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1.
Anticancer Res ; 40(1): 9-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892549

RESUMO

BACKGROUND/AIM: Inhibition of apoptosis is one of the hallmarks of cancer, and anti-apoptotic genes are often targets of genetic and epigenetic alterations. Cellular inhibitor of apoptosis 2 (cIAP2) has a role in degrading caspases by linking them to ubiquitin molecules, and is upregulated in triple-negative breast cancer (TNBC). Previous studies have demonstrated that cIAP2 may play a role in the epithelial-to-mesenchymal transition (EMT). MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was administered to triple-negative breast cancer (TNBC) cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. RESULTS: The compounds were able to decrease the expression of cIAP2 while increasing the expression of pro-apoptotic caspase 7. There were also changes in histone modifications, suggesting a role of epigenetic mechanisms in these changes in expression of cIAP2. These changes resulted in an increase in apoptosis. SAHA and EGCG were also capable of limiting TNBC cell migration across a fibronectin (FN) matrix. CONCLUSION: SAHA and EGCG reduce the metastatic potential of TNBC by inducing the apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/genética , Catequina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Vorinostat/farmacologia , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Catequina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Presse Med ; 48(10): 1092-1100, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31706893

RESUMO

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação , Fatores Etários , Antígenos CD/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/genética , Caderinas/genética , Saúde da Família , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , França , Genes BRCA1 , Genes BRCA2 , Genes p53 , Testes Genéticos , Síndrome do Hamartoma Múltiplo/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Gravidez , Mastectomia Profilática , Fatores de Risco , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/genética
3.
Life Sci ; 239: 117009, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669239

RESUMO

INTRODUCTION: Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide. Despite the early detection of breast cancer and increasing knowledge of its biology and chemo-resistance, metastatic breast cancer is largely incurable disease. We provide a review of the intertumor and intratumor heterogeneity, explain the differences between triple-negative breast cancer subtypes. Also, we describe the interaction of breast tumor cells with their microenvironment cells and explain how this interaction contributes to the tumor progression, metastasis formation and resistance to the treatment. DISCUSSION: One of the main causes that complicate the treatment is tumor heterogeneity. It is observed among patients (intertumor heterogeneity) and in each individual tumor (intratumor heterogeneity). In the case of intratumor heterogeneity, the tumor consists of different phenotypical cell populations. During breast cancer subtype identification, a small piece of solid tumor tissue does not necessarily represent all the tumor composition. Breast tumor cell phenotypical differences may appear due to cell localization in different tumor sites, unique response to the treatment, cell interaction with tumor microenvironment or tumor cell interaction with each other. This heterogeneity may lead to breast cancer aggressiveness and challenging treatment. CONCLUSION: Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Identification of differences between populations and their response to anticancer drugs would help to predict the potential resistance to chemotherapy and thus would help to select the most suitable anticancer treatment.


Assuntos
Neoplasias da Mama/patologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral
4.
Nat Med ; 25(10): 1526-1533, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570822

RESUMO

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.


Assuntos
Recidiva Local de Neoplasia/genética , Prognóstico , Neoplasias de Mama Triplo Negativas/genética , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA/genética , Intervalo Livre de Doença , Feminino , Genética Populacional , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Regiões Promotoras Genéticas , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia
5.
Life Sci ; 238: 116963, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639396

RESUMO

AIMS: Triple-negative breast cancer (TNBC) is a special subtype of breast cancer that lacks receptor expression and is difficult to cure. Epigenetic regulators have been suggested as targets for cancer therapy in recent years. Our previous study indicated that the chromodomain-helicase-DNA-binding protein 4 (CHD4) is a prognostic biomarker of TNBC and therapeutic target in patients with TNBC. However, the exact mechanisms regulated by CHD4 are still unclear. METHODS: In this study, we compared differences in gene expression in parental and CHD4-deficient cells by next-generation sequencing and Ingenuity Pathway Analysis. KEY FINDINGS: We found that ß1 integrin is a downstream target gene of CHD4, which could be transcriptionally regulated by CHD4 in TNBC cells. Consistent with in vitro data, immunohistochemistry revealed that co-expression of ß1 integrin and CHD4 was significantly associated with metastatic state, recurrence, and survival status in TNBC patients. It also showed a positive correlation between ß1 integrin and CHD4 in vivo. SIGNIFICANCE: This is the first study to suggest that CHD4 regulates ß1 integrin in TNBC. Overall, CHD4-ß1 integrin axis could potentially be a predictive marker in patients with TNBC and the use of ß1 integrin inhibitors may be a therapeutic option for TNBC patients with high CHD4 expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Integrina beta1/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Integrina beta1/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas
6.
Gene ; 720: 144088, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476404

