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1.
Lancet Oncol ; 22(3): 361-369, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33556324

RESUMO

BACKGROUND: Screening for breast cancer and cervical cancer in the newly independent states of the former Soviet Union is largely opportunistic, and countries in the region have among the highest cervical cancer incidence in the WHO European Region. We aimed to compare the stage-specific distributions and changes over time in breast cancer and cervical cancer incidence in the newly independent states of the former Soviet Union. METHODS: We collected breast cancer and cervical cancer incidence data from official statistics from Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, Ukraine, and Uzbekistan for the years 2008-17 by tumour, node, metastasis (TNM) stage, and by age where population-based cancer registry data were available. We used log-linear regression to quantify the changes over time in age-standardised rates. FINDINGS: During the period 2013-17, more than 50% of breast cancer cases across the analysed countries, and more than 75% of breast cancer cases in Belarus, Kazakhstan, and Ukraine, were registered at stages I-II. The proportion of stage I breast cancer cases was highest in the screening age group (50-69 years) compared with other ages in Moldova and the Russian registries, but was highest in those aged 15-49 years in Georgia and Ukraine. Breast cancer stage-specific incidence rates increased over time, most prominently for stage I cancers. For cervical cancer, the proportions of cancers diagnosed at a late stage (stages III and IV) were high, particularly in Moldova and Armenia (>50%). The proportion of stage I cervical cancer cases decreased with age in all countries, whereas the proportions of late stage cancers increased with age. Stage-specific incidence rates of cervical cancer generally increased over the period 2008-17. INTERPRETATION: Our results suggest modest progress in early detection of breast cancer in the newly independent states of the former Soviet Union. The high proportions of early-stage disease in the absence of mammography screening (eg, in Belarus) provide a benchmark for what is achievable with rapid diagnosis. For cervical cancer, there is a need to tackle the high burden and unfavourable stage-specific changes over time in the region. A radical shift in national policies away from opportunistic screening toward organised, population-based, quality-assured human papillomavirus vaccination and screening programmes is urgently needed. FUNDING: Union for International Cancer Control, WHO Regional Office for Europe, and Ministry of Health of Ukraine.


Assuntos
Neoplasias da Mama/patologia , Neoplasias do Colo do Útero/patologia , Adolescente , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/epidemiologia , Detecção Precoce de Câncer , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Estadiamento de Neoplasias , U.R.S.S./epidemiologia , Neoplasias do Colo do Útero/classificação , Neoplasias do Colo do Útero/epidemiologia , Adulto Jovem
2.
Anticancer Res ; 41(2): 795-802, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517284

RESUMO

BACKGROUND/AIM: Chloride intracellular channel protein (CLIC1), E- and P-cadherin (Ecad, Pcad) are certified factors of aggressivity, but they have not been studied in breast cancer to date. The aim was to study CLIC1, Ecad and Pcad impact on breast cancer in terms of defining new high-risk subgroups. MATERIALS AND METHODS: Ninety-seven breast cancer biopsies were immunohistochemically evaluated for CLIC1, Ecad and Pcad expression related to molecular subtypes. CLIC1 expression was assessed in both tumor cells (CLIC1T) and blood vessels (CLIC1V). RESULTS: For 23% of Luminal A cases, both cadherins and CLIC1V were positive. Luminal B/HER2 subtype, had two specific phenotypes: Ecad-/Pcad-/CLIC1T-/CLIC1V+ and Ecad+/Pcad-/CLIC1T-/CLIC1V+. All TNBC cases were clustered into two subgroups: 60% were Ecad+/Pcad+/CLIC1T+/CLIC1V+) while 40% were Ecad+/Pcad+/CLIC1T+/CLIC1V-). CONCLUSION: CLIC1, Ecad and Pcad association stratifies molecular types of breast cancer in subgroups that may explain different response to therapy and different aggressiveness previously observed by other authors within the same molecular subtype.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/classificação , Caderinas/metabolismo , Canais de Cloreto/metabolismo , Biópsia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Medicina de Precisão , Receptor ErbB-2/metabolismo , Análise Serial de Tecidos , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
3.
Anal Chem ; 93(2): 709-714, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33315384

