s-LNT alone. This work provides a novel strategy for fabricating triplex ß-glucan as delivery vectors with active tumor-targetability.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/administração & dosagem , Lentinano/farmacologia , Neoplasias Mamárias Experimentais/terapia , Terapia de Alvo Molecular/métodos , Poli A/administração & dosagem , Animais , Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Linhagem Celular Tumoral , Portadores de Fármacos , Feminino , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Humanos , Injeções Intravenosas , Lentinano/química , Células MCF-7 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Poli A/química , Poli A/genética , Coloração e Rotulagem/métodos
10.
Nat Commun ; 11(1): 5436, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116123

RESUMO

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Frutoquinases/metabolismo , Frutose/administração & dosagem , Frutose/metabolismo , Proteínas 14-3-3/antagonistas & inibidores , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Animais , Carcinógenos/administração & dosagem , Carcinógenos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Fosforilação , Transdução de Sinais , beta Carioferinas/metabolismo
11.
Nucleic Acids Res ; 48(19): 10768-10784, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32986841

RESUMO

Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/genética , Código das Histonas , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/metabolismo , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Elementos de Resposta
12.
Anticancer Res ; 40(7): 3697-3705, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620608

RESUMO

BACKGROUND/AIM: Time restricted feeding (TRF) mitigates the high-fat diet-enhanced mammary tumorigenesis in a MMTV-PyMT breast cancer model. MATERIALS AND METHODS: We performed untargeted metabolomic and targeted transcriptomic analyses on mammary tumors from MMTV-PyMT mice fed a standard AIN93G diet, a high-fat diet (HFD), or HFD with TRF (12 h, dark phase) and mammary glands from wild-type mice fed the AIN93G diet. RESULTS: The metabolic profile of mammary tumors differed from that of mammary glands; there was no impact of TRF upon tumor metabolome. TRF did reduce elevated expression of Hmgcr, Srebp1, Fads2, and Ppard in mammary tumors, indicating a down-regulation of lipid metabolism. CONCLUSION: The null effect of TRF on the metabolomic profile does not rule out changes in more refined intracellular signaling pathways. It suggests that the protection of TRF against mammary tumorigenesis may rely upon its action on the host rather than a direct effect on tumor metabolism.


Assuntos
Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Metaboloma/fisiologia , Obesidade/metabolismo , Animais , Carcinogênese/metabolismo , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Feminino , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos
13.
DNA Cell Biol ; 39(9): 1649-1656, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32552056

RESUMO

Annexin A4 (encoded by the ANXA4 gene) is a calcium ion (Ca2+)- and phospholipid-binding protein of the Annexin family. In this study, we checked the expression profile of ANXA4 in basal-like breast cancer (BLBC) and its association with survival outcomes using pan-cancer data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Then, using MDA-MB-231 and MDA-MB-468 cells, we explored the functional role of ANXA4 in regulating a cancer-related signaling pathway and identified potential partners of ANXA4. The results showed that expression of total ANXA4 and the two dominant ANXA4 protein-coding transcripts (ENST00000409920.5 and ENST00000394295.4) was consistently upregulated in tumor tissues compared with normal breast tissues. BLBC patients with high ANXA4 expression had significantly worse overall survival, progression-free survival, and disease-free survival than those with low ANXA4 expression. ANXA4 could positively modulate cyclin D1 expression and G1/S progression in the two cell lines. An in vivo tumor model showed that ANXA4 inhibition significantly slowed the growth of tumors derived from the two BLBC cell lines. ANXA4 could increase JAK1 expression and STAT3 phosphorylation (Y705). ANXA4 colocalized with ANXA1 in some MDA-MB-231 cells. A co-immunoprecipitation assay confirmed direct binding between ANXA4 and ANXA1. Knockdown of ANXA1 reduced JAK1 expression and STAT3 phosphorylation and impaired ANXA4-induced upregulation of JAK1 and p-STAT3. In conclusion, this study revealed that aberrant ANXA4 upregulation is associated with poor survival in BLBC. ANXA4 could activate JAK-STAT3 signaling by elevating the expression of JAK1 and p-STAT3, which was mediated by direct interaction with ANXA1.


Assuntos
Anexina A1/metabolismo , Anexina A4/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Transdução de Sinais , Animais , Anexina A1/genética , Anexina A4/genética , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
14.
PLoS One ; 15(6): e0234548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542046

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. METHODS: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. RESULTS: Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. CONCLUSIONS: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.