RESUMO

BACKGROUND: Secretory leukocyte protease inhibitor (SPLI) was a secreted protein which belongs to a member of whey acidic protein four-disulfide core family. In breast cancer (BC) it may inhibit cell proliferation and promote cancer metastasis. In this study, a comprehensive bioinformatics analysis was performed to identify the expression and prognostic value of SLPI in breast cancer. METHODS: SLPI expression in breast cancer was analyzed in Oncomine online database, which was subsequently confirmed by quantitative PCR (qPCR) in 18 BC samples and western blotting in 26 BC samples. Breast cancer gene-expression miner v4.1 was used to access the expression level with clinicopathological parameters in breast cancer patients. The prognostic values of SLPI in breast cancer were evaluated using the PrognoScan database. RESULTS: Our results indicated that SLPI was downregulated in breast cancer than in normal tissues. SLPI expression was found to be negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) status. SLPI expression level was decreased in negative basal-like status patients compared with positive basal-like status. Meanwhile, triple-negative breast cancer status positive correlated with SLPI. We confirmed a positive correlation between SLPI and interleukin 17 receptor B (IL17RB) express in breast cancer tissues via oncomine co-expression analysis. Ten proteins: Elastase, Granulin, Lipocalin, Defensin beta 103B, Defensin beta 103A, Tubulin, Heparin-binding EGF-like growth factor, Interleukin 6, Epidermal growth factor, Phospholipid scramblase 1 were determinate interactions with SLPI by STRING. CONCLUSION: SLPI could as a biomarker to predict the prognosis values of breast cancer. However, further comprehensive study and mining more evidence are needed to clarify our results.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Inibidor Secretado de Peptidases Leucocitárias/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
7.
BMC Complement Altern Med ; 19(1): 216, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412862

RESUMO

BACKGROUND: Breast cancer is still the most common malignant tumor that threatens the female's life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. Lack of targeted therapies brings about urgent demand for novel treatments. In this study we aim to investigate the anti-tumor activity of Berberine (BBR), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 and elucidate its mechanism referring to anti-inflammation. METHODS: Cell inhibition rate was measured by Cell Proliferation Assay, the cytotoxic effects was detected by Lactate dehydrogenase (LDH) leakage assay, the colony formation and migration potential were evaluated by colony formation assay and wound healing assay, the release of inflammatory cytokines was detected by EMD multifactor detection, and alterations of proteins and genes related to the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway were analyzed using western blotting and real-time Polymerase Chain Reaction (PCR). RESULTS: BBR reduce the viability of MDA-MB-231 cells and increased the release of LDH from the cells in a dose-dependent manner, with and inhibition of colony formation potential and migration of the cells. BBR also caused a marked reduction in the secretion of proinflammatory cytokines, Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Besides, a down-regulated behavior was observed with the expression of P2X purinoceptor 7 (P2X7), NLRP3, pro-caspase-1, apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1 p20, Interleukin-18 (IL-18), IL-1ß proteins and NLRP3, Caspase-1 and ASC mRNAs in the NLRP3 inflammasome cascade. CONCLUSIONS: Our results confirmed that BBR can effectively affect both tumor outgrowth and spontaneous metastasis in TNBC, and that we identified a new mechanism associated with inhibition the NLRP3 inflammasome pathway, suggesting its potential therapeutic relevance in clinical use.


Assuntos
Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Apoptose/efeitos dos fármacos , Caspase 1/genética , Caspase 1/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
8.
Breast Cancer Res ; 21(1): 87, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383035

RESUMO

BACKGROUND: Approximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development. METHODS: We assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes. RESULTS: Analysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2. CONCLUSIONS: We conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.


