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1.
Asian Pac J Cancer Prev ; 21(3): 629-637, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32212787

RESUMEN

OBJECTIVE: Hypoxia-associated biomarkers profiling may provide information for prognosis, staging, and subsequent therapy. We aim to evaluate whether the quantitative gene and protein expression of hypoxic response tumor markers - carbonic anhydrase IX (CAIX) and hypoxia- inducible factor 1 alpha (HIF1A) - may have a role in predicting survival in advanced breast cancer of Indonesian population. METHODS: Tumor tissues and peripheral blood samples were collected from treatment - naïve locally advanced (LABC) or metastatic breast cancer patients (MBC) at Wahidin Sudirohusodo General Hospital (Makassar, South Sulawesi) and its referral network hospitals from July 2017 to March 2019. The level of mRNA (of blood and tumor tissue samples) and soluble protein (of blood samples) of CAIX and HIF1A were measured by RT-qPCR and ELISA methods, respectively, besides the standard histopathological grading and molecular subtype assessment. The CAIX and HIF1A expression, patients' age, tumor characteristics, surgery status, and neoadjuvant chemotherapy drug classes were further involved in survival analyses for overall survival (OS) and progression-free survival (PFS). RESULTS: Forty (30 LABC, 10 MBC) eligible patients examined were 21 hormone-receptors positives (15 Luminal A, 6 Luminal B) and 19 hormone-receptors negatives (10 HER2-enriched, 9 triple-negative). The CAIX blood mRNA and CAIX soluble protein levels in hormone-receptors negative patients were higher than in hormone-receptor-positive patients (p < 0.05). In univariate analysis, both CAIX and HIF1A levels predict OS (except HIF1A protein) with CAIX tissue mRNA has the highest hazard ratio (HR 8.04, 95%CI:2.45-26.39), but not PFS. Cox proportional hazard model confirmed that CAIX tissue mRNA is the independent predictor of OS (HR 6.10, 95%CI: 1.16-32.13) along with surgical status and tumor advancement type (LABC or MBC). CONCLUSIONS: CAIX mRNA expression of tumor tissue in treatment-naïve advanced breast cancer has a predictive value for OS.
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Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Adulto , Anciano , Anciano de 80 o más Años , Anhidrasa Carbónica IX/genética , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Persona de Mediana Edad , ARN Mensajero/genética , Análisis de Supervivencia
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 415-418, 2020 Apr 10.
Artículo en Chino | MEDLINE | ID: mdl-32219825

RESUMEN

OBJECTIVE: To detect potential variant in an ethical Han Chinese pedigree affected with breast cancer. METHODS: The proband and her relatives were subjected to next-generation sequencing using a target capture sequencing kit containing 121 cancer-related genes. Candidate variants were selected by analysis of their type, frequency in population, and segregation with the phenotype. Candidate variant was verified by Sanger sequencing and TA cloning. RESULTS: A c.2013_2014ins GT variant was detected in the BRCA1 gene among all breast cancer patients from this pedigree but not among healthy females. The variant was not recorded in the 1000 Genome Project database or the Exome Aggregation Consortium (ExAC) database. The frameshifting insertion was predicted to form an premature stop codon in gene transcript and can give rise to a truncated protein. CONCLUSION: The BRCA1 c.2013_2014ins GT variant probably underlies the pathogenesis of breast cancer in this Chinese pedigree.


Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Grupo de Ascendencia Continental Asiática , Exoma , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linaje , Fenotipo
3.
Medicine (Baltimore) ; 99(10): e19345, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32150073

