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1.
Life Sci ; 238: 116963, 2019 Oct 19.
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.

2.
Kaohsiung J Med Sci ; 35(10): 640-645, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31271510

RESUMO

Stereotactic vacuum-assisted biopsy (SVAB) is an alternative method of breast biopsy for nonpalpable lesions detected by mammography. Considering the diagnostic effectiveness, a direct comparison of SVAB and open surgical biopsy (OSB) is lacking. We performed a retrospective review of 276 (33.8%) SVAB and 541 (66.2%) OSB to compare the diagnostic accuracy and the total number of procedures the patients underwent. The negative predictive values of OSB and SVAB were 99.77% and 99.61%, and their false-negative rates were 0.96% and 4.76%, respectively. SVAB, as the first-line biopsy method, obviated 92.3% of operations. All malignancies diagnosed using SVAB could be treated with single therapeutic surgery. By contrast, 48% of malignancies of OSB group received two operations. Breast Imaging Reporting and Data System (BI-RADS) category used at the study correlated well with the percentage of malignancy and can thus be used to predict biopsy results. Our study concluded that SVAB is reliable for diagnosing nonpalpable breast lesions and is the better biopsy method for categories 3 and 4A lesions, which reduces the benign surgery rate. For lesions with a higher likelihood of malignancy, BI-RADS 4B, 4C and 5, SVAB has an advantage over OSB, which lowers the total number of operations for malignancy treatment.

3.
Int J Med Sci ; 16(6): 893-901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337963

RESUMO

Background: The application of adipose tissue-derived stromal cells (ASCs) in regenerative medicine has become a growing trend due to its abundance and differentiation potentials. However, several breast cancer studies indicated that ASCs promote tumor progression, therefore, the use of ASCs for reconstruction after oncological surgery poses potential risks. In this study, we aimed to examine whether cancerous or non-cancerous breast cells will exhibit different responses to ASC-derived CM. Methods: ASCs were isolated from residuals of subcutaneous adipose tissue obtained from patients undergoing surgery. Cancerous MCF-7, MDA-MB231, and MDA-MB468 cell lines and one non-cancerous M10/H184B5F5 cell line were cultured with variant concentrations of ASC-derived conditioned medium (CM) for analysis. Results: ASC-derived CM significantly reduced cell viability by triggering apoptosis in MCF-7, MDA-MB231, and MDA-MB468 cell lines. ATM-Chk2-dependent DNA damage response was activated early in cancer cells when exposed to ASC-derived CM. By contrast, prompted cell proliferation instead of cell death was detected in M10/H184B5F5 cells under the treatment of lower CM concentration. Even when exposed to the highest concentration of CM, only cell cycle arrest accompanied by a weak DNA damage response were detected in M10/H184B5F5 cells, no cell deaths were observed. Conclusions: Overall, this study demonstrated that cancerous and non-cancerous breast cells respond differently to ASC-derived CM. ASC-derived CM triggered significant cell death in breast cancer cell lines, however non-cancerous breast cells exhibited dissimilar response to ASC-derived CM.

