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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802957

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancers with poor prognosis. The etiology of triple-negative breast cancer (TNBC) is involved in various biological signal cascades and multifactorial aberrations of genetic, epigenetic and microenvironment. New therapeutic for TNBC is urgently needed because surgery and chemotherapy are the only available modalities nowadays. A better understanding of the molecular mechanisms would be a great challenge because they are triggered by cascade signaling pathways, genetic and epigenetic regulations, and drug-target interactions. This would allow the design of multi-molecule drugs for the TNBC and non-TNBC. In this study, in terms of systems biology approaches, we proposed a systematic procedure for systems medicine design toward TNBC and non-TNBC. For systems biology approaches, we constructed a candidate genome-wide genetic and epigenetic network (GWGEN) by big databases mining and identified real GWGENs of TNBC and non-TNBC assisting with corresponding microarray data by system identification and model order selection methods. After that, we applied the principal network projection (PNP) approach to obtain the core signaling pathways denoted by KEGG pathway of TNBC and non-TNBC. Comparing core signaling pathways of TNBC and non-TNBC, essential carcinogenic biomarkers resulting in multiple cellular dysfunctions including cell proliferation, autophagy, immune response, apoptosis, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), and cell differentiation could be found. In order to propose potential candidate drugs for the selected biomarkers, we designed filters considering toxicity and regulation ability. With the proposed systematic procedure, we not only shed a light on the differences between carcinogenetic molecular mechanisms of TNBC and non-TNBC but also efficiently proposed candidate multi-molecule drugs including resveratrol, sirolimus, and prednisolone for TNBC and resveratrol, sirolimus, carbamazepine, and verapamil for non-TNBC.


Assuntos
Carcinogênese/patologia , Análise de Sistemas , Neoplasias de Mama Triplo Negativas/terapia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/genética
2.
BMC Cancer ; 21(1): 434, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879104

RESUMO

BACKGROUND: Interactions between adipocyte and breast cancer (BC) cells have yet to be fully elucidated. Here we investigated the prognostic impact of marginal adipose tissue invasion in both luminal breast cancer (HR+/HER2-) and triple-negative breast cancer (TNBC) (HR-/HER2-). METHODS: A total of 735 patients with early-stage invasive BC (1999-2014) were retrospectively registered. Median length of patient follow-up was 8.9 years. Survival curves were calculated using a Kaplan-Meier cumulative survival plot. The prognostic difference between two groups were assessed by the univariate Cox-proportional hazard regression model. RESULTS: Patients with adipose tissue invasion (n = 614) had a significantly poorer prognosis than those without adipose tissue invasion (n = 121) in overall survival (OS) (hazard ratio, 2.1; 95% Confidence interval [CI], 1.1 to 4.0; P = 0.025). While a poorer prognosis was observed in TNBC (n = 137) than in luminal BC patients (n = 496) (hazard ratio, 0.45; 95% CI, 0.30 to 0.68, P < 0.001), this aggressive nature of TNBC was noted in node-positive disease (hazard ratio, 0.3; 95% CI, 0.18 to 0.5, P < 0.001) but not in node-negative disease (hazard ratio, 0.78; 95% CI, 0.39 to 1.55, P = 0.472), and also noted in adipose tissue invasion-positive patients (hazard ratio, 0.4; 95% CI, 0.26 to 0.6, P < 0.001) but not in adipose tissue invasion-negative patients (hazard ratio, 0.73; 95% CI, 0.16 to 3.24, P = 0.675). In addition, although patients suffering from TNBC with adipose tissue invasion had a poorer outcome than those without adipose tissue invasion (hazard ratio, 3.63; 95% CI, 1.11 to 11.84; P = 0.033), the difference was not observed in luminal BC (hazard ratio, 1.75; 95% CI, 0.64 to 4.82; P = 0.277). CONCLUSIONS: Adipose tissue invasion was correlated with poor survival in TNBC. Cancer cell invasion into local fat may be a first step on cancer progression and systemic disease in TNBC.