RESUMO

Exosomes are considered promising indicators for early cancer diagnosis. The multiple protein biomarkers carried by exosomes are associated with diverse significant biological processes and are important biomarkers of cancer subtypes. However, it is challenging to sensitively and accurately quantify protein biomarkers from a few exosomes. Herein, we propose an ultrasensitive method for quantitatively profiling protein biomarkers on the surface of exosomes by integrating mass spectrometry imaging and gold nanoparticle (AuNP)-based signal amplification. Organic oligomers as mass tags and specific antibodies are modified on AuNPs to form biomarker probes. Exosomes captured by the antibody-coated gold chip are recognized by the AuNPs probes, forming a sandwich immunoassay. By mass spectrometry imaging the mass tags, multiple protein biomarkers can be quantitatively detected from the exosomes, with a limit-of-detection (LOD) down to 50 exosome particles. As a proof of concept, exosomes secreted by different breast-cancer cell subtypes, i.e. MCF-7 and MDA-MB231, were distinguished by the level of surface protein biomarkers of CD9, CD44, and epithelial cell adhesion molecule (EpCAM) acquired by the method, demonstrating that exosomes could be used for the diagnosis of cancer at subtype level. In consideration of the advantages of the ultrasensitivity, accuracy, and simplicity, the strategy has potential prospects in biomarker discovery, cellular phenotype characterization, and cancer diagnosis.


Assuntos
Exossomos/química , Imunoensaio/métodos , Espectrometria de Massas/métodos , Biomarcadores/química , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Receptores de Hialuronatos , Limite de Detecção , Análise Serial de Proteínas , Tetraspanina 29
4.
PLoS One ; 15(7): e0236187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692762

RESUMO

The definitive characterization of common cancer stem cell (CSCs) subpopulations in breast cancer subtypes with distinct genotypic and phenotypic features remains an ongoing challenge. In this study, we have used a non-biased genome wide screening approach to identify transcriptional networks that may be specific to the CSC subpopulations in both luminal and basal breast cancer subtypes. In depth studies of three CSC-enriched breast cancer cell lines representing various subtypes of breast cancer revealed a striking hyperactivation of the mevalonate metabolic pathway in comparison to control cells. The upregulation of metabolic networks is a key feature of tumour cells securing growth and proliferative capabilities and dysregulated mevalonate metabolism has been associated with tumour malignancy and cellular transformation in breast cancer. Furthermore, accumulating evidence suggests that Simvastatin therapy, a mevalonate pathway inhibitor, could affect breast cancer progression and reduce breast cancer recurrence. When detailing the mevalonate pathway in breast cancer using a single-cell qPCR, we identified the mevalonate precursor enzyme, HMGCS1, as a specific marker of CSC-enriched subpopulations within both luminal and basal tumour subtypes. Down-regulation of HMGCS1 also decreased the CSC fraction and function in various model systems, suggesting that HMGCS1 is essential for CSC-activities in breast cancer in general. These data was supported by strong associations between HMGCS1 expression and aggressive features, such as high tumour grade, p53 mutations as well as ER-negativity in lymph node positive breast cancer. Importantly, loss of HMGCS1 also had a much more pronounced effect on CSC-activities compared to treatment with standard doses of Simvastatin. Taken together, this study highlights HMGCS1 as a potential gatekeeper for dysregulated mevalonate metabolism important for CSC-features in both luminal and basal breast cancer subtypes. Pharmacological inhibition of HMGCS1 could therefore be a superior novel treatment approach for breast cancer patients via additional CSC blocking functions.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Hidroximetilglutaril-CoA Sintase/metabolismo , Ácido Mevalônico/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Linfonodos/patologia , Redes e Vias Metabólicas , Invasividade Neoplásica
5.
PLoS One ; 15(6): e0234752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525929