Assuntos
Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Variações do Número de Cópias de DNA , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Mutação , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Neoplasia Residual , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Transdução de Sinais , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Proteína Supressora de Tumor p53/genética
9.
Virchows Arch ; 475(6): 709-725, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407032

RESUMO

The proliferation marker Ki-67 is frequently used to assess aggressiveness in the pathological evaluation of cancer, but its role remains uncertain in triple-negative breast cancer (TNBC). We aimed to quantify and localize Ki-67 expression in both epithelial and immune compartments in TNBC and investigate its association with clinicopathological parameters and survival outcomes. A total of 406 TNBC cases diagnosed between 2003 and 2015 at Singapore General Hospital were recruited. Using state-of-the-art, 7-colour multiplex immunofluorescence (mIF) tissue microarrays (TMAs) were stained to assess the abundance, density and spatial distribution of Ki-67-positive tumour cells and immune cells co-decorated with cytokeratin (CK) and leukocyte common antigen (CD45) respectively. Furthermore, MKI67 mRNA profiles were analysed using NanoString technology. In multivariate analysis adjusted for tumour size, histologic grade, age at diagnosis, and lymph node stage, a high Ki-67 labelling index (LI) > 0.3% was associated with improved disease-free survival (DFS; HR = 0.727; p = 0.027). High Ki-67-positive immune cell count per TMA was a favourable prognostic marker for both DFS (HR = 0.379; p = 0.00153) and overall survival (OS; HR = 0.473; p = 0.0482). The combination of high Ki-67 LI and high MKI67 expression was associated with improved DFS (HR = 0.239; p = 0.00639) and OS (HR = 0.213; p = 0.034). This study is among the first to highlight that Ki-67 is associated with favourable prognosis in an adjuvant setting in TNBC, and the mIF-based evaluation of Ki-67 expression on both tumour and immune cells represents a novel prognostic approach.


Assuntos
Antígeno Ki-67/genética , Linfonodos/patologia , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Feminino , Humanos , Queratinas/genética , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Mama Triplo Negativas/diagnóstico
10.
Int J Mol Sci ; 20(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461932

RESUMO

Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data were obtained from The Cancer Genome Atlas (TCGA, n = 1079) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1904). TNBC patients had significantly higher levels of ANXA1 expression compared to the other subtypes in both TCGA and METABRIC cohorts (p < 0.001). ANXA1 protein expression was assessed by immunohistochemistry in Japanese TNBC patient cohort (n = 48), where 17 cases (35.4%) had positive ANXA1 staining, and their overall survival was significantly shorter compared with negative staining group (p = 0.008). The CIBERSORT algorithm was used to calculate immune cell infiltrations. ANXA1 high tumors were associated with activated mast cells and M2 macrophages (p > 0.01), but did not show any association with tumor heterogeneity nor cytolytic activity. High expression of ANXA1 group enriched inflammation, epithelial-to-mesenchymal transition (EMT), and angiogenesis-related genes in a gene set enrichment assay in both cohorts. To our knowledge, this is the first study to demonstrate that ANXA1 is associated with infiltration of mast cells and inflammation that is associated with the aggressive phenotype of TNBC, such as EMT and angiogenesis.


Assuntos
Anexina A1/genética , Movimento Celular , Mastócitos/patologia , Neovascularização Patológica/genética , Neoplasias de Mama Triplo Negativas/genética , Anexina A1/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Macrófagos/patologia , Macrófagos/fisiologia , Mastócitos/fisiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
11.
Anticancer Res ; 39(8): 4043-4053, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366486

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is the most aggressive subtype, predominant in African American women. In this study, the antioxidant/anticancer activity of muscadine grape extracts and the role of their phenolic and flavonoid contents in exerting these properties were investigated in TNBC cells. MATERIALS AND METHODS: Berry extracts from muscadine genotypes were investigated for total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity, and anticancer effects using breast cancer cell lines, representing Caucasians and African Americans. RESULTS: The antioxidant activity was associated with high TPC content. Extracts showed cytotoxicity up to 78.6% in Caucasians and 90.7% in African American cells, with an association with high antioxidant capacity. There was a strong correlation between TPC and anticancer/antioxidant activities. CONCLUSION: The anticancer and antioxidant effects of muscadine grapes are attributed to the TPC of extracts, which showed a stronger positive correlation with growth inhibition of African American breast cancer cells compared to Caucasians.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitis/química , Afro-Americanos/genética , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
12.
Anticancer Res ; 39(8): 4149-4164, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366500