Assuntos
Tecido Adiposo/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Comunicação Celular , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral
3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670942

RESUMO

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia/métodos , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , /imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Feminino , Humanos , Imunoterapia Adotiva/métodos , Terapia de Alvo Molecular , Receptores de Antígenos Quiméricos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
4.
BMC Cancer ; 21(1): 239, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676425

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAFs) are some of the most abundant components of the tumour microenvironment. A recent study suggested that in some cancers, CAFs express programmed death ligand 1 (PD-L1), which can act as a prognostic marker. The aim of this study was to investigate the clinicopathological significance of CAF PD-L1 expression in patients with triple-negative breast cancer (TNBC) and to identify the most suitable primary antibody for immunostaining for CAF PD-L1. METHODS: Immunohistochemical staining (primary antibodies of 73-10, SP142, and E1L3N) and tissue microarrays were used to analyse the expression profiles of PD-L1 in CAF in 61 patients with TNBC who underwent surgery. Overall survival (OS) was compared based on CAF PD-L1 expression, and the risk factors for OS were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Thirty-four (55.7%) patients were positive for CAF PD-L1 (73-10) expression. Compared with CAF PD-L1 negativity, there was a significant correlation between CAF PD-L1 positivity and better OS (p = 0.029). CAF PD-L1 expression, evaluated using SP-142 or E1L3N, did not correlate with OS. CAF PD-L1-positivity (73-10) correlated significantly with better prognosis in multivariate analyses (hazard ratio: 0.198; 95% confidence interval: 0.044-0.891; p = 0.035). CONCLUSIONS: CAF PD-L1 expression is a novel marker for a better prognosis of patients with TNBC, and the 73-10 assay may be suitable for immunostaining CAF PD-L1.


Assuntos
Fibroblastos Associados a Câncer/imunologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Mama/imunologia , Mama/patologia , Mama/cirurgia , Fibroblastos Associados a Câncer/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
5.
BMC Cancer ; 21(1): 238, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676449

RESUMO

BACKGROUND: Liver metastasis is a significant adverse predictor of overall survival (OS) among breast cancer patients. The purpose of this study was to determine the risk and prognostic factors of breast cancer with liver metastases (BCLM). METHODS: Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were included. Logistic regression was used to identify risk factors for liver metastasis. Cox proportional hazards regression model was adopted to determine independent prognostic factors in BCLM patients. RESULTS: Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+) were risk factors for developing liver metastasis. The median OS after liver metastasis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. Molecular subtypes also played a critical role in the survival of BCLM patients. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS (38.0 for SEER vs. 34.0 months for FUSCC), whereas triple-negative breast cancer had the shortest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR) = 2.62; 95% confidence interval (CI) = 1.88-3.66; P < 0.001) and HR-/HER2+ (HR = 3.43; 95% CI = 2.28-5.15; P < 0.001) were associated with a significantly increased death risk in comparison with HR+/HER2- patients if these patients did not receive HER2-targeted therapy. For those who underwent HER2-targeted therapy, however, HR+/HER2+ subtype reduced death risk compared with HR+/HER2- subtype (HR = 0.74; 95% CI = 0.58-0.95; P < 0.001). CONCLUSIONS: Breast cancer patients at a high risk for developing liver metastasis deserve more attention during the follow-up. BCLM patients with HR+/HER2+ subtype displayed the longest median survival than HR+/HER2- and triple-negative patients due to the introduction of HER2-targeted therapy and therefore it should be recommended for HER2+ BCLM patients.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/terapia , Quimiorradioterapia Adjuvante/métodos , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Receptor ErbB-2/análise , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/análise , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Adulto Jovem
6.
BMC Cancer ; 21(1): 286, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726701

RESUMO

BACKGROUND: In this study, we investigated CD20+ TILs in triple-negative breast cancer (TNBC) and their relationship with T lymphocyte subsets (CD4+, CD8+, CD25+, and FOXP3+), including their combined prognostic value using an immunohistochemical staining method. METHODS: We investigated 107 patients with TNBC for whom a full-face section stained by hematoxylin and eosin between 2006 and 2018 at Dokkyo Medical University Hospital was available. RESULTS: The strongest association of infiltrating CD20+ TILs was with CD4+ TILs. There was a significant relationship between CD20+ and CD4+ TILs (r = 0.177; p < 0.001), CD8+ TILs (r = 0.085; p = 0.002), and FOXP3+ TILs (r = 0.0043; p = 0.032). No significant relationships were observed between the CD20+ and CD25+ TILs (r = 0.012; p = 0.264). Multivariate analysis revealed that only the CD20+/FOXP3 ratio was an independent factor for relapse-free survival (p < 0.001) and overall survival (p < 0.001). Patients with tumors highly infiltrated by CD4+, CD8+, and CD20+ TILs had a good prognosis. In contrast, those with tumors weakly infiltrated by CD20+ TILs but highly infiltrated by CD25+ and FOXP3+ TILs had a poor prognosis. CONCLUSIONS: CD20+ TILs may support an increase in CD4+ and CD8+ TILs, which altered the anti-tumor response, resulting in a positive prognosis. CD20+ TILs correlated with FOXP3+ Treg lymphocytes, which were reported to be correlated with a poor prognosis. Our study suggested that TIL-B cells have dual and conflicting roles in TIL-T immune reactions in TNBC.