RESUMO

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which had a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 96 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as mitochondrial function or extracellular matrix between breast cancer subtypes, including our new defined subtype TN-like. In addition, one of the components, mainly related with extracellular matrix processes, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Proteômica , Teorema de Bayes , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Matriz Extracelular/metabolismo , Ontologia Genética , Humanos , Prognóstico
6.
PLoS One ; 15(5): e0232127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365142

RESUMO

In this study, we proposed a novel convolutional neural network (CNN) architecture for classification of benign and malignant breast cancer (BC) in histological images. To improve the delivery and use of feature information, we chose the DenseNet as the basic building block and interleaved it with the squeeze-and-excitation (SENet) module. We conducted extensive experiments with the proposed framework by using the public domain BreakHis dataset and demonstrated that the proposed framework can produce significantly improved accuracy in BC classification, compared with the state-of-the-art CNN methods reported in the literature.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Algoritmos , Neoplasias da Mama/classificação , Feminino , Humanos , Redes Neurais de Computação
7.
Breast Cancer Res ; 22(1): 38, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321558

RESUMO

BACKGROUND: The highest incidence of breast cancer is in the Western world. Several aspects of the Western lifestyle are known risk factors for breast cancer. In particular, previous studies have shown that cholesterol levels can play an important role in the regulation of tumor progression. METHODS: In the present study, we modulated cholesterol metabolism in the human breast cancer cell lines MCF-7 and MDA-MB-231 using a genetic approach. Apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) were expressed in these cell lines to modulate cholesterol metabolism. The effects of these apolipoproteins on cancer cell properties were examined. RESULTS: Our results show that both apolipoproteins can regulate cholesterol metabolism and can control the epithelial-to-mesenchymal transition process. However, these effects were different depending on the cell type. We show that expressing apoA-I or apoE stimulates proliferation, migration, and tumor growth of MCF-7 cells. However, apoA-I or apoE reduces proliferation and migration of MDA-MB-231 cells. CONCLUSIONS: These data suggest that modulating sterol metabolism may be most effective at limiting tumor progression in models of triple-negative cancers.


Assuntos
Apolipoproteína A-I/metabolismo , Apolipoproteínas E/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Colesterol/metabolismo , Metabolismo dos Lipídeos , Animais , Neoplasias da Mama/classificação , Linhagem Celular Tumoral , Movimento Celular , Bases de Dados Genéticas , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Camundongos Nus , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Am J Surg Pathol ; 44(8): 1092-1103, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32317606

RESUMO

To date, the apocrine variant of lobular carcinoma in situ (AP-LCIS) has been cursorily described as a subtype of lobular carcinoma in situ (LCIS). We retrospectively reviewed 34 cases of AP-LCIS (including 23 associated with invasive lobular carcinoma) to fully characterize it. AP-LCIS typically presented with screen-detected calcifications in older women (mean age: 65 y) and was characterized by distended terminal duct lobular units with relatively large "pleomorphic" cells, central necrosis, and calcifications. AP-LCIS cells exhibited abundant eosinophilic occasionally granular cytoplasm, hyperchromatic nuclei, and prominent nucleoli. Synchronous classic and/or florid LCIS was identified in 24/34 (70%) AP-LCIS, and in 9/11 (82%) pure AP-LCIS. Most (68%) cases of AP-LCIS were estrogen receptor-positive (50% strongly), 35% were progesterone receptor-positive, 26% were human epidermal growth factor 2-positive, 18% demonstrated high-proliferation rate (Ki67: >15%), and 90% were androgen receptor-positive. Aurora kinase A, immunoreactive in 38% of AP-LCIS cases, was not significantly associated with recurrence, development of invasion, or nodal positivity (P>0.05). Compared with conventional (nonapocrine) pleomorphic lobular carcinoma in situ (P-LCIS), aurora kinase A was expressed in a significantly greater proportion of P-LCIS (100%). AP-LCIS and P-LCIS did not otherwise differ in clinicopathologic features. Next-generation sequencing utilizing the Oncomine Comprehensive Panel v2, performed on 27 AP-LCIS cases, showed no specific molecular findings. In a mean follow-up of 57 months, 2 (of 11, 18%) pure AP-LCIS cases recurred (2 both in situ and invasive) and none metastasized or proved fatal. AP-LCIS should be regarded as another high-grade LCIS similar to P-LCIS in many respects, and pending additional studies should be managed similarly.


