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1.
BMC Bioinformatics ; 21(Suppl 14): 359, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998692

RESUMO

BACKGROUND: The abundance of molecular profiling of breast cancer tissues entailed active research on molecular marker-based early diagnosis of metastasis. Recently there is a surging interest in combining gene expression with gene networks such as protein-protein interaction (PPI) network, gene co-expression (CE) network and pathway information to identify robust and accurate biomarkers for metastasis prediction, reflecting the common belief that cancer is a systems biology disease. However, controversy exists in the literature regarding whether network markers are indeed better features than genes alone for predicting as well as understanding metastasis. We believe much of the existing results may have been biased by the overly complicated prediction algorithms, unfair evaluation, and lack of rigorous statistics. In this study, we propose a simple approach to use network edges as features, based on two types of networks respectively, and compared their prediction power using three classification algorithms and rigorous statistical procedure on one of the largest datasets available. To detect biomarkers that are significant for the prediction and to compare the robustness of different feature types, we propose an unbiased and novel procedure to measure feature importance that eliminates the potential bias from factors such as different sample size, number of features, as well as class distribution. RESULTS: Experimental results reveal that edge-based feature types consistently outperformed gene-based feature type in random forest and logistic regression models under all performance evaluation metrics, while the prediction accuracy of edge-based support vector machine (SVM) model was poorer, due to the larger number of edge features compared to gene features and the lack of feature selection in SVM model. Experimental results also show that edge features are much more robust than gene features and the top biomarkers from edge feature types are statistically more significantly enriched in the biological processes that are well known to be related to breast cancer metastasis. CONCLUSIONS: Overall, this study validates the utility of edge features as biomarkers but also highlights the importance of carefully designed experimental procedures in order to achieve statistically reliable comparison results.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Máquina de Vetores de Suporte , Área Sob a Curva , Neoplasias da Mama/genética , Feminino , Redes Reguladoras de Genes/genética , Humanos , Modelos Logísticos , Metástase Neoplásica , Mapas de Interação de Proteínas/genética , Curva ROC
2.
Medicine (Baltimore) ; 99(33): e20996, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32871976

RESUMO

INTRODUCTION: Pure mucinous carcinoma is a rare type of breast carcinoma, but it usually has a favorable prognosis. Tumors of pure mucinous carcinoma are typically positive for both estrogen receptor (ER) and progesterone receptor (PR), and they do not commonly overexpress human epidermal growth factor receptor 2 (HER2). However, when tumors have HER2 overexpression and are progesterone receptor negative, the prognosis is worse. PATIENT CONCERNS: A 59-year-old female reported a slow growth mass of 3 years, which was radiologically diagnosed as fibroadenoma at another institution. The patient came to our institution for treatment and follow-up. She had no salient past history. DIAGNOSIS: Excisional biopsy revealed a pure mucinous breast carcinoma that was ER (100%, moderate-strong intensity), PR(-), 5% Ki-67 (+), and HER2(3+) by immunohistochemistry. The HER2 gene was found to be amplified by fluorescence in situ hybridization (FISH). The clinical staging was T2N0M0, with pathological grade I, subtype luminal B. INTERVENTIONS: After a modified radical mastectomy, she received four 21-day cycles of intravenous docetaxel (75 mg/m), intravenous cyclophosphamide (600 mg/m), and intravenous trastuzumab (8 mg/kg) (loading dose) on day 1 followed by 6 mg/kg every 3 weeks to complete a full year of treatment. She then received 2.5 mg of letrozole daily for 5 years. OUTCOMES: After following up for 2 years, the patient's outcome was survival without recurrence. Cardiac ultrasounds were performed every 3 months and there was no change in the left ventricular ejection fraction (LEVF). CONCLUSION: It is essential to correctly diagnose the ER(+), PR(-) HER2(+) subtype in mucinous carcinoma. This type should be treated with chemotherapy and anti-HER2 therapy, as well as aromatase inhibitor endocrine therapy.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Receptor ErbB-2/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
3.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
4.
Anticancer Res ; 40(10): 5925-5932, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988924