4.
Environ Toxicol ; 34(8): 891-901, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31157515

RESUMO

Nepenthes plants are regarded as a kind of Traditional Chinese Medicine for several diseases but its anticancer activity remain unclear. The subject of this study is to evaluate the antiproliferation effects on oral cancer cells by Nepenthes plants using ethyl acetate extract of Nepenthes adrianii x clipeata (EANA). Cell viability was detected using MTS assay. Its detailed mechanisms including cell cycle, apoptosis, oxidative stress, and DNA damage were explored by flow cytometry or western blotting. For 24 hours EANA treatment, five kinds of oral cancer cells (CAL 27, Ca9-22, OECM-1, HSC-3, and SCC9) show IC50 values of cell viability ranging from 8 to 17 µg/mL but the viability of normal oral cells (HGF-1) remains over 80%. Subsequently, CAL 27 and Ca9-22 cells with high sensitivity to EANA were chosen to investigate the detailed mechanism. EANA displays the time course and concentration effects for inducing apoptosis based on flow cytometry (subG1 and annexin V analyses) and western blotting [cleaved poly (ADP-ribose) polymerase (c-PARP)]. Oxidative stress and DNA damage were induced by EANA treatments in oral cancer cells through reactive oxygen species (ROS), mitochondrial membrane potential disruption, mitochondrial superoxide, and γH2AX. All these changes of EANA treatments in oral cancer cells were reverted by the ROS scavenger N-acetylcysteine pretreatment. Therefore, EANA induces preferential killing, apoptosis, and DNA damage against oral cancer cells through oxidative stress.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Bucais/tratamento farmacológico , Estresse Oxidativo , Traqueófitas , Acetatos , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Bucais/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
Biomed Res Int ; 2019: 2304128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058185

RESUMO

Breast cancer is the most common cancer among women and is considered a major public health concern worldwide. Biogeography-based optimization (BBO) is a novel metaheuristic algorithm. This study analyzed the relationship between the clinicopathologic variables of breast cancer using Cox proportional hazard (PH) regression on the basis of the BBO algorithm. The dataset is prospectively maintained by the Division of Breast Surgery at Kaohsiung Medical University Hospital. A total of 1896 patients with breast cancer were included and tracked from 2005 to 2017. Fifteen general breast cancer clinicopathologic variables were collected. We used the BBO algorithm to select the clinicopathologic variables that could potentially contribute to predicting breast cancer prognosis. Subsequently, Cox PH regression analysis was used to demonstrate the association between overall survival and the selected clinicopathologic variables. C-statistics were used to test predictive accuracy and the concordance of various survival models. The BBO-selected clinicopathologic variables model obtained the highest C-statistic value (80%) for predicting the overall survival of patients with breast cancer. The selected clinicopathologic variables included tumor size (hazard ratio [HR] 2.372, p = 0.006), lymph node metastasis (HR 1.301, p = 0.038), lymphovascular invasion (HR 1.606, p = 0.096), perineural invasion (HR 1.546, p = 0.168), dermal invasion (HR 1.548, p = 0.028), total mastectomy (HR 1.633, p = 0.092), without hormone therapy (HR 2.178, p = 0.003), and without chemotherapy (HR 1.234, p = 0.491). This number was the minimum number of discriminators required for optimal discrimination in the breast cancer overall survival model with acceptable prediction ability. Therefore, on the basis of the clinicopathologic variables, the survival prediction model in this study could contribute to breast cancer follow-up and management.


Assuntos
Neoplasias da Mama/epidemiologia , Gerenciamento Clínico , Filogeografia/métodos , Prognóstico , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Terapia de Reposição Hormonal , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Receptor ErbB-2/genética , Receptores de Progesterona/genética
6.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013830

RESUMO

Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming.


Assuntos
Neoplasias da Mama/etiologia , Transformação Celular Neoplásica , Reprogramação Celular , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem da Célula/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Células-Tronco/metabolismo , Células-Tronco/patologia
7.
Kaohsiung J Med Sci ; 35(7): 408-416, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001932

RESUMO

Breast cancer is the most common female-specific malignancy in Taiwan and developed countries worldwide, and its incidence continues to grow. 14-3-3ε (YWHAE), which belong to 14-3-3 family, it has been reported up-regulated in breast cancer tissues. However, the clinical implication and function of YWHAE in breast cancer remains unclear. In this study, we investigated the prognostic value of the YWHAE in human breast cancer. Immunohistochemistry was used to analyze YWHAE expression in breast cancer tissues. Cell model was applied to examine the functions of YWHAE. The chemotherapeutic agents were used to evaluate the effect of YWHAE in breast cancer cell lines. YWHAE expression was associated with tumor size, lymph node metastasis, and poor patient survival in patients with breast cancer. YWHAE overexpression significantly increased the proliferation, migration, and invasion abilities of breast cancer cells. Knockdown of YWHAE expression reduced the expression of Snail and Twist in breast cancer cells. We also found that YWHAE was responsible for the resistance of breast cancer cells to chemotherapeutic agents, and knockdown of YWHAE enhanced sensitivity to multiple chemotherapeutic agents in breast cancer cells. Taken together, our findings indicated that YWHAE promoted cancer progression and chemoresistance in breast cancer cells and can be a potential therapeutic target for breast cancer.