Assuntos
Glândulas Apócrinas , Carcinoma de Mama in situ/classificação , Neoplasias da Mama/classificação , Idoso , Glândulas Apócrinas/química , Glândulas Apócrinas/patologia , Aurora Quinase A/análise , Carcinoma de Mama in situ/química , Carcinoma de Mama in situ/genética , Carcinoma de Mama in situ/patologia , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Calcinose , Proliferação de Células , Bases de Dados Factuais , Fator de Crescimento Epidérmico/análise , Feminino , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Necrose , Recidiva Local de Neoplasia , Prognóstico , Receptores Androgênicos/análise , Receptores de Progesterona/análise , Estudos Retrospectivos
9.
Breast Cancer Res Treat ; 181(3): 487-497, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32333293

RESUMO

The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/terapia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus/isolamento & purificação , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Infecções por Coronavirus/virologia , Feminino , Recursos em Saúde , Humanos , Invasividade Neoplásica , Pandemias , Pneumonia Viral/virologia , Telemedicina , Triagem
10.
PLoS One ; 15(4): e0231289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287294

RESUMO

Breast cancer (BC) is the most prevalent type of cancer in women in western countries. BC mortality has not declined despite early detection by screening, indicating the need for better informed treatment decisions. Therefore, a novel noninvasive diagnostic tool for BC would give the opportunity of subtype-specific treatment and improved prospects for the patients. Heterogeneity of BC tumor subtypes is reflected in the expression levels of enzymes in lipid metabolism. The aim of the study was to investigate whether the subtype defined by the transcriptome is reflected in the lipidome of BC cell lines. A liquid chromatography mass spectrometry (LC-MS) platform was applied to analyze the lipidome of six cell lines derived from human BC cell lines representing different BC subtypes. We identified an increased abundance of triacylglycerols (TG) ≥ C-48 with moderate or multiple unsaturation in fatty acyl chains and down-regulated ether-phosphatidylethanolamines (PE) (C-34 to C-38) in cell lines representing estrogen receptor and progesterone receptor positive tumor subtypes. In a cell line representing HER2-overexpressing tumor subtype an elevated expression of TG (≤ C-46), phosphatidylcholines (PC) and PE containing short-chained (≤ C-16) saturated or monounsaturated fatty acids were observed. Increased abundance of PC ≥ C-40 was found in cell lines of triple negative BC subtype. In addition, differences were detected in lipidomes within these previously defined subtypes. We conclude that subtypes defined by the transcriptome are indeed reflected in differences in the lipidome and, furthermore, potentially biologically relevant differences may exist within these defined subtypes.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Metabolismo dos Lipídeos , Lipidômica/métodos , Linhagem Celular Tumoral , Feminino , Humanos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Triglicerídeos/metabolismo
11.
Anticancer Res ; 40(4): 2141-2150, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234907