RESUMEN

OBJECTIVES: Breast cancer susceptibility gene 1/2 (BRCA1/2) is a promising tumor marker in many types of cancer. However, the methylation frequency of BRCA1/2 gene with occurrence risk and survival benefit of patients with breast carcinoma remains controversy. The aim of the present study was to assess the relationship between BRCA1/2 gene promoter methylation and the occurrence and prognosis in breast carcinoma based on a meta-analysis, meanwhile, this article explored the differential expression levels of BRCA1/2 gene promoter methylation in peripheral blood and tumor tissues of breast cancer patients. METHODS: Electronic databases (PubMed, Medline, Cochrane Library, and CNKI) were searched up to June 2019. The number of BRCA1/2 promoter methylation-positive and -negative patients in breast carcinoma patients were measured, and hazard ratio (HR) with 95% confidence interval (CI) for the association between BRCA1/2 gene promoter methylation and the prognosis of breast carcinoma patients. Primary end points were presence of breast cancer, overall survival (OS), disease-free survival (DFS). Statistical analysis was performed with STATA 12.0. RESULTS AND CONCLUSIONS: Fifty-eight articles including 19,084 individuals met full eligibility criteria. We observed that the frequency of BRCA1 gene promoter methylation was higher in breast cancer tissues compared with normal tissues, and the prognostic analysis suggested that BRCA1 gene promoter methylation was significantly associated with poor overall survival and poor disease-free survival. This study also verified that there was no statistically significant difference in the methylation frequency of BRCA1 gene promoter between peripheral blood and tumor tissues in breast cancer patients, which suggests that the detection of BRCA1 promoter methylation in peripheral blood may be a non-invasive and rapid way to monitor the occurrence breast cancer.


Asunto(s)
Proteína BRCA1/análisis , Proteína BRCA2/análisis , Neoplasias de la Mama/genética , Metilación de ADN/genética , Pronóstico , Proteína BRCA1/sangre , Proteína BRCA2/sangre , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/fisiopatología , Femenino , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales
5.
Science ; 367(6485): 1468-1473, 2020 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-32029688

RESUMEN

Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.


Asunto(s)
Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/patología , Proteínas Ribosómicas/genética , Animales , Neoplasias de la Mama/genética , Sistemas CRISPR-Cas , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trasplante de Neoplasias , Análisis de Secuencia de ARN
6.
Life Sci ; 248: 117454, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088211

RESUMEN

AIMS: Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS: Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-ß1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-ß1/Smads signaling and Snail expression in DHA-treated cells, in TGFß1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFß1/TGFß1 inhibitor SD-208. KEY FINDINGS: Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-ß1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFß1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-ß1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-ß1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE: DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-ß1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-ß1 pathway inhibitor.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Artemisininas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal , Femenino , Humanos , Metástasis Linfática , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Pteridinas/farmacología , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factores de Transcripción de la Familia Snail/antagonistas & inhibidores , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Life Sci ; 248: 117463, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32097663

RESUMEN

Breast cancer is one of the well-known malignant tumors among women. In spite of attempts to classifying breast cancer according to its histological and molecular properties, it is almost considered as a dilemma in treatment. Nowadays, public and medical attentions have primary focused on foods with anti-cancer properties to alleviate the cancer problems. Flavonoid components such as Quercetin (Qu) as dietary substances with high attention of ordinary people might provide potential of alternative or complementary medicine in breast cancer. With regard to the wide range of health benefits of Qu, researchers have been generally convinced to bring Qu as natural compounds in cancer therapy. Moreover, the high cost of standard cancer treatments and the failure of most conventional treatments have led the medical community to pursue cost-effective prevention and treatment. As a result, a great deal of concentration is attracted to diet/cancer reciprocal action. Therefore, this review study has aimed to identify what has revealed the critical properties of Qu such as anti-inflammatory, anti-oxidant, and even its effect on proliferation, angiogenesis, or apoptosis that are considered as anti-tumor property to enhance breast cancer treatment.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/tratamiento farmacológico , Quercetina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Femenino , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Life Sci ; 248: 117469, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32109485

RESUMEN

AIMS: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. MAIN METHODS: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. KEY FINDINGS: Our results demonstrated that SB939 at 0.5-1 µmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SIGNIFICANCE: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Vimentina/genética , Vimentina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Anticancer Res ; 40(2): 837-840, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014926