8.
Int J Med Sci ; 16(3): 366-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911270

RESUMO

Long-chain fatty acids are the most abundant fatty acids and are essential for various physiological processes. Translocation of long-chain fatty acids across cell membrane is dependent on transport proteins. Solute carrier family 27 member 6 (SLC27A6) is a transport protein which mediates long-chain fatty acid uptake. The bioinformatic analysis revealed that the expression of SLC27A6 in non-tumoral breast tissue was higher than that in tumoral breast cancer in clinic samples. When SLC27A6 expression in non-tumorigenic cell H184B5F5/M10 was repressed, the fatty acids uptake capacity and cell proliferation was inhibited, and cell cycle was delayed. The protein expression of cell cycle regulators including cell division protein kinase 4 (CDK4), CDK6, and cyclin D1 was significantly decreased in SLC27A6-silenced H184B5F5/M10. By contrast, relatively low SLC27A6 expression in tumorigenic breast cancer cell Hs578T when compared to H184B5F5/M10. Repressing SLC27A6 expression did not affect these phenotypes in Hs578T. The interaction network of SLC27A6 was further investigated via STRING database. The function of these SLC27A6-associated proteins mainly involved in lipid biosynthesis, fatty acid metabolic process, and fatty acid transport. In conclusion, this study reveals inverse correlation between SLC27A6 expression and tumoral tissues and provides a new insight into SLC27A6-mediated cell growth and cell cycle regulation in non-tumorigenic breast cells.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Transporte de Ácido Graxo/genética , Ácidos Graxos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Glândulas Mamárias Humanas/citologia , Mapas de Interação de Proteínas
9.
Int J Mol Sci ; 19(11)2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388870

RESUMO

Fatty acid metabolism is important in the regulation of breast cancer progression. Some of the proteins involved in fatty acid transport have been demonstrated to promote the proliferation, migration, and invasion in breast cancer cells. Solute carrier family 27 member 4 (SLC27A4) is a fatty acid transporter protein and is related to very long chain acyl-CoA synthetase activity. In the present study, bioinformatic analysis revealed that relatively high SLC27A4 expression was observed in all subtypes of breast tumor tissues when compared to normal breast tissues. Silencing SLC27A4 expression significantly reduced uptake of free fatty acids in two breast cancer cell lines, Hs578T and MDA-MB-231. Cell growth inhibition was observed in SLC27A4-silenced Hs578T and cell cycle was arrested at G2/M. In addition, the capacity of migration and invasion decreased in both cell lines after knockdown of SLC27A4. The epithelial⁻mesenchymal transition signaling pathway was inhibited because protein expression of Slug, vimentin, α-smooth muscle actin, and other regulators was lower than that in control cells. Taken together, our results confirm that high SLC27A4 is associated with tumor progression in breast cancer cells. It is worth investigating whether SLC27A4 serves a diagnostic marker and therapeutic target in further studies.