Assuntos
Imunossupressão , Neoplasias Mamárias Experimentais/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Imunossupressores/farmacologia , Ativação Linfocitária/genética , Ativação Linfocitária/fisiologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Atividade Motora/genética , Atividade Motora/fisiologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Células Supressoras Mieloides/patologia , Células Supressoras Mieloides/fisiologia
15.
Breast Cancer Res ; 22(1): 59, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493400

RESUMO

BACKGROUND: Breast cancer is a heterogeneous disease. Hence, stratification of patients based on the subtype of breast cancer is key to its successful treatment. Among all the breast cancer subtypes, basal-like breast cancer is the most aggressive subtype with limited treatment options. Interestingly, we found focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase, is highly overexpressed and activated in basal-like breast cancer. METHODS: To understand the role of FAK in this subtype, we generated mice with conditional deletion of FAK and a knock-in mutation in its kinase domain in MMTV-Wnt1-driven basal-like mammary tumors. Tumor initiation, growth, and metastasis were characterized for these mice cohorts. Immunohistochemical and transcriptomic analysis of Wnt1-driven tumors were also performed to elucidate the mechanisms underlying FAK-dependent phenotypes. Pharmacological inhibition of FAK and mTOR in human basal-like breast cancer cell lines was also tested. RESULTS: We found that in the absence of FAK or its kinase function, growth and metastasis of the tumors were significantly suppressed. Furthermore, immunohistochemical analyses of cleaved caspase 3 revealed that loss of FAK results in increased tumor cell apoptosis. To further investigate the mechanism by which FAK regulates survival of the Wnt1-driven tumor cells, we prepared an isogenic pair of mammary tumor cells with and without FAK and found that FAK ablation increased their sensitivity to ER stress-induced cell death, as well as reduced tumor cell migration and tumor sphere formation. Comparative transcriptomic profiling of the pair of tumor cells and gene set enrichment analysis suggested mTOR pathway to be downregulated upon loss of FAK. Immunoblot analyses further confirmed that absence of FAK results in reduction of AKT and downstream mTOR pathways. We also found that inhibition of FAK and mTOR pathways both induces apoptosis, indicating the importance of these pathways in regulating cell survival. CONCLUSIONS: In summary, our studies show that in a basal-like tumor model, FAK is required for survival of the tumor cells and can serve as a potential therapeutic target.


Assuntos
Carcinoma Basocelular/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína Wnt1/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/genética , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas , Proteína Wnt1/genética
16.
Environ Toxicol ; 35(10): 1125-1136, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449848

RESUMO

This study aimed to evaluate the in vivo anticancer effects of daucosterol which was earlier reported to possess in vitro anticancer effects. Breast tumor was induced in 30 rats using the environmental carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) while 6 control rats received olive oil (NOR). Animals with palpable tumors were randomized into five groups (n = 6) each as follows: negative control group treated with the vehicle (DMBA); positive control group treated with 5 mg/kg BW doxorubicin (DOXO + DMBA); three groups treated with daucosterol at doses of 2.5, 5, and 10 mg/kg BW (DAU + DMBA). Treatment lasted 28 days afterward, tumor (mass, volume, cancer antigen [CA] 15-3 level and histoarchitecture), hematological and toxicological parameters were examined. The tumor volume gradually increased in the DMBA group during the 28 days, with a tumor volume gain of ∼390 cm3 . Daucosterol at all doses reduced tumor volume (∼133.7 cm3 at 10 mg/kg) as well as protein, malondialdehyde (MDA), and CA 15-3 levels compared to DMBA rats. Tumor sections in daucosterol-treated rats showed a lower proliferation of mammary ducts with mild (5 and 10 mg/kg) to moderate (2.5 mg/kg) inflammatory responses. Moreover, it exhibited an antioxidant effect, evidenced by a significant and dose-dependent decreased in MDA levels, as well as an increase in catalase activity compared to the DMBA group. Daucosterol showed for the first time in vivo antitumor effects that corroborate its previous in vitro effects.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Capparaceae/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Sitosteroides/farmacologia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/metabolismo , Carcinógenos/toxicidade , Relação Dose-Resposta a Droga , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Estrutura Molecular , Casca de Planta/química , Ratos , Ratos Wistar , Sitosteroides/isolamento & purificação , Sitosteroides/uso terapêutico
17.
Oncogene ; 39(24): 4728-4740, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32404986

RESUMO

An epithelial to mesenchymal transition (EMT) is an embryonic dedifferentiation program which is aberrantly activated in cancer cells to acquire cellular plasticity. This plasticity increases the ability of breast cancer cells to invade into surrounding tissue, to seed metastasis at distant sites and to resist to chemotherapy. In this study, we have observed a higher expression of interferon-related factors in basal-like and claudin-low subtypes of breast cancer in patients, known to be associated with EMT. Notably, Irf1 exerts essential functions during the EMT process, yet it is also required for the maintenance of an epithelial differentiation status of mammary gland epithelial cells: RNAi-mediated ablation of Irf1 in mammary epithelial cells results in the expression of mesenchymal factors and Smad transcriptional activity. Conversely, ablation of Irf1 during TGFß-induced EMT prevents a mesenchymal transition and stabilizes the expression of E-cadherin. In the basal-like murine breast cancer cell line 4T1, RNAi-mediated ablation of Irf1 reduces colony formation and cell migration in vitro and shedding of circulating tumor cells and metastasis formation in vivo. This context-dependent dual role of Irf1 in the regulation of epithelial-mesenchymal plasticity provides important new insights into the functional contribution and therapeutic potential of interferon-regulated factors in breast cancer.


