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1.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802237

RESUMEN

Breast cancer is the most frequent cancer in the female population worldwide. The role of germline genetic variability in cytochromes P450 (CYP) in breast cancer prognosis and individualized therapy awaits detailed elucidation. In the present study, we used the next-generation sequencing to assess associations of germline variants in the coding and regulatory sequences of all human CYP genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 22 prioritized variants associating with a response or survival in the above evaluation phase were then analyzed by allelic discrimination in the large confirmation set (n = 802). Associations of variants in CYP1B1, CYP4F12, CYP4X1, and TBXAS1 with the response to the neoadjuvant cytotoxic chemotherapy were replicated by the confirmation phase. However, just association of variant rs17102977 in CYP4X1 passed the correction for multiple testing and can be considered clinically and statistically validated. Replicated associations for variants in CYP4X1, CYP24A1, and CYP26B1 with disease-free survival of all patients or patients stratified to subgroups according to therapy type have not passed a false discovery rate test. Although statistically not confirmed by the present study, the role of CYP genes in breast cancer prognosis should not be ruled out. In conclusion, the present study brings replicated association of variant rs17102977 in CYP4X1 with the response of patients to the neoadjuvant cytotoxic chemotherapy and warrants further research of genetic variation CYPs in breast cancer.


Asunto(s)
Neoplasias de la Mama , Sistema Enzimático del Citocromo P-450 , Variación Genética , Terapia Neoadyuvante , Proteínas de Neoplasias , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tasa de Supervivencia
2.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802562

RESUMEN

VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 × 10-4); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.


Asunto(s)
Metilación de ADN/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Islas de CpG/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sitios de Carácter Cuantitativo/genética
3.
Gene ; 786: 145616, 2021 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-33811963

RESUMEN

Breast cancer acts as an assassin among women. According to WHO (world health organisation), about 6, 27,000 deaths have occurred in 2018 due to breast cancer. Since, the evolution of cancer involves many complicated pathway, in this article we have decided to focus on wild type p53. P53 is also called as tumor suppressor gene. As the name suggest, p53 is a real guardian of genome, if it is not mutated or subjected to degradation. It can perform a wide range of activities during cancer progression. It either stimulates or inhibits the genes or proteins that are responsible for cell cycle arrest, apoptosis, anti-angiogenic activity and anti-metastatic activity. At times, the p53 will be unable to produce its action due to various reasons like mutation or degradation by other proteins or degrading ligases. Since, we are focusing on wild type p53, it will be inhibited occasionally by mdm2 resulting in proteosomal degradation of p53. However, this condition can be prevented by possible treatment regimen. With the above points in mind, we have focused on p53 activation, complex formation between p53 and mdm2, and inhibition of the complex in order to free p53 and allow them to perform their action for rehabilitation of cancer. Furthermore, we have also discussed pathways involved in eradicating cancer through p53 activation. By considering the following aspects, hope that p53 can be considered for management of breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Mama/genética , Progresión de la Enfermedad , Femenino , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteína p53 Supresora de Tumor/genética
4.
Medicine (Baltimore) ; 100(14): e25344, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832110

RESUMEN

ABSTRACT: Excision repair cross complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), ß-tubulin III (TUBB3), thymidylate synthetase (TYMS), and topoisomerase IIα (TOP2A) genes have been shown to be associated with the pathogenesis and prognosis of various types of carcinomas; however, their roles in breast cancer have not been fully validated. In this study, we evaluated the correlations among these biomarkers and the associations between their expression intensity and the clinicopathological characteristics to investigate whether the above genes are underlying biomarkers for patients with breast cancer.Ninety-seven tissue specimens collected from breast cancer patients. The expression levels of these biomarkers were measured by the multiplex branched DNA liquidchip (MBL) technology and clinicopathological characteristics were collected simultaneously.The expression levels of ERCC1, TUBB3, TYMS, and TOP2A were significantly associated with the characteristics of menopausal status, tumor size, lymph node metastasis, hormone receptor status, triple-negative status, Ki-67 index, and epidermal growth factor receptor. The expression intensity of ERCC1 negatively associated with that of TUBB3 and TYMS, and positively associated with that of RRM1. The expression intensity of TOP2A positively associated with that of TYMS. Hierarchical clustering analysis and difference test indicated that breast cancer with higher levels of TUBB3, TYMS, and TOP2A, as well as lower levels of ERCC1 and RRM1 tended to have higher histological grade and Ki-67 index.Our studies showed that ERCC1, TYMS, TUBB3, and TOP2A may be potential biomarkers for prognosis and individualized chemotherapy guidance, while there may be interactions between ERCC1 and RRM1, or TUBB3, or TYMS, as well as between TOP2A and TYMS in pathogenesis and development of breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adulto , Anciano , Biomarcadores de Tumor , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Receptores ErbB/biosíntesis , Femenino , Expresión Génica , Humanos , Antígeno Ki-67/biosíntesis , Metástasis Linfática/patología , Menopausia/fisiología , Persona de Mediana Edad , Ribonucleótido Reductasas/genética , Timidilato Sintasa/genética , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral
5.
Arkh Patol ; 83(3): 46-51, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33822554