RESUMO

BACKGROUND/AIM: Paired box 8 (PAX8) is an organ-specific marker discriminating Müllerian and breast carcinomas. Recent studies have described PAX8 expression in a small subset of breast carcinomas, which may cause a diagnostic pitfall in the determination of cancer origin. The aim of this study was to investigate characteristics of PAX8-expressing metastatic breast carcinomas (MBCs) to help elucidate the primary site of occurrence. PATIENTS AND METHODS: Using immunohistochemistry, we examined PAX8 status in 80 MBCs and 52 matched primary breast carcinomas (PBCs). RESULTS: A total of 20% of MBCs displayed PAX8 expression and the concordance rate of PAX8 expression between MBCs and PBCs was 92.3%. In MBCs, PAX8 expression was significantly associated with high-grade features (p=0.042), estrogen and progesterone receptor negativities (p=0.005 and p=0.017, respectively). CONCLUSION: PAX8 may be identified in MBCs with high-grade and non-luminal molecular subtypes. Careful assessment is needed when designating a primary site relying principally on PAX8 positivity.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Imuno-Histoquímica , Fator de Transcrição PAX8/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade
5.
BMC Bioinformatics ; 21(1): 401, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912137

RESUMO

BACKGROUND: As an important non-coding RNA, microRNA (miRNA) plays a significant role in a series of life processes and is closely associated with a variety of Human diseases. Hence, identification of potential miRNA-disease associations can make great contributions to the research and treatment of Human diseases. However, to our knowledge, many existing computational methods only utilize the single type of known association information between miRNAs and diseases to predict their potential associations, without focusing on their interactions or associations with other types of molecules. RESULTS: In this paper, we propose a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information. Firstly, a heterogeneous network is constructed by integrating known associations among miRNA, protein and disease, and the network representation method Learning Graph Representations with Global Structural Information (GraRep) is implemented to learn the behavior information of miRNAs and diseases in the network. Then, the behavior information of miRNAs and diseases is combined with the attribute information of them to represent miRNA-disease association pairs. Finally, the prediction model is established based on the Random Forest algorithm. Under the five-fold cross validation, the proposed NEMPD model obtained average 85.41% prediction accuracy with 80.96% sensitivity at the AUC of 91.58%. Furthermore, the performance of NEMPD is also validated by the case studies. Among the top 50 predicted disease-related miRNAs, 48 (breast neoplasms), 47 (colon neoplasms), 47 (lung neoplasms) were confirmed by two other databases. CONCLUSIONS: The proposed NEMPD model has a good performance in predicting the potential associations between miRNAs and diseases, and has great potency in the field of miRNA-disease association prediction in the future.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias do Colo/diagnóstico , Biologia Computacional/métodos , Neoplasias Pulmonares/diagnóstico , MicroRNAs/metabolismo , Algoritmos , Área Sob a Curva , Neoplasias da Mama/genética , Neoplasias do Colo/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Curva ROC
6.
Nat Commun ; 11(1): 4637, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934226

RESUMO

An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09-0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.


Assuntos
Neoplasias da Mama/genética , Fatores de Transcrição GATA/genética , Esquizofrenia/genética , Idoso , Cromossomos Humanos Par 19/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Suécia
7.
BMC Bioinformatics ; 21(1): 396, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894041

RESUMO

BACKGROUND: MicroRNAs are a class of important small noncoding RNAs, which have been reported to be involved in the processes of tumorigenesis and development by targeting a few genes. Existing studies show that the imbalance between cell proliferation and apoptosis is closely related to the initiation and development of cancers. However, the impact of miRNAs on this imbalance has not been studied systematically. RESULTS: In this study, we first construct a cell fate miRNA-gene regulatory network. Then, we propose a systematical method for calculating the global impact of miRNAs on cell fate genes based on the shortest path. Results on breast cancer and liver cancer datasets show that most of the cell fate genes are perturbed by the differentially expressed miRNAs. Most of the top-identified miRNAs are verified in the Human MicroRNA Disease Database (HMDD) and are related to breast and liver cancers. Function analysis shows that the top 20 miRNAs regulate multiple cell fate related function modules and interact tightly based on their functional similarity. Furthermore, more than half of them can promote sensitivity or induce resistance to some anti-cancer drugs. Besides, survival analysis demonstrates that the top-ranked miRNAs are significantly related to the overall survival time in the breast and liver cancers group. CONCLUSION: In sum, this study can help to systematically study the important role of miRNAs on proliferation and apoptosis and thereby uncover the key miRNAs during the process of tumorigenesis. Furthermore, the results of this study will contribute to the development of clinical therapy based miRNAs for cancers.