Assuntos
Carcinoma/terapia , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias de Mama Triplo Negativas/terapia , Linfócitos B/imunologia , Mama/citologia , Mama/imunologia , Mama/patologia , Carcinoma/imunologia , Carcinoma/mortalidade , Carcinoma/patologia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Medição de Risco/métodos , Subpopulações de Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
7.
Bull Cancer ; 108(1): 67-79, 2021 Jan.
Artigo em Francês | MEDLINE | ID: mdl-33422340

RESUMO

Compared with other breast cancer subtypes, patients with metastatic triple-negative breast cancer (TNBC) are younger and have a worst overall survival with a median of 15 to 18 months. These tumors have long suffered from a purely negative definition, but the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological heterogeneity of TNBC. Moreover, based on these genomic analyses, new generation of clinical trials, using many innovative therapies directed against novel targets, had been conducted. Some TNBC have DNA damage response defects, particularly linked to germinal BRCA1/2 mutations. At the present time, two poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for patients with germinal BRCA1/2 mutation. Breast cancers are not the more immunogenic solid tumors, but some of them have a high percentage of tumor infiltrating lymphocytes (TILs), express PD-L1 (about 40%) or have a high tumor mutational burden. These features of TNBC have given a strong rational to investigate the role of immune checkpoint inhibitors. One of them has been approved by FDA in association with a cytotoxic as a first line treatment. At last, targeting surface receptors outside genomic landscape with antibody drug conjugate (ADC) is a new strategy for metastatic TNBC. Sacituzumab-govitecan is the first ADC approved by FDA in advanced TNBC beyond two lines of treatment.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Distúrbios no Reparo do DNA/tratamento farmacológico , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia
8.
Life Sci ; 266: 118886, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310044

RESUMO

AIMS: Triple negative breast cancer (TNBC) has drawn more and more attention due to its high mitotic indices, high metastatic rate and poor prognosis. Gene therapy, especially RNA interference (RNAi), has become a promising targeted therapy. However, improvement of transfection efficiency and discovery of target genes are major problems for the delivery of small interfering RNAs (siRNA). MATERIALS AND METHODS: In the present study, we developed GALA- and CREKA-modified PEG-SS-PEI to deliver siRNAs targeting on EGFR and BRD4 for TNBC therapy. The PEG-SS-PEI/siRNA complexes were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The release characteristic, stability, cellular uptake and intracellular localization of the complexes were also studied. The effect of the complexes on cell viability was measured in MDA-MB-231 and HUVEC cells. The in vitro anti-tumor activities of the complexes were analyzed by Transwell invasion assay and wound healing assay. The gene silencing effect was evaluated by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. KEY FINDINGS: The results revealed that the GALA- and CREKA-modified PEG-SS-PEI/siRNA complexes showed excellent transfection efficiency with redox-sensitive release profile and good biological compatibility. The complexes protected siRNA from the degradation of RNA enzymes. The complexes significantly inhibited the proliferation, invasion and migration of MDA-MB-231 cells via the synergistic inhibition of EGFR/PI3K/Akt and BRD4/c-Myc pathways. SIGNIFICANCE: Taken together, co-delivery of siEGFR and siBRD4 by GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI may provide a more effective strategy for the treatment of TNBC.