RESUMEN

Triple negative breast cancer (BC) is a heterogeneous group of carcinomas that substantially differ in clinical, morphological, and molecular genetic characteristics, tumor response to chemotherapy, and prognosis. These features define triple negative BC today as a special clinical problem that has not yet been completely solved. The review is devoted to the description and systematization of the currently available literature data concerning molecular and genetic features and differences in a fairly significant group of breast carcinomas with a severe, aggressive course and an extremely poor prognosis. The review presents the existing molecular genetic classification of triple negative BC based on the results of studies conducted by M.D. Burstein (2015) and B.D. Lehmann (2016), which determines the presence of 4 tumor-specific subtypes: basal-like type (type 1 and type 2), mesenchymal, and luminal androgen receptor types. The paper reflects the main stages of transformation of the proposed classification over the past decade and an attempt has been make to describe the molecular characteristics of each subtype of these carcinomas.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Humanos , Biología Molecular , Pronóstico , Receptor ErbB-2/genética , Neoplasias de la Mama Triple Negativas/genética
6.
Nat Commun ; 12(1): 2357, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33883548

RESUMEN

Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Ácidos Nucleicos Libres de Células/genética , Neoplasias Pulmonares/genética , Transcriptoma , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Ácidos Nucleicos Libres de Células/sangre , Estudios de Cohortes , Bases de Datos de Ácidos Nucleicos , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/sangre , Anotación de Secuencia Molecular , Especificidad de Órganos/genética , ARN Mensajero/sangre , ARN Mensajero/genética
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(3): 263-271, 2021 Mar 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-33927073

RESUMEN

OBJECTIVES: Clarifying the expression of breast cancer receptor is the key to clinical treatment for breast cancer. This study aims to explore the correlation between X-ray and clinical characteristics of 4 molecular subtypes and their receptor types of breast cancer. METHODS: A total of 439 breast cancer patients who confirmed by pathology and performed X-ray examination were enrolled. The X-ray and clinical characteristics of 4 molecular subtypes and the expression of their receptors were analyzed. RESULTS: Luminal A type showed the highest proportion of spiculate masses, and the lowest calcification score, showing significant difference with other 3 subtypes (all P<0.001). The age in the human epidermal growth factor 2 (HER2) overexpression type group was older, the proportions of menopause, the calcification score, and the calcification score with 9-12 were higher, the sizes of the tumor were greater in the HER2 overexpression type group than those in the other 3 molecular subtype groups (age P<0.05, the rest P<0.01). The proportions of regular shape, edge indistinct, and high-grade invasive ductal carcinoma in the triple-negative type group were higher than those in the other 3 molecular subtype groups (all P<0.001). The proportions of non-menopausal patients and spiculate tumors in the estrogen receptor (ER) positive and/or progesterone receptor (PR) positive groups were higher than those in both ER and PR negative group (P<0.001 and P=0.001, respectively). The proportions of calcification fraction and high-grade invasive ductal carcinoma were higher, tumor sizes were greater in the HER2 positive group, Ki-67≥20% group than those in the HER2 negative group, Ki-67<20% group, respectively (P<0.001 or P<0.05, respectively). CONCLUSIONS: Four molecular subtypes of breast cancer and their receptor expressions are correlated with X-ray and clinical characteristics, which can provide a basis for clinical diagnosis and treatment.