RESUMEN

BACKGROUND/AIM: The study aimed to test the potential for increasing the antiproliferative activity of 5-fluorouracil against breast cancer cells of various molecular subtypes by vitamin D receptor (VDR) agonists, calcitriol and tacalcitol, used at a low concentration of 10 nM. MATERIALS AND METHODS: Calcitriol and tacalcitol were used to increase the antiproliferative effect of 5-fluorouracil against the following human breast cancer cell lines: MCF-7, T47D, BT-474 (luminal); JIMT-1, SKBR-3 (HER2-enriched); MDA-MB-231 (triple-negative/basal-B), and non-malignant MCF-10A breast epithelial cells. RESULTS: Both calcitriol and tacalcitol significantly increased the sensitivity of MCF-7 and BT-474 cells to the antiproliferative effect of 5-fluorouracil, while no increase in the sensitivity of MDA-MB-231 cells to 5-fluorouracil treatment was observed. CONCLUSION: The VDR agonist used at the relatively low concentration of 10 nM may increase the sensitivity of breast cancer cells, at least of the luminal subtype, to the antiproliferative effect of 5-fluorouracil.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fluorouracilo/uso terapéutico , Receptores de Calcitriol/agonistas , Línea Celular Tumoral , Fluorouracilo/farmacología , Humanos , Células MCF-7/metabolismo
10.
Anticancer Res ; 40(2): 645-652, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014905

RESUMEN

BACKGROUND/AIM: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse. MATERIALS AND METHODS: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53. RESULTS: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women. CONCLUSION: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis.


Asunto(s)
Neoplasias de la Mama/genética , Recurrencia Local de Neoplasia/genética , Receptor ErbB-2/genética , Receptores Estrogénicos/metabolismo , Adulto , Anciano , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/biosíntesis , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética
11.
Gen Physiol Biophys ; 39(1): 59-67, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32039825

RESUMEN

MT1JP is a LncRNA that is reportedly involved in gastric cancer development, but a biological role and mechanism for MT1JP in breast cancer is unknown. Quantitative RT-PCR was performed to detect the level of MT1JP and miR-92a-3p, and Western blotting assays ware performed to measure the expression of CDK2, cyclinE1, P21, CD151, CD147, MMP2 and MMP9 in breast cells. Subsequently, cell viability was analyzed with CCK-8 assay. Cell migration and invasion were analyzed with Transwell and Scratch Test, respectively. The results demonstrated that MT1JP was significantly down-regulated in breast cells. Additionally, we found that overexpression of MT1JP in breast cancer cells significantly inhibited cell proliferation, migration and invasion, and regulate the expression of CDK2, cyclinE1 and P21. We then investigated a possible mechanism for these results, MT1JP significantly inhibited CD151, CD147, MMP2 and MMP9 protein expression in breast cancer cells. Moreover, we found that MT1JP binds to and negatively regulates miR-92-3p, which is known to be an oncogene in some human cancers. Our data indicate that MT1JP functions as an anti-tumor LncRNA and downregulates miR-92-3p, CD151 and CD147, and may serve as a novel diagnostic and therapeutic marker in breast cancer.


Asunto(s)
Neoplasias de la Mama , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos
12.
Medicine (Baltimore) ; 99(8): e19083, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080081

RESUMEN

BACKGROUND: Breast cancer is the most prevalent cancer in females and disease recurrence remains a significant problem. To prevent recurrence, tamoxifen is prescribed for at least 5 years. However, among patients who receive tamoxifen, individual responses are highly variable. These responses are affected by the type, frequency, and severity of endocrine symptoms, as well as adherence rates. Polymorphisms in genes involved in the metabolism of tamoxifen (ie, CYP3A4, CYP2D6) may influence responses to tamoxifen. In this study, the inter-relationships among endocrine symptoms, drug adherence, and genetic polymorphisms in Chinese breast cancer patients receiving tamoxifen therapy will be examined. We hypothesize that patients with more severe endocrine symptoms will be less likely to adhere to tamoxifen treatment. In addition, we hypothesize that a relationship will exist between the severity of tamoxifen-induced symptoms and allelic variations in tamoxifen metabolism-related genes. Although many association studies have determined that select genotypes influence the efficacy of tamoxifen, very few studies have investigated for associations between tamoxifen-induced endocrine symptoms and these polymorphisms. OBJECTIVES: The aim of this study was to characterize genetic polymorphisms in tamoxifen metabolism-associated genes in Chinese women with breast cancer and to explore the inter-relationships between genetic polymorphisms, endocrine symptoms, and adherence to tamoxifen. METHOD: We will conduct a prospective cohort study that follows 200 Chinese women over 18 months and assess treatment-related symptoms and genetic variations. Endocrine symptoms and drug adherence will be determined through interview-administered standardized questionnaires. Polymorphisms in drug metabolism genes will be determined using real-time polymerase chain reaction based genotyping method. Data will be analyzed to determine associations between allelic variations, endocrine symptoms, and adherence. DISCUSSION: The proposed study will evaluate for polymorphisms in gene(s) that are associated with tamoxifen-related endocrine symptoms and adherence with tamoxifen. We will explore the relationships between genotypes, endocrine symptoms, and drug adherence in Chinese breast cancer patients. Findings from this study may assist clinicians to identify patients at higher risk for a worse symptom experience and lower adherence rates and enable them to initiate appropriate interventions. In the long term, the findings from this study may be used to develop and test tailored symptom management interventions for these patients.


Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Enfermedades del Sistema Endocrino/inducido químicamente , Tamoxifeno/efectos adversos , Alelos , Antineoplásicos Hormonales/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Grupo de Ascendencia Continental Asiática/genética , Neoplasias de la Mama/epidemiología , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Cooperación del Paciente , Polimorfismo de Nucleótido Simple , Prevalencia , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Tamoxifeno/metabolismo , Tamoxifeno/uso terapéutico
13.
Medicine (Baltimore) ; 99(8): e19217, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080114

RESUMEN

Breast cancer is a molecularly heterogeneous disorder associated with high lethal malignant tumors among women worldwide. Genetic factors play an important role in breast cancer development. Several single nucleotide polymorphisms in the 8q24 region associated with risk of breast cancer have been identified. Fifteen studies including 32,955 cases and 43,716 controls were collected to conduct a meta-analysis to evaluate the associations between variants in 8q24 region and risk of breast cancer. Our study showed that only rs13281615 is associated with breast cancer risk in this large-scale research synopsis and meta-analysis. Further studies are needed to explore the role of the 8q24 variants in the development of breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Alelos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo
14.
BMC Bioinformatics ; 21(1): 30, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992186

RESUMEN

BACKGROUND: High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability normally preclude processing samples across multiple technologies, making it challenging to directly evaluate performance and whether data from different platforms can be reliably compared or integrated. METHODS: This study describes our experiences of nine new and established mRNA profiling techniques including Lexogen QuantSeq, Qiagen QiaSeq, BioSpyder TempO-Seq, Ion AmpliSeq, Nanostring, Affymetrix Clariom S or U133A, Illumina BeadChip and RNA-seq of formalin-fixed paraffin embedded (FFPE) and fresh frozen (FF) sequential patient-matched breast tumour samples. RESULTS: The number of genes represented and reliability varied between the platforms, but overall all methods provided data which were largely comparable. Crucially we found that it is possible to integrate data for combined analyses across FFPE/FF and platforms using established batch correction methods as required to increase cohort sizes. However, some platforms appear to be better suited to FFPE samples, particularly archival material. CONCLUSIONS: Overall, we illustrate that technology selection is a balance between required resolution, sample quality, availability and cost.


Asunto(s)
Perfilación de la Expresión Génica , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Fijadores , Formaldehído , Humanos , Análisis por Micromatrices , Adhesión en Parafina , Reproducibilidad de los Resultados
15.
PLoS One ; 15(1): e0225402, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31967989

RESUMEN

BACKGROUND: The prevalence of vitamin D inadequacy and breast cancer are both high among women living in Karachi, Pakistan. METHODS: A matched case control study was conducted in two hospitals of Karachi, Pakistan to evaluate the association of vitamin D (serum 25-hydroxyvitamin D) concentrations, vitamin D supplementation and sun exposure with breast cancer among Pakistani women. A total of 411 newly diagnosed histologically confirmed primary breast cancer cases were enrolled and 784 controls, free of breast and any other cancers, were matched by age (year of birth ± 5 years), residence in the same geographic area and study site. Information was collected on sociodemographic history, history of vitamin D supplementation, past medical and obstetrical history, family history of breast cancer, sun exposure history, histopathology reports and anthropometric measurement and venous blood was collected to measure serum 25-hydroxyvitamin D (25(OH)D) concentration. RESULTS: Compared to patients with sufficient serum vitamin D (>30 ng/ml), women with serum vitamin D deficiency (<20ng/ml), had a higher risk of breast cancer (OR = 1.65, 95%CI: 1.10, 2.50). Women with history of vitamin D supplementation one year prior to enrollment, had significant protective effect against breast cancer (OR = 0.32, 95% CI: 0.24, 0.43). CONCLUSIONS AND RECOMMENDATION: Serum vitamin D deficiency was associated with increased risk of breast cancer, while vitamin D supplementation was associated with decreased risk of breast cancer. In Pakistani women, where vitamin D deficiency is common, raising and maintaining serum vitamin D at population level is a safe and affordable strategy. It may play a role in reducing the incidence of both vitamin D deficiency and breast cancer, particularly among poor women where the breast cancer mortality is highest due to limited resources for early detection, diagnosis, and treatment. The effects of vitamin D with regard to breast cancer risk in Karachi Pakistan should be further evaluated.