10.
Eur J Cancer Prev ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30339576

RESUMO

Both breast cancer and autoimmune diseases (ADs) are predominant in women. NSAIDs are common medications for AD. Evidence on the association between NSAIDs use and breast cancer risk is controversial. We investigated the association between NSAIDs exposure and breast cancer risk in female patients with AD. AD patients older than 18 years of age were enrolled from Taiwan Longitudinal Health Insurance Database 2005. The NSAID users were defined as AD patients who had ever taken NSAIDs for at least 3 months between 2000 and 2009. All individuals were followed from the date of first diagnosis of AD to the end of 2013 to evaluate the risk of breast cancer. We estimated the adjusted hazard ratio (HR) using Cox proportional hazard regression after adjusting for age, comorbidities and medications. A total of 12 331 NSAID users and 12 331 non-NSAID users were included in this study after 1 : 1 individual matching. The NSAID users were less likely to develop breast cancer than the non-NSAID users (adjusted HR: 0.37; 95% confidence interval: 0.27-0.50; P<0.001), even if they used NSAIDs with low cumulative defined daily doses (adjusted HR: 0.42; 95% confidence interval: 0.34-0.53; P<0.001). The incidence of new-onset breast cancer in NSAID users was significantly decreased in users taking selective cyclooxygenase 2 inhibitors, diclofenac, ibuprofen and piroxicam. Lower cumulative hazard rates were found in the AD patients who used NSAIDs (P<0.001). NSAID exposure is associated with a decreased risk of breast cancer in female AD patients.

11.
Oncol Rep ; 40(5): 2766-2777, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226539

RESUMO

A disintegrin and metalloproteinase domain 33 (ADAM33) gene is a transmembrane glycoprotein that mediates changes in cell adhesion and plays an important role in cancer progression. Since bisphenol A (BPA) and phthalates are epigenetically toxic, the purpose of this study was to examine whether BPA and phthalate metabolites, including monoethyl phthalate (MEP), mono­n­butyl phthalate (MBP), mono­isobutyl phthalate (MIBP), mono(2­ethylhexyl) phthalate (MEHP), mono(2­ethyl­5­hydroxyhexyl) phthalate (MEHHP), mono(2­ethyl­5­carboxypentyl) phthalate (MECPP), and mono(2­ethyl­5­oxohexyl) phthalate (MEOHP), have an epigenetic impact on ADAM33 and the incidence of breast cancer. CpG islands of breast cancer microarray datasets obtained from the Gene Expression Omnibus (GEO) were used to assess the ADAM33 methylation profile. We designed a case­control study including 44 cases and 22 age­matched controls to detect the methylation status of intron 1 in ADAM33 from peripheral blood mononuclear cells (PBMCs) in blood, using BSP, nested PCR, and bisulfite sequencing, and measured the in vivo gene expression of ADAM33 and the urinary concentrations of endocrine­disrupting chemicals (EDCs), using real­time PCR, high­performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC­MS). Only one dataset, GSE32393, reached significance (P=0.016). ADAM33 expression and methylation frequencies at CpG site 3 in intron 1 were higher in the control group. We found a positive association between intron 1 methylation level and ADAM33 expression as well as urinary concentrations of MEHHP, MECPP, MEOHP and Σ4MEHP (the sum of MEHP, MECPP, MEHHP, and MEOHP) in the cases. This study suggests that metabolites of phthalate such as MEHHP, MECPP, MEOHP and Σ4MEHP may increase the intron 1 methylation level to elevate ADAM33 gene expression and have a protective effect on reducing the risk of breast cancer.

12.
Semin Cancer Biol ; 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30149066

RESUMO

To achieve preferential effects against cancer cells but less damage to normal cells is one of the main challenges of cancer research. In this review, we explore the roles and relationships of oxidative stress-mediated apoptosis, DNA damage, ER stress, autophagy, metabolism, and migration of ROS-modulating anticancer drugs. Understanding preferential anticancer effects in more detail will improve chemotherapeutic approaches that are based on ROS-modulating drugs in cancer treatments.

14.
Oncogene ; 37(30): 4137-4150, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29706651

RESUMO

The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and ß1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7-CYFIP1-mediated signaling pathways.