Assuntos
Transição Epitelial-Mesenquimal , Fator Regulador 1 de Interferon/biossíntese , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Proteínas de Neoplasias/biossíntese , Animais , Linhagem Celular Tumoral , Feminino , Fator Regulador 1 de Interferon/genética , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Proteínas de Neoplasias/genética
18.
J Steroid Biochem Mol Biol ; 202: 105697, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461092

RESUMO

Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cinamatos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cinamatos/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Nus , Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/farmacologia
19.
Res Vet Sci ; 131: 87-91, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32311590

RESUMO

Isoflavones, such as genistein, have been proposed to have beneficial effects on health, including preventive or therapeutic actions in carcinogenesis. Their structural similarity to oestrogens allows them to bind at the cellular level with oestrogen receptors. Therefore, this study attempted to determine the antitumoural effects of genistein administered in a canine inflammatory mammary cancer xenograft model, in terms of tumour proliferation, appearance of metastases and steroid hormone regulation. Using histology and immunohistochemical analyses as well as the EIA technique for hormonal determinations, the antitumoural effects of genistein on an inflammatory mammary cancer xenograft model were assessed for 3 weeks. Mice treated with genistein showed higher Ki-67 levels than the control group. There were significantly more distant metastases in the genistein-treated xenografts versus the control group. Intratumoural and serum progesterone, androstenedione and oestrogen levels in treated mice were elevated, whereas intratumoural testosterone levels were decreased compared to the control group. These results revealed that genistein ingestion promotes tumour proliferation and elevates metastatic rates by increasing intratumoural and circulating oestrogen levels in a mammary cancer xenograft model.


Assuntos
Anticarcinógenos/uso terapêutico , Doenças do Cão/metabolismo , Estrogênios/metabolismo , Genisteína/uso terapêutico , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Animais , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Genisteína/farmacologia , Inflamação/metabolismo , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos
20.
Biomater Sci ; 8(8): 2227-2233, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32129325

RESUMO

An enveloped virus with soft and rough shells has strong penetration ability for cells. Inspired by the unique structure of virus, we successfully constructed virus-mimicking mesoporous organosilica nanocapsules (denoted as VMONs) for the first time by decorating small-sized silica nanoparticles on soft mesoporous organosilica hollow spheres. TEM and SEM images reveal that the prepared VMONs display uniform diameters (240 nm), a soft framework, a rough surface, and excellent dispersity. Quantitative nanomechanical mapping further demonstrates that the VMONs possess an extremely low Young's modulus (36 MPa) and a scraggly surface. In view of the successful construction of the virus-mimicking nanocapsules, the VMONs are further modified with human serum albumin (HSA) and Cy5.5-maleimide (Mal-Cy5.5) to investigate their cell penetration ability. Flow cytometry analysis reveals that the internalization of VMONs@HSA-Cy5.5 increases 2.74-fold compared to that of the conventional mesoporous nanosphere. Confocal laser scanning microscopy images show that the VMONs@HSA-Cy5.5 diffuses deeper for multicellular spheroids compared to both hard and soft mesoporous organosilica nanospheres. The penetration ability of the VMONs and SMONs increases 18.49 and 6.13-fold compared to that of MONs at the depth of 60 µm. Thanks to the excellent cellular penetration ability, the virus-mimicking VMONs@HSA-Cy5.5 can effectively deliver the anticancer drug doxorubicin (Dox) into drug-resistant MCF-7/ADR human breast cancer cells and significantly enhance the chemotherapeutic efficacy. Taken together, the constructed virus-mimicking organosilica nanocapsules with a soft framework and a rough surface possess strong cellular internalization and tumor penetration abilities, providing a unique and effective nanoplatform for biomedical applications.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Neoplasias Mamárias Experimentais/metabolismo , Nanocápsulas/administração & dosagem , Compostos de Organossilício/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacocinética , Transporte Biológico , Carbocianinas/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacocinética , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Compostos de Organossilício/farmacocinética , Porosidade , Albumina Sérica Humana/administração & dosagem , Propriedades de Superfície
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