Assuntos
Apoptose/genética , Proliferação de Células/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida
8.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879317

RESUMO

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Duplicação Gênica , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Taxa de Mutação , Metástase Neoplásica/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Análise de Célula Única , Sequenciamento Completo do Exoma
9.
PLoS Med ; 17(9): e1003302, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915777

RESUMO

BACKGROUND: A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). METHODS AND FINDINGS: Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. CONCLUSIONS: We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.


Assuntos
Neoplasias da Mama/genética , Lipídeos/análise , Lipídeos/sangue , Adulto , Neoplasias da Mama/metabolismo , Colesterol/análise , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Triglicerídeos/sangue
10.
Nat Commun ; 11(1): 4875, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978388

RESUMO

Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.


Assuntos
Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lesões Pré-Cancerosas/genética , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Heterogeneidade Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/patologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Mutação , Lesões Pré-Cancerosas/patologia , Transcriptoma
11.
Nat Commun ; 11(1): 4861, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978398

RESUMO

Advanced tumours are often heterogeneous, consisting of subclones with various genetic alterations and functional roles. The precise molecular features that characterize the contributions of multiscale intratumour heterogeneity to malignant progression, metastasis, and poor survival are largely unknown. Here, we address these challenges in breast cancer by defining the landscape of heterogeneous tumour subclones and their biological functions using radiogenomic signatures. Molecular heterogeneity is identified by a fully unsupervised deconvolution of gene expression data. Relative prevalence of two subclones associated with cell cycle and primary immunodeficiency pathways identifies patients with significantly different survival outcomes. Radiogenomic signatures of imaging scale heterogeneity are extracted and used to classify patients into groups with distinct subclone compositions. Prognostic value is confirmed by survival analysis accounting for clinical variables. These findings provide insight into how a radiogenomic analysis can identify the biological activities of specific subclones that predict prognosis in a noninvasive and clinically relevant manner.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Biomarcadores Tumorais/genética , Mama , Ciclo Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Imageamento Tridimensional/métodos , Análise Multivariada , Prognóstico , Análise de Sobrevida , Transcriptoma
12.
Anticancer Res ; 40(10): 5379-5391, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988857

RESUMO

BACKGROUND/AIM: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1α is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1α level and this link might be exploited. MATERIALS AND METHODS: Poly(I:C)-induced signaling pathway and expression of HIF1α and HIF1α targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. RESULTS: Poly(I:C) increased expression of HIF1α and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1α was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1α-dependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1α induction. CONCLUSION: Combined treatment with poly(I:C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/agonistas
13.
Anticancer Res ; 40(10): 5471-5480, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988869

RESUMO

BACKGROUND/AIM: Accurate regulation of the spindle assembly checkpoint (SAC) and anaphase promoting complex/cyclosome (APC/C) are essential for the correct execution of mitosis. In this work, we focused on MAD2L2 (REV7), a central translesion (TLS) protein, which also functions as a mitotic regulator by inhibiting APC/C in prometaphase. MATERIALS AND METHODS: Using bioinformatics analysis, live cell imaging and APC/C protein binding and degradation assays, we explored the influence of MAD2L2 over-expression in breast cancer. RESULTS: A significant over-expression of MAD2L2 was found in triple negative breast cancers (TNBC), compared to other breast cancers, correlating to poor patient prognosis. We also identified significant over-expression of MAD2L2 in the MDA-MB-157 triple negative (TN) cell line. A high percentage of MDA-MB-157 cells failed to complete mitosis and died during mitosis or shortly after. In addition, these cells completed mitosis at a significantly slower rate than control cells. MDA-MB-157 cells present high levels of mitotic slippage upon nocodazole treatment and acute dysregulation in APC/C function and substrate degradation. Moreover, silencing of MAD2L2 in the MDA-MB-157 cell line improved mitotic phenotypes. CONCLUSION: MAD2L2 over-expression supports the carcinogenic phenotype of MDA-MB-157 cells by promoting uncontrolled mitosis.