Assuntos
Proteínas de Ciclo Celular/administração & dosagem , Peptídeos Penetradores de Células/química , Inativação Gênica , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , RNA Interferente Pequeno/administração & dosagem , Fatores de Transcrição/administração & dosagem , Neoplasias de Mama Triplo Negativas/terapia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proliferação de Células , Receptores ErbB/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Terapia Genética , Humanos , Polietilenoimina/química , RNA Interferente Pequeno/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
9.
Cell Prolif ; 54(2): e12966, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33314471

RESUMO

Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher risk of distant recurrence and metastasis, leading to a relatively aggressive biological behaviour and poor outcome. So far, the clinical management of TNBC is challenging because of its heterogeneity and paucity of specific targeted therapy. Recently, various studies have identified a lot of differently expressed long non-coding RNAs (lncRNAs) in TNBC. Those lncRNAs have been reported to play important roles in the multistep process of TNBC tumorigenesis. Here, we review the biological characteristics of lncRNAs, and present the current state of knowledge concerning the expression, function and regulation of lncRNAs in TNBC. Accumulating studies explored the potential lncRNAs-based therapeutics in TNBC, including the techniques of genetic modification using antisense oligonucleotides, locked nucleic acid and RNA nanotechnology. In current review, we also discuss the future prospects of studies about lncRNAs in TNBC and development of lncRNA-based strategies for clinical TNBC patients.


Assuntos
RNA Longo não Codificante/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Metástase Neoplásica , Oligonucleotídeos Antissenso/uso terapêutico , Prognóstico , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia
10.
Nat Commun ; 11(1): 5696, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173046

RESUMO

Poorly immunogenic tumors, including triple negative breast cancers (TNBCs), remain resistant to current immunotherapies, due in part to the difficulty of reprogramming the highly immunosuppressive tumor microenvironment (TME). Here we show that peritumorally injected, macroporous alginate gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) for concentrating dendritic cells (DCs), CpG oligonucleotides, and a doxorubicin-iRGD conjugate enhance the immunogenic death of tumor cells, increase systemic tumor-specific CD8 + T cells, repolarize tumor-associated macrophages towards an inflammatory M1-like phenotype, and significantly improve antitumor efficacy against poorly immunogenic TNBCs. This system also prevents tumor recurrence after surgical resection and results in 100% metastasis-free survival upon re-challenge. This chemo-immunotherapy that concentrates DCs to present endogenous tumor antigens generated in situ may broadly serve as a facile platform to modulate the suppressive TME, and enable in situ personalized cancer vaccination.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígenos de Neoplasias/metabolismo , Biotecnologia/métodos , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias de Mama Triplo Negativas/imunologia , Microambiente Tumoral/imunologia
11.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
12.
Int J Nanomedicine ; 15: 6791-6811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982234

RESUMO

Purpose: Folic acid and cyclic arginylglycylaspartic acid peptides were introduced to the surface of negatively charged lipid-coated hybrid polydopamine-cysteine cores for the delivery of epirubicin (EPI) (E/PCF-NPs). The combined chemo-photothermal therapy using E/PCF-NPs for triple-negative breast cancer was evaluated. Materials and Methods: The temperature elevation and thermal toxicity of nanoparticles were studied. The morphology and properties of E/PCF-NPs were characterized by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Physicochemical properties, including particle size, zeta potential, drug loading, entrapment efficiency (EE%), stability and in vitro release, were determined. The cell viability, reactive oxygen species (ROS) levels, ratios of oxidized nicotinamide adenine dinucleotide to its reduced form (NAD+/NADH), apoptosis assays, and cellular uptake of E/PCF-NPs were determined on 4T1 cells. Pharmacokinetic studies and tissue distributions were performed and detected by an ultra-high performance liquid chromatography/mass spectrometry system. The antitumor effects of E/PCF-NPs under near-infrared (NIR) laser irradiation were also evaluated. Results: The sphere-like morphology of E/PCF-NPs showed a high EE%, uniform size of 106.7 nm, remarkable stability, and highly improved cytotoxicity under NIR laser, when compared to that of photothermal treatment alone. In vitro release of EPI from E/PCF-NPs was pH sensitive, and a greater response was achieved under NIR laser irradiation. Compared to chemotherapy or photothermal treatment alone, the combined treatment in vitro significantly inhibited the survival rate of 4T1 cells to 17.7%, induced ROS generation, and reduced NAD+/NADH significantly. Treatment with E/PCF-NPs under irradiation induced 4T1 cell apoptosis in approximately 93.6% cells. In vitro cellular uptake of E/PCF-NPs was time-dependent. The long-circulating and higher tumor accumulation of E/PCF-NPs resulted in complete ablation of breast tumor tissue through the enhanced photothermal effect by NIR laser irradiation-mediated cell apoptosis. Conclusion: E/PCF-NPs show enhanced anti-cancer effects due to synergistic effects of chemotherapy with photothermal therapy and may be potential therapeutic agents for cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Indóis/química , Nanopartículas/administração & dosagem , Fototerapia/métodos , Polímeros/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Epirubicina/farmacocinética , Feminino , Humanos , Hipertermia Induzida/métodos , Indóis/administração & dosagem , Lasers , Camundongos Endogâmicos BALB C , NAD/metabolismo , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polímeros/administração & dosagem , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Temperatura , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
13.
Nat Commun ; 11(1): 3806, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732922

RESUMO

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.