RESUMO

BACKGROUND/AIM: Signaling regulation of myeloid zinc finger 1 (MZF1) has been implicated in the progression of many human malignancies; however, the mechanistic action of MZF1 in triple-negative breast cancer (TNBC) progression remains elusive. In this study, the aim was to investigate the molecular mechanisms of MZF1 and its functional role in TNBC cellular migration and invasion. MATERIALS AND METHODS: Hs578T and MDA-MB-231 cells were transfected to stably express the acidic domain of MZF1 (MZF160-72), or were transfected with MZF1-specific or ELK1-specific short hairpin RNA (shRNA). Changes in cell morphology and distributions of cellular proteins were observed and subsequently migration and invasion were measured by wound healing and transwell assays. Expression levels of epithelial-mesenchymal transition (EMT)-related genes were carried out using immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. Data of transcriptional regulation were obtained from promoter-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: Herein, we found that MZF1 in high-level MZF1-expressing TNBC cells is associated with cell migration, invasion, and mesenchymal phenotype. MZF1 interacted with the promoter region of insulin-like growth factor 1 receptor (IGF1R) to drive invasion and metastasis of high-level MZF1-expressing TNBC cells. Exogenous expression of the acidic domain of MZF1 repressed the binding of endogenous MZF1 to IGF1R promoter via blocking the interaction with ETS-like gene 1 (ELK1). This blockage not only caused MZF1 protein degradation, but also restrained ELK1 nuclear localization in high-level MZF1-expressing TNBC cells. MZF1, but not ELK1, was necessary for the retention of mesenchymal phenotype by repressing IGF1R promoter activity in TNBC cells expressing high levels of MZF1. Activation of the IGF1R-driven p38MAPK-ERα-slug-E-cadherin signaling axis mediated the conversion of mesenchymal cell to epithelial phenotype, caused by MZF1 destabilization. These results suggest that MZF1 is an oncogenic inducer. CONCLUSION: Blocking of the MZF1/ELK1 interaction to reduce MZF1 protein stability by saturating the endogenous MZF1/ELK1 binding domains might be a promising therapeutic strategy for the treatment of high-level MZF1-expressing TNBC.


Assuntos
Fatores de Transcrição Kruppel-Like/genética , Receptores de Somatomedina/genética , Neoplasias de Mama Triplo Negativas/genética , Proteínas Elk-1 do Domínio ets/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regiões Promotoras Genéticas/genética , Domínios Proteicos/genética , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
13.
Oncol Rep ; 42(4): 1569-1579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364749

RESUMO

Triple­negative breast cancer (TNBC) is characterized by fast progression with high potential for metastasis, and poor prognosis. The dysregulation of microRNAs (miRNAs) occurring in the initiation or progression of cancers often leads to aberrant gene expression. The aim of the present study was to explore the function of miR­126 in TNBC cells. Expression levels of miR­126­3p were determined by quantitative real­time PCR. Then, the effects of miR­126­3p on migration, proliferation, invasion, and angiogenesis were assessed through in vitro experiments including Cell Counting Kit­8, colony formation, Transwell invasion and vasculogenic mimicry formation assays. One of the target genes for miR­126­3p predicted by TargetScan was confirmed by luciferase activity assay. Results indicated that miR­126­3p expression was reduced in TNBC cell lines. Functional assays revealed that miR­126­3p overexpression inhibited cell proliferation, migration, invasion, colony formation capacity and vasculogenesis by 1.2­, 1.8­, 2.3­, 2.0­ and 3.3­fold, respectively, compared to the miRNA­negative control group of MDA­MB­231 cells (P<0.001, respectively). In addition, the regulator of G­protein signaling 3 (RGS3) was hypothesized and validated as a direct target of miR­126­3p in TNBC. The proliferation, migration, invasion, colony formation capacity and vasculogenesis of MDA­MB­231 cells were significantly increased by 1.4­, 2.0­, 1.8­, 1.4­ and 3.2­fold, respectively, in cells transfected with pcDNA3.0­RGS3 compared to pcDNA3.0­negative control groups (P<0.001, respectively). The influence of miR­126­3p expression was reversed by RGS3 restoration. Collectively, the present study revealed that miR­126­3p plays a role as a tumor suppressor in regulating TNBC cell activities by targeting RGS3, indicating that the miR­126­3p/RGS3 axis may be a potential treatment target.