Assuntos
Neoplasias da Mama/genética , Proteínas Mad2/genética , Mitose/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/genética , Prometáfase/genética
14.
Crit Rev Oncol Hematol ; 154: 103070, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32871325

RESUMO

Cancer is a heterogeneous disease, occurs due to transcriptional changes in genetic and epigenetic including numerous genes and proteins. Worldwide, breast cancer (BC) is the life-threatening malignancies in women, is characterized by the occurrence of more than one molecular alteration. The incidence and mortality of BC are growing every day because of the adoption of western living standards, metropolitanization, and more life expectancy. Even though many modern approaches are available for the detection and treatment of BC, despite of these, it remains the topmost cause of death in women. This review highlights various approaches, including the importance of clinical, pathological, and molecular aspects of BC. Moreover, risk factors, biomarkers, immunotherapy, investigational drugs, and their role through tumor targets and immune systems have been discussed for management of BC. Furthermore, various targeting approaches for tumors through nanocarriers and their clinical trials have been elaborated in BC challenges and future perspectives.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Drogas em Investigação , Feminino , Humanos , Imunoterapia
15.
Medicine (Baltimore) ; 99(38): e22331, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957402

RESUMO

Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following T-DM1 and clarify the predictive factors of their prognosis.We retrospectively identified patients with HER2-positive MBC who received T-DM1 between April 1, 2014, and December 31, 2018, at the National Cancer Center Hospital, and focused on the population that received another line of therapy following T-DM1 discontinuation.Thirty patients were available for the outcome analysis. Median progression-free survival (PFS) of the first subsequent therapy was 6.0 months [95% confidence interval (95% CI) 4.1-6.4], whereas the median overall survival (OS) from the first subsequent therapy was 20.6 months (95% CI 13.5 months to not reached). We divided the patients into 2 groups according to their PFS with T-DM1 treatment and compared their PFS with the subsequent therapy. The results revealed a significant difference in the median PFS with the first subsequent treatment between patients with the PFS of less than and more than 3 months [5.1 (95% CI 1.7-6.2) vs 6.2 (95% CI 4.0-11.3) months, P = .03].This is the first study to evaluate the survival outcomes of post-T-DM1 therapy in Japanese patients with HER2-positive MBC. A short PFS with T-DM1 might affect the PFS with a treatment after T-DM1.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2 , Estudos Retrospectivos , Resultado do Tratamento
16.
Nat Commun ; 11(1): 4642, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934200

RESUMO

Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Glândulas Mamárias Animais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem da Célula , Metilação de DNA , Proteínas de Ligação a DNA/genética , Sistema Endócrino/metabolismo , Epigênese Genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética
17.
PLoS One ; 15(8): e0238295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866190

RESUMO

African American breast cancer genetics is less understood compared to European American breast cancer susceptibility. Despite the many advantages of gene panel screening, studies investigating African American inherited breast cancer risk and comparing variant contributions between ethnicities are infrequent. Thus, 97 breast cancer-affected individuals of African and European descent from the Alabama Hereditary Cancer Cohort were screened using the research-based gene-panel, B.O.P. (Breast, Ovarian, and Prostate cancer). Upon sequencing and bioinformatic processing, rare coding variants in 14 cancer susceptibility genes were categorized according to the American College of Medical Genetics guidelines and compared between ethnicities. Overall, 107 different variants were identified, the majority of which were benign/likely benign. A pathogenic/likely pathogenic variant was detected in 8.6% and 6.5% of African American and European American cases, respectively, which was not statistically significant. However, African Americans were more likely to have at least one variant of uncertain significance (VUS; p-value 0.006); they also had significantly more VUSs in BRCA1/2 compared to European Americans (p-value 0.015). Additionally, 51.4% of African Americans and 32.3% of European Americans harbored multiple rare variants, and African Americans were more likely to have at least one VUS and one benign/likely benign variant (p-value 0.032), as well as multiple benign/likely benign variants (p-value 0.089). Moreover, of the 15 variants detected in multiple breast cancer cases, ATM c.2289T>C (p.F763L), a VUS, along with two likely benign variants, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls. Ultimately, B.O.P. screening provides essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities, stressing the need for future research to elucidate inherited breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Grupos Populacionais/genética , Detecção Precoce de Câncer/métodos , Feminino , Testes Genéticos/métodos , Humanos
18.
Adv Exp Med Biol ; 1252: 129-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32816272

RESUMO

Genetic testing should be offered to all women less than 40 years of age who are diagnosed with breast cancer, and patients with PABC are generally among them. However, there is no specific study about these cases, and whether genetic testing should be carried out during or after pregnancy is not known. Generally, testing before delivery should only be performed if positive results change management plans, such as undergoing fetal testing and choosing mastectomy instead of breast conserving surgery.