RESUMO

BACKGROUND/AIM: Patients with non-luminal breast cancer subtypes with high levels of tumor infiltrating lymphocytes (TILs) have better prognosis than those with luminal subtype. We evaluated the role of TILs according to the subtype. MATERIALS AND METHODS: An immunohistochemical analysis of 139 breast cancer cases was conducted to calculate the FOXP3+/CD8+ T cell ratios and their relationships with TILs and disease-free survival (DFS) were evaluated. RESULTS: FOXP3+/CD8+ T cell ratios were significantly associated with TIL levels only in luminal breast cancers (p=0.0001). Low FOXP3+/CD8+ T cell ratio was significantly associated with longer DFS (p=0.017). All luminal subtype patients with high TIL levels had high FOXP3+/CD8+ T cell ratios compared to only half of non-luminal subtype patients with high TIL levels. CONCLUSION: High FOXP3+/CD8+ T cell ratios in breast cancers may partly explain the worse prognosis of luminal breast cancers, but not that of non-luminal breast cancers with high TIL levels.


Assuntos
Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/biossíntese , Contagem de Linfócitos , Pessoa de Meia-Idade , Prognóstico
12.
JCO Clin Cancer Inform ; 4: 290-298, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32216637

RESUMO

PURPOSE: Machine Learning Package for Cancer Diagnosis (MLCD) is the result of a National Institutes of Health/National Cancer Institute (NIH/NCI)-sponsored project for developing a unified software package from state-of-the-art breast cancer biopsy diagnosis and machine learning algorithms that can improve the quality of both clinical practice and ongoing research. METHODS: Whole-slide images of 240 well-characterized breast biopsy cases, initially assembled under R01 CA140560, were used for developing the algorithms and training the machine learning models. This software package is based on the methodology developed and published under our recent NIH/NCI-sponsored research grant (R01 CA172343) for finding regions of interest (ROIs) in whole-slide breast biopsy images, for segmenting ROIs into histopathologic tissue types and for using this segmentation in classifiers that can suggest final diagnoses. RESULT: The package provides an ROI detector for whole-slide images and modules for semantic segmentation into tissue classes and diagnostic classification into 4 classes (benign, atypia, ductal carcinoma in situ, invasive cancer) of the ROIs. It is available through the GitHub repository under the Massachusetts Institute of Technology license and will later be distributed with the Pathology Image Informatics Platform system. A Web page provides instructions for use. CONCLUSION: Our tools have the potential to provide help to other cancer researchers and, ultimately, to practicing physicians and will motivate future research in this field. This article describes the methodology behind the software development and gives sample outputs to guide those interested in using this package.


Assuntos
Algoritmos , Neoplasias da Mama/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Software/normas , Neoplasias da Mama/classificação , Feminino , Humanos
13.
Biomed Khim ; 66(1): 89-94, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32116231

RESUMO

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.


Assuntos
Neoplasias da Mama/metabolismo , Receptores Androgênicos/metabolismo , Receptores da Prolactina/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Feminino , Humanos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona
14.
Sci Rep ; 10(1): 4113, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139710

RESUMO

Early detection of breast cancer and its correct stage determination are important for prognosis and rendering appropriate personalized clinical treatment to breast cancer patients. However, despite considerable efforts and progress, there is a need to identify the specific genomic factors responsible for, or accompanying Invasive Ductal Carcinoma (IDC) progression stages, which can aid the determination of the correct cancer stages. We have developed two-class machine-learning classification models to differentiate the early and late stages of IDC. The prediction models are trained with RNA-seq gene expression profiles representing different IDC stages of 610 patients, obtained from The Cancer Genome Atlas (TCGA). Different supervised learning algorithms were trained and evaluated with an enriched model learning, facilitated by different feature selection methods. We also developed a machine-learning classifier trained on the same datasets with training sets reduced data corresponding to IDC driver genes. Based on these two classifiers, we have developed a web-server Duct-BRCA-CSP to predict early stage from late stages of IDC based on input RNA-seq gene expression profiles. The analysis conducted by us also enables deeper insights into the stage-dependent molecular events accompanying IDC progression. The server is publicly available at http://bioinfo.icgeb.res.in/duct-BRCA-CSP.