Assuntos
MicroRNAs/genética , Proteínas RGS/genética , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/biossíntese , Invasividade Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteínas RGS/biossíntese , Proteínas RGS/metabolismo , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
14.
Int J Radiat Biol ; 95(11): 1507-1516, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31348739

RESUMO

Purpose: Based on clinical and molecular data, breast cancer is a heterogeneous disease. Breast cancers that have no expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are defined as triple negative breast cancers (TNBCs); luminal cancers have different expressions of ER, PR and/or HER2. TNBCs are frequently linked with advanced disease, poor prognosis and occurrence in young African women, and about 15% of the cases are associated with germline BRCA1/2 mutations. Since radiotherapy is utilized as a principle treatment in the management of TNBC, we aimed to investigate the chromosomal instability and radiosensitivity of lymphocytes in TNBC patients compared to luminal breast cancer patients and healthy controls using the micronucleus (MN) assay. The effect of mutations in breast cancer susceptibility genes on chromosomal radiosensitivity was also evaluated.Methods: Chromosomal radiosensitivity was evaluated in the G0 (83 patients and 90 controls) and S/G2 (34 patients and 17 controls) phase of the cell cycle by exposing blood samples from all patients and controls to 2 and 4 Gy ionizing radiation (IR).Results: In the G0 MN assay, the combined cohort of all breast cancer, TNBC and luminal patients' exhibit significantly elevated spontaneous MN values compared to controls indicating chromosomal instability. Chromosomal radiosensitivity is also significantly elevated in the combined cohort of all breast cancer patients compared to controls. The TNBC patients, however, do not exhibit enhanced chromosomal radiosensitivity. Similarly, in the S/G2 phase, 76% of TNBC patients do not show enhanced chromosomal radiosensitivity compared to the controls. In both the G0 and S/G2 phase, luminal breast cancer patients demonstrate a shift toward chromosomal radiosensitivity compared to TNBC patients and controls.Conclusions: The observations of the MN assay suggest increased chromosomal instability and chromosomal radiosensitivity in South African breast cancer patients. However, in TNBC patients, the irradiated MN values are not elevated. Our results suggest that the healthy lymphocytes in TNBC patients could handle higher doses of IR.


Assuntos
Instabilidade Cromossômica , Cromossomos/efeitos da radiação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Proteína BRCA1/genética , Estudos de Casos e Controles , Ciclo Celular , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Testes para Micronúcleos , Pessoa de Meia-Idade , Mutação , Tolerância a Radiação , Radiação Ionizante
15.
Biol Res ; 52(1): 38, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349873

RESUMO

BACKGROUND: Breast cancer is the second common malignant cancer among females worldwide. Accumulating studies have indicated that deregulation of miRNA expression in breast cancer will contribute to tumorigenesis and form different cancer subtypes. However, the reported studies on miR-29b-3p-regulated breast cancer are limited so far. Herein, we investigated the role and mechanism of miR-29b-3p in the triple negative breast cancer cell line MDA-MB-231. METHODS: The relative miR-29b-3p expression in different breast cancer cell lines were determined by qRT-PCR. CCK8 and colony formation assay were used to determine the influence of miR-29b-3p on cell proliferation. Migration assay and invasion assay were performed for cell migration and invasion respectively. To study the cell integrity immunofluorescence was performed. TUNEL assay, flow cytometry assay, hoechst staining and western blot were conducted to determine the influence of miR-29b-3p inhibitor on cell apoptosis. TRAF3 was found to be the target gene of miR-29b-3p using bioinformatics predictions. Dual-luciferase assay was performed to determine the relative luciferase activity in NC, miR-29b-3p mimic, miR-29b-3p inhibitor with TRAF3 3'-UTR wt or TRAF3 3'-UTR mt reporter plasmids. The proteins expression of NF-κB signaling pathway in MDA-MB-231 after transfection with NC, miR-29b-3p mimic, miR-29b-3p inhibitor were determined by western blot. RESULTS: The miR-29b-3p expression was significantly increased in MDA-MB-231 compare with MCF-10A. miR-29b-3p inhibitor reduced the cell viability of MDA-MB-231 and inhibited cell migration and invasion. Cell cytoskeleton integrity destroyed after miR-29b-3p inhibitor treatment. Furthermore, we identified the mechanism and found miR-29b-3p targets the TRAF3 and activates NF-κB signaling pathway. CONCLUSIONS: From the above studies, our results indicated that miR-29b-3p acts as a promoter for the development of MDA-MB-231.