Assuntos
Neoplasias da Mama/genética , Testes Genéticos , Lactação , Complicações Neoplásicas na Gravidez/genética , Adulto , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Mastectomia , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Diagnóstico Pré-Natal
19.
BMC Bioinformatics ; 21(1): 339, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736513

RESUMO

BACKGROUND: It has been widely accepted that long non-coding RNAs (lncRNAs) play important roles in the development and progression of human diseases. Many association prediction models have been proposed for predicting lncRNA functions and identifying potential lncRNA-disease associations. Nevertheless, among them, little effort has been attempted to measure lncRNA functional similarity, which is an essential part of association prediction models. RESULTS: In this study, we presented an lncRNA functional similarity calculation model, IDSSIM for short, based on an improved disease semantic similarity method, highlight of which is the introduction of information content contribution factor into the semantic value calculation to take into account both the hierarchical structures of disease directed acyclic graphs and the disease specificities. IDSSIM and three state-of-the-art models, i.e., LNCSIM1, LNCSIM2, and ILNCSIM, were evaluated by applying their disease semantic similarity matrices and the lncRNA functional similarity matrices, as well as corresponding matrices of human lncRNA-disease associations coming from either lncRNADisease database or MNDR database, into an association prediction method WKNKN for lncRNA-disease association prediction. In addition, case studies of breast cancer and adenocarcinoma were also performed to validate the effectiveness of IDSSIM. CONCLUSIONS: Results demonstrated that in terms of ROC curves and AUC values, IDSSIM is superior to compared models, and can improve accuracy of disease semantic similarity effectively, leading to increase the association prediction ability of the IDSSIM-WKNKN model; in terms of case studies, most of potential disease-associated lncRNAs predicted by IDSSIM can be confirmed by databases and literatures, implying that IDSSIM can serve as a promising tool for predicting lncRNA functions, identifying potential lncRNA-disease associations, and pre-screening candidate lncRNAs to perform biological experiments. The IDSSIM code, all experimental data and prediction results are available online at https://github.com/CDMB-lab/IDSSIM .


Assuntos
Algoritmos , Biologia Computacional/métodos , Doença/genética , Modelos Genéticos , RNA Longo não Codificante/genética , Semântica , Adenocarcinoma/genética , Área Sob a Curva , Neoplasias da Mama/genética , Bases de Dados Genéticas , Feminino , Humanos , Curva ROC
20.
Mol Biol (Mosk) ; 54(4): 688-698, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32840490

RESUMO

A majority of BRCA1/2 (BRCA) pathogenic variants (PVs) are single nucleotide substitutions or small insertions/deletions. Copy number variations (CNVs), also known as large genomic rearrangements (LGRs), have been identified in BRCA genes. LGRs detection is a mandatory analysis in hereditary breast and ovarian cancer families, if no predisposing PVs are found by sequencing. Next generation sequencing (NGS) may be used to detect structural variation, since quantitative analysis of sequencing reads, when coupled with appropriate bioinformatics tools, is capable of estimating and predicting germline LGRs (gLGRs). However, applying this approach to tumor tissue is challenging, and the pipelines for determination of CNV are yet to be optimized. The aim of this study was to validate the Next Generation Tumor Sequencing (NGTS) technology to detect various gLGRs of BRCA1 locus in surgical tumor tissue samples. In this study, seven different BRCA1 gLGRs, previously found in high-grade serous ovarian cancers (HGSOC) patients, were detected in tumor samples collected from the patients at a time of HGSOC surgery. This study demonstrated that NGS can accurately detect BRCA1 gLGRs in primary tumors, suggesting that gLGR evaluation in BRCA1 locus should be performed in cases when the screening for BRCA alterations starts from tumor instead of blood. NGS sequencing of tumor samples may become the preferred method to detect both somatic and germline gLGRs in BRCA-encoding loci.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Genes BRCA1 , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Ovarianas/genética , Variações do Número de Cópias de DNA/genética , Feminino , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Humanos
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