Assuntos
Neoplasias da Mama/classificação , Carcinoma Ductal de Mama/classificação , Aprendizado de Máquina Supervisionado , Transcriptoma , Algoritmos , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Detecção Precoce de Câncer , Feminino , Ontologia Genética , Humanos , Aprendizado de Máquina , Análise em Microsséries , Modelos Biológicos , Estadiamento de Neoplasias , Mapas de Interação de Proteínas , RNA Neoplásico , RNA-Seq , Reprodutibilidade dos Testes
15.
PLoS One ; 15(3): e0230261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176735

RESUMO

BACKGROUND: We aimed to evaluate the expression of APOBEC3A (A3A), 3B (A3B) mRNA, and germline APOBEC3A/B deletion polymorphism in patients with breast cancers and to investigate the correlation between their expressions and clinicopathological characteristics. METHODS: RNA and DNA samples were extracted from 138 breast cancer tissues and adjacent normal breast tissues. The levels of A3A and A3B mRNA transcripts were determined using quantitative real-time polymerase chain reaction. Insertion and deletion PCR assays were performed to detect the A3B deletion allele. The serum concentrations of soluble programmed death-ligand 1 (sPD-L1) and interferon gamma were determined using enzyme-linked immunosorbent assays. RESULTS: A3B mRNA expression levels were significantly higher in triple-negative breast cancers compared to hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancers. Older age of the patient and high ki-67 expression were associated with increased expression levels of A3A and A3B mRNA. Advanced tumor stage, presence of lymph node involvement, and high histological grade were associated with increased expression levels of A3A mRNA. The APOBEC3A/B deletion allele was found in 77 (55.8%) patients. TP53 and PIK3CA mutations were detected in 62 (44.9%) and 31 (22.5%) patients, respectively. The presence of a PIK3CA mutation was associated with lower A3A mRNA expression levels. There was a weak positive relationship between A3A mRNA expression levels and serum sPD-L1 levels. CONCLUSIONS: There was a difference in A3B mRNA expression levels according to breast cancer subtypes, and high levels of A3A and A3B mRNA expressions were associated with an aggressive phenotype. There was a high incidence of APOBEC3A/B deletion allele. Further studies are needed to identify the clinical significance of APOBEC in Asian patients with breast cancer.


Assuntos
Neoplasias da Mama/genética , Citidina Desaminase/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Menor/genética , Proteínas/genética , Antígeno B7-H1/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/classificação , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Predisposição Genética para Doença , Humanos , Interferon gama/sangue , Pessoa de Meia-Idade , Polimorfismo Genético , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Deleção de Sequência , Proteína Supressora de Tumor p53/genética
16.
Cancer Sci ; 111(5): 1829-1839, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162442

RESUMO

Lysine acetyltransferases (KATs) are a highly diverse group of epigenetic enzymes that play important roles in various cellular processes including transcription, signal transduction, and cellular metabolism. However, our knowledge of the genomic and transcriptomic alterations of KAT genes and their clinical significance in human cancer remains incomplete. We undertook a metagenomic analysis of 37 KATs in more than 10 000 cancer samples across 33 tumor types, focusing on breast cancer. We identified associations among recurrent genetic alteration, gene expression, clinicopathologic features, and patient survival. Loss-of-function analysis was carried out to examine which KAT has important roles in growth and viability of breast cancer cells. We identified that a subset of KAT genes, including NAA10, KAT6A, and CREBBP, have high frequencies of genomic amplification or mutation in a spectrum of human cancers. Importantly, we found that 3 KATs, NAA10, ACAT2, and BRD4, were highly expressed in the aggressive basal-like subtype, and their expression was significantly associated with disease-free survival. Furthermore, we showed that depletion of NAA10 inhibits basal-like breast cancer growth in vitro. Our findings provide a strong foundation for further mechanistic research and for developing therapies that target NAA10 or other KATs in human cancer.