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Deficiencia de Vitamina D/genética , Vitamina D/genética , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Suplementos Dietéticos , Femenino , Humanos , Persona de Mediana Edad , Pakistán/epidemiología , Luz Solar , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/patología
16.
Mol Cell Biochem ; 465(1-2): 199-214, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31894529

RESUMEN

The emerging significance of the bitter taste receptors (T2Rs) role in the extraoral tissues alludes to their potential role in many pathophysiological conditions. The dysregulation of T2R expression and function in disease conditions has now been demonstrated in airways diseases, neurological disorders, and in some cancers. However, the role of T2Rs in the pathophysiology of breast cancer is unexplored thus far. Previously, we demonstrated differential expression of the 25 T2Rs in breast cancer (BC) cells. Based on our previous findings we selected two T2Rs, T2R4 and T2R14 for this work. The objective of the current study is to investigate the expression of T2R4 and T2R14 in BC clinical samples and to examine their physiological role using highly metastatic BC and non-cancerous cell lines. Using approaches, which involve receptor knockdown, pharmacological activation and biochemical assays we report that (i) T2R4 and T2R14 expression patterns are dissimilar, with decreased levels of T2R4 and increased levels of T2R14 in BC clinical samples compared to non-cancerous controls. (ii) Activation of T2Rs with their respective agonist elicited physiological responses in metastatic breast cancer cells, and no responses were seen in non-tumorigenic breast epithelial cells. (iii) Agonist activation of T2Rs (irrespective of T2R subtype) induced anti-proliferative, pro-apoptotic, and anti-migratory responses in highly metastatic breast cancer cells. Taken together, our findings demonstrate that the chemosensory T2R signaling network is involved in evoking physiological responses in the metastatic breast cancer cell line.


Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Receptores Acoplados a Proteínas G/biosíntesis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Receptores Acoplados a Proteínas G/genética
17.
Nucleic Acids Res ; 48(3): 1572-1582, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31919512

RESUMEN

BCDIN3 domain containing RNA methyltransferase, BCDIN3D, monomethylates the 5'-monophosphate of cytoplasmic tRNAHis with a G-1:A73 mispair at the top of an eight-nucleotide-long acceptor helix, using S-adenosyl-l-methionine (SAM) as a methyl group donor. In humans, BCDIN3D overexpression is associated with the tumorigenic phenotype and poor prognosis in breast cancer. Here, we present the crystal structure of human BCDIN3D complexed with S-adenosyl-l-homocysteine. BCDIN3D adopts a classical Rossmann-fold methyltransferase structure. A comparison of the structure with that of the closely related methylphosphate capping enzyme, MePCE, which monomethylates the 5'-γ-phosphate of 7SK RNA, revealed the important residues for monomethyl transfer from SAM onto the 5'-monophosphate of tRNAHis and for tRNAHis recognition by BCDIN3D. A structural model of tRNAHis docking onto BCDIN3D suggested the molecular mechanism underlying the different activities between BCDIN3D and MePCE. A loop in BCDIN3D is shorter, as compared to the corresponding region that forms an α-helix to recognize the 5'-end of RNA in MePCE, and the G-1:A73 mispair in tRNAHis allows the N-terminal α-helix of BCDIN3D to wedge the G-1:A73 mispair of tRNAHis. As a result, the 5'-monophosphate of G-1 of tRNAHis is deep in the catalytic pocket for 5'-phosphate methylation. Thus, BCDIN3D is a tRNAHis-specific 5'-monomethylphosphate capping enzyme that discriminates tRNAHis from other tRNA species, and the structural information presented in this study also provides the molecular basis for the development of drugs against breast cancers.