Assuntos
Apoptose/efeitos dos fármacos , Regulação para Baixo/genética , MicroRNAs/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Luciferases/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Neoplasias de Mama Triplo Negativas/patologia
16.
J Exp Clin Cancer Res ; 38(1): 309, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307523

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors' expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. METHODS: We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels' correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. RESULTS: APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. CONCLUSIONS: APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas Nucleares/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Compostos de Platina/farmacologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
17.
Nat Commun ; 10(1): 2983, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278301

RESUMO

Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential for cancer cell migration, amplified in human primary breast tumors and associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF causes primarily down regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B is essential for TNBC metastasis formation in vivo, making PRPF4B a candidate for further drug development.


Assuntos
Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Matriz Extracelular/metabolismo , Feminino , Adesões Focais/genética , Humanos , Microscopia Intravital , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Processamento de RNA/genética , RNA Interferente Pequeno/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/genética , Transdução de Sinais/genética , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
18.
Artif Cells Nanomed Biotechnol ; 47(1): 2800-2809, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31284781

RESUMO

Triple-negative breast cancer (TNBC) is a distinct subtype of breast cancer characterized by high recurrence rates and poor prognosis compared to other breast cancers. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of various post-transcriptional gene and silence a broad set of target genes. Many recent studies have demonstrated that miRNAs play an important role in the initiation, promotion, malignant conversion, progression, and metastasis of TNBC. Therefore, the aim of this review is to focus on recent advancements of microRNAs-based potential applications in diagnosis, treatment and prognosis of triple-negative breast cancer.


Assuntos
MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia , Humanos , MicroRNAs/genética , Prognóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
19.
Mol Carcinog ; 58(10): 1863-1875, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31264274

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Carcinogênese/genética , Proteínas da Matriz Extracelular/genética , Proteínas de Homeodomínio/genética , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia
20.
Int J Mol Med ; 44(3): 1015-1025, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257479

RESUMO

Breast cancer (BRCA) is the most common type of cancer in adult females. Estrogen receptor (ER)+/progesterone receptor (PR)+, human epidermal­growth factor receptor 2 (HER2)­ BRCA and triple­negative breast cancer (TNBC) are two important subtypes of this disease. Long non­coding RNA (lncRNA)­mediated transcriptional dysregulation triplets (lncTDTs) may contribute to the development of cancer; however, the precise functional roles of lncTDTs in ER+/PR+, HER2­ BRCA and TNBC require further investigation. In the present study, an integrated and computational approach was conducted to identify lncTDTs based on transcription factor (TF), gene, lncRNA expression profiles and experimentally verified TF­gene interactions. The regulatory patterns of these lncTDTs are complex and differed in ER+/PR+, HER2­ BRCA and TNBC. Of note, five common lncTDTs were reported for these BRCA subtypes. Functional analysis revealed lncTDTs to be enriched in the PI3K/AKT signaling pathway within the two BRCA subtypes. Additionally, certain lncTDTs were associated with survival and may be considered candidate prognostic biomarkers for BRCA subtypes. Collectively, the results of the present study provide novel insight into the functions and mechanisms of lncRNAs in ER+/PR+, HER2­ BRCA and TNBC, and may aid the development of targeted treatments against certain subtypes of BRCA.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Interferência de RNA , RNA Longo não Codificante/genética , Neoplasias de Mama Triplo Negativas/genética , Proteína BRCA2/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Transcriptoma , Ubiquitina-Proteína Ligases/genética
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