Assuntos
Genoma Humano/genética , Lisina Acetiltransferases/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteína de Ligação a CREB/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Intervalo Livre de Doença , Proteína p300 Associada a E1A/genética , Dosagem de Genes , Expressão Gênica , Histona Acetiltransferases/genética , Humanos , Lisina Acetiltransferases/metabolismo , Mutação , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Neoplasias/mortalidade , Prognóstico , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Fatores de Transcrição/genética
17.
PLoS One ; 15(3): e0229903, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214335

RESUMO

BACKGROUND: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). METHODS: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (ß-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). RESULTS: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. CONCLUSIONS: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.


Assuntos
Neoplasias da Mama/sangue , Caderinas/sangue , Molécula de Adesão da Célula Epitelial/sangue , Células Neoplásicas Circulantes/metabolismo , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/classificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Contagem de Células , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Vimentina/sangue
18.
J. health med. sci. (Print) ; 6(1): 21-27, ene.-mar. 2020. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1096529

RESUMO

El cáncer de mama es una de las patologías más frecuentes a nivel mundial y en el Ecuador ocupa un sitio importante dentro de la mortalidad; en pacientes con tumores de estadios avanzados la quimioterapia neodyuvante es el procedimiento indicado para lograr una reducción tumoral satisfactoria. El objetivo fue determinar la respuesta clínica y patológica en pacientes con cáncer de mama tratadas con quimioterapia neoadyuvante según cada subtipo molecular, atendidos en el hospital "Teodoro Maldonado Carbo" en el período 2015 a 2017. Se hizo uso de un diseño no experimental, transversal de tipo correlacional. Pacientes con cáncer de mama que recibieron neoadyuvancia, en su mayoría con quimioterapia basada en antraciclinas y taxanos. Se clasificó a las pacientes por sus subtipos moleculares, los mismos se obtuvieron en base a las características inmunohistoquímicas de los reportes de patología que constan en el sistema AS-400. Se comprobó la respuesta clínica al tratamiento usando los Criterios RECIST 1.1. Como resultado los 171 pacientes fueron analizados. La edad promedio de las pacientes fue 55 13 años de edad; el 25% fueron luminal B (HER+), 24% luminal B (HER-), 22% triple negativo, 18% HER2+ y 12% luminal A; el 52% de las pacientes tuvieron estadio III de la enfermedad; el 75% (129) de las pacientes fue realizada una mastectomía radical modificada. Se pudo concluir que la respuesta patológica completa en pacientes con tratamiento neoadyuvante se relaciona con los subtipos moleculares y esto es estadísticamente significativo. Además, se evidenció las mayores tasas de respuesta patológica completa en los grupos moleculares de HER2+ y triple negativo.


Breast cancer is one of the most frequent pathologies worldwide and in Ecuador it occupies an important place in mortality. In patients with advanced stage tumors, the neo-adjuvant chemotherapy is the indicated procedure to achieve a satisfactory tumor reduction. The aim was to determine the clinical and pathological response in patients with breast cancer treated with neoadjuvant chemotherapy according to each molecular subtype, treated at the "Teodoro Maldonado Carbo" hospital in the period 2015 to 2017. We used a non-experimental, crosssectional type design. Patients with breast cancer who received neoadjuvant, mostly with chemotherapy based on anthracyclines and taxanes. The patients were classified by their molecular subtypes, they were obtained based on the immunohistochemical characteristics of the pathology reports that appear in the AS-400 system. The clinical response to treatment was checked using the RECIST 1.1 Criteria. As a result, a sum of 171 patients were analyzed. The average age of the patients was 55 + 13 years old; 25% were luminal B (Her +), 24% luminal B (Her-), 22% triple negative, 18% Her2 + and 12% luminal A; 52% of the patients had stage III of the disease; 75% (129) of the patients underwent a modified radical mastectomy. As a conclusion, the complete pathological response in patients with neoadjuvant treatment is related to molecular subtypes and this is statistically significant. Also, the highest rates of complete pathological response in the molecular groups of Her2 + and triple negative were evident.