Assuntos
Autofagia/imunologia , Linfócitos T CD8-Positivos/imunologia , Tenascina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia Adotiva , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Evasão Tumoral/genética
14.
Acta Clin Croat ; 59(1): 97-108, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32724280

RESUMO

Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous disease, with specific molecular characteristics and natural dynamics of early recurrence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%).


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Croácia/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/terapia
15.
Nat Commun ; 11(1): 3747, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719340

RESUMO

Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.


Assuntos
Proteína BRCA1/genética , Mutação/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteína BRCA1/deficiência , Estudos de Coortes , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia
17.
In Vivo ; 34(3 Suppl): 1661-1665, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503826

RESUMO

COVID-19 has been officially declared as a pandemic by the WHO. Italy was the first European country to be strongly affected by this outbreak. All elective and health promotion activities were reduced. Accordingly, Italian Breast Units and breast cancer (BC) screening programs scaled down significantly their activities. The aim of this study was to evaluate measures that could potentially reduce the clinical impact of COVID-19 on BC patients. Temporary recommendations are needed that could assist specialists in preventing COVID-19 infection and optimizing resources for diagnosis and treatment of BC patients.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Infecções por Coronavirus , Procedimentos Cirúrgicos Eletivos/psicologia , Hospitais Universitários , Hospitais Urbanos , Mastectomia/psicologia , Pandemias , Pneumonia Viral , Recusa do Paciente ao Tratamento/psicologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Carcinoma/diagnóstico por imagem , Carcinoma/psicologia , Carcinoma/cirurgia , Carcinoma/terapia , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/psicologia , Carcinoma Intraductal não Infiltrante/cirurgia , Terapia Combinada , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/psicologia , Diagnóstico Tardio , Gerenciamento Clínico , Detecção Precoce de Câncer , Estrogênios , Feminino , Humanos , Mamografia , Programas de Rastreamento , Terapia Neoadjuvante , Neoplasias Hormônio-Dependentes/diagnóstico por imagem , Neoplasias Hormônio-Dependentes/psicologia , Neoplasias Hormônio-Dependentes/cirurgia , Neoplasias Hormônio-Dependentes/terapia , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/psicologia , Roma , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/psicologia , Neoplasias de Mama Triplo Negativas/cirurgia , Neoplasias de Mama Triplo Negativas/terapia
18.
Cancer Immunol Immunother ; 69(10): 2063-2073, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32447412

RESUMO

Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3+ regulatory T cells (Treg), on lung metastases, using a mouse model of breast cancer. After Treg-depletion, generation of an immune response to the primary tumour was a critical determinant for limiting development of metastasis. Indeed, resection of the primary tumour abrogated any effect of Treg-depletion on metastases. In addition, whilst the immune response, generated by the primary tumour, prevented metastases development, it had little impact on controlling established disease. Collectively, the data indicate that metastatic cells in the lung are not controlled by immune responses induced by the primary tumour. These findings indicate that targeting Tregs alone will not suffice for treating lung metastases.


Assuntos
Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Depleção Linfocítica/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
19.
Sci Rep ; 10(1): 7073, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341426

RESUMO

BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44-0.90 for BRCA1; HR = 0.72; 95%CI, 0.47-1.1 for BRCA2; p = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40-1.1 for BRCA1; HR = 0.78; 95%CI, 0.44-1.38 for BRCA2; p = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28-0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11-1.25, for BRCA2; p = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21-0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11-1.9 for BRCA2; p = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas , Adulto , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia
20.
Life Sci ; 251: 117604, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32243929

RESUMO

AIMS: Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis. MATERIALS AND METHODS: TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm3, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg-1) (iii) morphine + ketorolac (10 mg kg-1 of morphine and 20 mg kg-1 of ketorolac) (iv) ketorolac (20 mg kg-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway. KEY FINDINGS: In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway. SIGNIFICANCE: Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cetorolaco/farmacologia , Morfina/toxicidade , Neovascularização Patológica/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Analgésicos Opioides/toxicidade , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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