15.
Cell Physiol Biochem ; 46(4): 1423-1438, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29689559

RESUMO

Distant metastases are the major cause of mortality in cancer patients. Bone metastases may cause bone fractures, local pain, hypercalcemia, bone marrow aplasia, and spinal cord compression. Therefore, the management of bone metastases is important in cancer treatment. Normal bone remodeling is regulated by osteoprotegerin ligand (OPGL), receptor activator of NF-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and other cytokines. In the tumor microenvironment, tumor cells induce a vicious cycle that promotes osteoblastic and osteolytic lesions. Studies support the idea that distant metastases may occur due to the immunosuppressive function of myeloid-derived suppressor cells (MDSCs). These cells inhibit T cells and natural killer (NK) cells and differentiate into tumor-associating macrophages (TAMs), monocytes, and dendritic cells (DCs). In this review, we summarize studies focusing on the role of MDSCs in bone metastasis and provide a strong foundation for developing anticancer immune treatments and anticancer therapies, in general.


Assuntos
Neoplasias Ósseas/patologia , Metástase Neoplásica , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/terapia , Remodelação Óssea , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Humanos , Sistema Imunitário , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/metabolismo , Microambiente Tumoral , Via de Sinalização Wnt
16.
Breast Cancer Res Treat ; 170(3): 583-591, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29623575

RESUMO

PURPOSE: The aim of this study was to confirm the therapeutic role of eribulin on Taiwanese women with metastatic breast cancer. METHODS: This retrospective study examined 449 females who received eribulin between March 2014 and June 2017 at 14 hospitals in Taiwan for treatment of locally advanced or metastatic breast cancer. RESULTS: The survival rate at 24 months was 57.2% (95% CI 51.0-62.9%) and the median time to treatment failure (TTF) was 3.91 months (95% CI 3.45-3.94). A total of 175 patients (40.1%) received eribulin for fewer than 90 days and the others received it for 90 days or more. Eight patients (1.83%) had complete remission, 82 (18.8%) had partial remission, 202 (46.3%) had stable disease, and 144 (33.0%) had progressive disease (PD). Patients' tumors with the luminal A subtype had a significantly better objective response rate. Kaplan-Meier analysis indicated that hormone receptor positivity, luminal A subtype, receipt of eribulin as the 1st to 3rd line therapy, and metastasis to fewer than 4 organs were significantly associated with longer TTF. Stepwise multivariate analysis showed that only receipt of eribulin as the 1st to 3rd line therapy was significantly associated with TTF (HR 1.49, p < 0.001). All toxicities were manageable and only 18 patients (4.1%) discontinued treatment due to adverse events. CONCLUSIONS: Eribulin appears to have better efficacy and cause fewer adverse events, especially neutropenia, in Taiwanese women than Western women.

17.
Molecules ; 23(4)2018 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-29642488

RESUMO

The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt (MTS) assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231) cells, but showed less effect on breast normal (M10) cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD) flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose) polymerase (PARP), caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC) pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS), mitochondrial membrane potential (MitoMP), mitochondrial superoxide, and 8-oxo-2'-deoxyguanosine (8-oxodG)). In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Dano ao DNA , Diterpenos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo
18.
BMC Cancer ; 18(1): 366, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29614988

RESUMO

BACKGROUND: Macrophage heterogeneity is the main feature of the tumour microenvironment. Breast cancer is one of the most life-threatening cancers. However, macrophage polarization patterns in different tumour stages and the importance of its relationship to human epidermal growth factor receptor 2 (HER2) in breast cancer remains highly unclear. The present study investigated the patterns of monocyte differentiation and macrophage polarization in breast cancer. METHODS: Patients with breast cancer (n = 48) and healthy controls (n = 39) were prospectively recruited. The percentages and subsets of circulating macrophage-like cells were analysed by flow cytometry, and the polarization patterns of these cells in the peripheral blood of patients with breast cancer were compared with those of healthy controls. In addition, macrophage polarization patterns in different stages and HER2 status in breast cancer were investigated. RESULTS: The percentages of circulating macrophages, which are defined as PM-2 K+ cells in the peripheral blood, were significantly higher in patients with breast cancer than in healthy controls. The percentages of M1-like macrophages were significantly lower, but those of M2-like macrophages were significantly higher in patients with breast cancer than in healthy controls. The percentage of M2c-like macrophages was significantly higher in advanced (stages II and III) breast cancer. However, the patterns of macrophage polarization were not associated with HER2 status in breast cancer. CONCLUSIONS: Aberrant macrophage polarization was observed in breast cancer and was correlated with breast cancer stage. These quantitative data may provide new molecular biomarkers and potential therapeutic targets in breast cancer.