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Antraciclinas/uso terapêutico , Taxoides/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Estudos Transversais , Relação Dose-Resposta a Droga , Quimioterapia Combinada
19.
BMC Med Genomics ; 13(Suppl 3): 20, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093737

RESUMO

BACKGROUND: Breast cancer is a collection of multiple tissue pathologies, each with a distinct molecular signature that correlates with patient prognosis and response to therapy. Accurately differentiating between breast cancer sub-types is an important part of clinical decision-making. Although this problem has been addressed using machine learning methods in the past, there remains unexplained heterogeneity within the established sub-types that cannot be resolved by the commonly used classification algorithms. METHODS: In this paper, we propose a novel deep learning architecture, called DeepTRIAGE (Deep learning for the TRactable Individualised Analysis of Gene Expression), which uses an attention mechanism to obtain personalised biomarker scores that describe how important each gene is in predicting the cancer sub-type for each sample. We then perform a principal component analysis of these biomarker scores to visualise the sample heterogeneity, and use a linear model to test whether the major principal axes associate with known clinical phenotypes. RESULTS: Our model not only classifies cancer sub-types with good accuracy, but simultaneously assigns each patient their own set of interpretable and individualised biomarker scores. These personalised scores describe how important each feature is in the classification of any patient, and can be analysed post-hoc to generate new hypotheses about latent heterogeneity. CONCLUSIONS: We apply the DeepTRIAGE framework to classify the gene expression signatures of luminal A and luminal B breast cancer sub-types, and illustrate its use for genes as well as the GO and KEGG gene sets. Using DeepTRIAGE, we calculate personalised biomarker scores that describe the most important features for classifying an individual patient as luminal A or luminal B. In doing so, DeepTRIAGE simultaneously reveals heterogeneity within the luminal A biomarker scores that significantly associate with tumour stage, placing all luminal samples along a continuum of severity.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/classificação , Aprendizado Profundo , Neoplasias da Mama/genética , Feminino , Humanos , Cinetocoros , Modelos Biológicos , RNA Neoplásico , RNA-Seq , Transcriptoma
20.
Breast Cancer Res Treat ; 180(2): 481-490, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32056055

RESUMO

PURPOSE: Breast cancer is a major public health concern worldwide and shows significant heterogeneity between male and female. Knowing the global incidence landscape in both sexes is critical for the breast cancer prevention and the reduction in disease burden. METHODS: We retrieved the incidence data of breast cancer in both sexes from the Global Burden of Disease 2017 database. Average annual percentage change was used to quantify the temporal trends of breast cancer incidence. RESULTS: Between 1990 and 2017, the number of newly diagnosed female breast cancer (FBC) cases increased from 870.2 thousand to 1937.6 thousand, with the age-standardized incidence rate (ASR) significantly increased from 39.2/100,000 to 45.9/100,000. A total of 166 countries experienced a significant increase in FBC-ASR. The most pronounced increase was mainly found in developing countries. The decrease was mostly detected in several developed countries, such as the USA and the UK. Male breast cancer (MBC) is a rare carcinoma and has no evident cluster across the world. Worldwide, the number of newly diagnosed MBC cases increased from 8.5 thousand in 1990 to 23.1 thousand in 2017, with the ASR significantly increased from 0.46/100,000 to 0.61/100,000. A total of 123 countries showed a significant increasing trend in MBC-ASR. CONCLUSIONS: Breast cancer incidence rates are increasing in most countries in both sexes, although the epidemiological features were not completely shared between FBC and MBC. More emphases should be placed on breast cancer primary prevention and the prevention strategies might need to be tailored for both FBC and MBC.


Assuntos
Neoplasias da Mama/epidemiologia , Países Desenvolvidos/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Carga Global da Doença/tendências , Agências Internacionais/organização & administração , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/diagnóstico , Feminino , Carga Global da Doença/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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