Asunto(s)
Metiltransferasas/ultraestructura , ARN de Transferencia de Histidina/ultraestructura , ARN de Transferencia/genética , S-Adenosilhomocisteína/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cristalografía por Rayos X , Citoplasma/química , Citoplasma/genética , Femenino , Regulación Enzimológica de la Expresión Génica/genética , Humanos , Metilación , Metiltransferasas/química , Metiltransferasas/genética , Conformación Proteica en Hélice alfa , Pliegue de Proteína , ARN de Transferencia/química , ARN de Transferencia de Histidina/química , ARN de Transferencia de Histidina/genética
18.
Cancer Sci ; 111(3): 924-931, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31943636

RESUMEN

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow-derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid-derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7-deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose-escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Twelve patients were enrolled in the study. Dose-limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)-6, in agreement with our previous mouse model. Also, IL-6 was downregulated in a PG dose-dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimiocina CCL2/antagonistas & inhibidores , Compuestos Organometálicos/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Humanos , Interleucina-6/genética , Japón , Macrófagos/efectos de los fármacos , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/efectos de los fármacos , ARN Mensajero/genética , Transducción de Señal/genética , Adulto Joven
19.
Hereditas ; 157: 1, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31908633

RESUMEN

Background: Breast cancer is a one of the malignant carcinomas partially caused by genetic risk factors. Germline BRCA1 gene mutations are reportedly associated with breast cancers. Identification of BRCA1 mutations greatly improves the preventive strategies and management of breast cancer. The aim of our study was to investigate the frequency of the deleterious BRCA1: p.Ile1845fs variant in breast carcinomas, as well as the correlation between p.Ile1845fs variant with clinicopathological parameters and clinical outcomes. Results: A total of 23,481 clinically high-risk patients with breast cancer and 6489 healthy controls were recruited for p.Ile1845fs variant sequencing (either sanger or next generation sequencing). We identified 94 breast cancer patients (0.40%, 94/23481) as well as 11 healthy controls (0.17%, 11/6489) carried p.Ile1845fs variant. BRCA1: p.Ile1845fs variant showed a higher frequency in patients with TNBC molecular typing (20.21%, 19/94) and family history (37.23%, 35/94) compared with non-carriers (P = 3.62E-6 and 0.034, respectively). According to our data, we advanced the frequency of p.Ile1845fs variant and we confirmed that BRCA1: p.Ile1845fs variant was associated with increased risk of breast cancer (OR = 2.36, 95%CI = 1.26-4.89, P = 0.004). Conclusions: BRCA1: p.Ile1845fs variant was a frequently pathogenic mutation in breast cancer in Han Chinese women and our data may be helpful for diagnosis and therapy of breast cancer.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Adulto , Anciano , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad
20.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 30-34, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950786

RESUMEN

Objective: To explore the relationship between the imaging features of ultrasonography and thermal tomography and molecular subtypes of breast cancer. Methods: 404 female breast cancer patients with complete imaging data and pathological findings from January 2014 to June 2017 were reviewed in the West China Hospital of Sichuan University. Breast cancer pathological molecules were classified into Luminal A like type, Luminal B like type, human epidermal growth receptor-2 (HER-2) overexpression type and Basal like type according to the expression of various immune markers. The correlation of ultrasonographic BI-RADS signs, thermal tomography characteristics and immunohistochemical results of breast cancer was analyzed. Results: Breast cancer lesions with regular morphology, sharp margins, and enhanced posterior echo were more common in Basal like type; Microcalcification was more likely tend to appear in HER-2 expression breast cancer than other subtypes; The q-r curve of Luminal A like breast cancer was nearly 30°, and that was more common between 30°and 45° of HER-2 expression and Basal like breast cancer;The ratio of vertical and horizontal ≥1 of tumors and limited lymph node metastasis could not be used for distinguishing between different subtypes. Conclusion: Different molecular subtypes of breast cancer may behave routine ultrasound and thermal tomography imaging features.


Asunto(s)
Neoplasias de la Mama , Tomografía , Ultrasonografía , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , China , Femenino , Humanos
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