19.
BMC Cancer ; 18(1): 219, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29471794

RESUMO

BACKGROUND: Cancer stem cells (CSCs) are believed to promote the malignant transformation of breast cancer via multiple signaling pathways, including the Wnt/ß-catenin pathway. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been identified as a CSC-associated Wnt-regulated target gene, but its clinical significance in the context of breast cancer remains elusive. Therefore, the purpose of this study was to investigate the clinical significance of the LGR5-ß-catenin axis in breast cancer. METHODS: Breast cancer tissue blocks from 126 patients were used to construct a tissue microarray (TMA). Histopathological and clinical data including age; tumor size; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) level; tumor grade; lymph node (LN) status; and survival were obtained from the cancer registry database and patients' medical records. Tissue on the breast TMA was scored for LGR5 and ß-catenin expression using semi-quantitative immunohistochemical (IHC) staining. We also analyzed LGR5 expression in cellular datasets available through ONCOMINE, a web-based cancer microarray database. RESULTS: Immunohistochemical staining revealed that 58 tumors (46%) exhibited high LGR5 expression, whereas 56 tumors (47%) displayed high ß-catenin expression. High levels of LGR5 expression were significantly associated with tumor size (p = 0.002), LN metastasis status (p = 0.044), and triple-negative breast cancer (p = 0.029), consistent with our findings from the ONCOMINE database. In addition, we also found that ß-catenin -expressing breast cancers were positive correlated with HER2 overexpression. Finally, with respect to clinical outcomes, patients with high levels of LGR5-ß-catenin axis expression exhibited poorer relapse-free survival (RFS) compared to patients with low levels of LGR5-ß-catenin axis expression (p = 0.027). CONCLUSION: LGR5 overexpression was significantly associated with high T stage and LN metastasis status. High LGR5 expression was also associated with reduced RFS, indicating that LGR5 may represent a promising prognostic marker for breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia , Receptores Acoplados a Proteínas-G/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/fisiologia , Prognóstico , Receptor ErbB-2/genética , Receptores Acoplados a Proteínas-G/metabolismo , Regulação para Cima , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
20.
Cancer Cell Int ; 18: 19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29449787

RESUMO

Background: Visfatin has been reported to be associated with breast cancer progression, but the interaction between the visfatin and clinicopathologic factors in breast cancer progression status requires further investigation. To address this problem, it is better to simultaneously consider multiple factors in sensitivity and specificity assays. Methods: In this study, a dataset for 105 breast cancer patients (84 disease-free and 21 progressing) were chosen. Individual and cumulative receiver operating characteristics (ROC) were used to analyze the impact of each factor along with interaction effects. Results: In individual ROC analysis, only 3 of 13 factors showed better performance for area under curve (AUC), i.e., AUC > 7 for hormone therapy (HT), tissue visfatin, and lymph node (LN) metastasis. Under our proposed scoring system, the cumulative ROC analysis provides higher AUC performance (0.746-0.886) than individual ROC analysis in predicting breast cancer progression. Considering the interaction between these factors, a minimum of six factors, including HT, tissue visfatin, LN metastasis, tumor stage, age, and tumor size, were identified as being highly interactive and associated with breast cancer progression, providing potential and optimal discriminators for predicting breast cancer progression. Conclusion: Taken together, the cumulative ROC analysis provides better prediction for breast cancer progression than individual ROC analysis.

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