Asunto(s)
Neoplasias de la Mama , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Femenino , Humanos , Receptor ErbB-2/genética , Receptores Estrogénicos , Receptores de Progesterona , Rayos X
8.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33807045

RESUMEN

Breast cancer is very heterogenous and the most common gynaecological cancer, with various factors affecting its development. While its impact on human lives and national health budgets is still rising in almost all global areas, many molecular mechanisms affecting its onset and development remain unclear. Conventional treatments still prove inadequate in some aspects, and appropriate molecular therapeutic targets are required for improved outcomes. Recent scientific interest has therefore focused on the non-coding RNAs roles in tumour development and their potential as therapeutic targets. These RNAs comprise the majority of the human transcript and their broad action mechanisms range from gene silencing to chromatin remodelling. Many non-coding RNAs also have altered expression in breast cancer cell lines and tissues, and this is often connected with increased proliferation, a degraded extracellular environment, and higher endothelial to mesenchymal transition. Herein, we summarise the known abnormalities in the function and expression of long non-coding RNAs, Piwi interacting RNAs, small nucleolar RNAs and small nuclear RNAs in breast cancer, and how these abnormalities affect the development of this deadly disease. Finally, the use of RNA interference to suppress breast cancer growth is summarised.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , ARN no Traducido/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Biopsia Líquida/métodos , Interferencia de ARN , ARN no Traducido/química
9.
Lancet Oncol ; 22(4): 489-498, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794206

RESUMEN

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/genética , Tiazoles/administración & dosificación , Adolescente , Adulto , Anciano , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Antagonistas del Receptor de Estrógeno/administración & dosificación , Femenino , Fulvestrant/administración & dosificación , Humanos , Persona de Mediana Edad , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Receptores Estrogénicos/genética , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/genética
10.
Nat Commun ; 12(1): 2186, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846305

RESUMEN

To gain mechanistic insights into the functions and developmental dynamics of tumor-infiltrated immune cells, especially B-lymphocytes, here we combine single-cell RNA-sequencing and antigen receptor lineage analysis to characterize a large number of triple-negative breast cancer infiltrated immune cells and report a comprehensive atlas of tumor-infiltrated B-lymphocytes. The single-cell transcriptional profiles reveal significant heterogeneity in tumor-infiltrated B-cell subgroups. The single-cell antigen receptor analyses demonstrate that compared with those in peripheral blood, tumor-infiltrated B-cells have more mature and memory B-cell characteristics, higher clonality, more class switching recombination and somatic hypermutations. Combined analyses suggest local differentiation of infiltrated memory B-cells within breast tumors. The B-cell signatures based on the single-cell RNA-sequencing results are significantly associated with improved survival in breast tumor patients. Functional analyses of tumor-infiltrated B-cell populations suggest that mechanistically, B-cell subgroups may contribute to immunosurveillance through various pathways. Further dissection of tumor-infiltrated B-cell populations will provide valuable clues for tumor immunotherapy.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Perfilación de la Expresión Génica , Linfocitos Infiltrantes de Tumor/inmunología , Receptores de Antígenos/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Anciano , Neoplasias de la Mama/sangre , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Estimación de Kaplan-Meier , Persona de Mediana Edad , Transcriptoma/genética
11.
Nat Commun ; 12(1): 2198, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33850160

RESUMEN

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Their identification is of paramount importance. Reduced expression of EFA6B (Exchange Factor for ARF6, B) is associated with breast cancer of poor prognosis. Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Animales , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Ratones , Ratones Desnudos , Transcriptoma , Proteína de Unión al GTP cdc42
12.
BMC Bioinformatics ; 22(1): 219, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33910505

RESUMEN

BACKGROUND: Identifying miRNA and disease associations helps us understand disease mechanisms of action from the molecular level. However, it is usually blind, time-consuming, and small-scale based on biological experiments. Hence, developing computational methods to predict unknown miRNA and disease associations is becoming increasingly important. RESULTS: In this work, we develop a computational framework called SMALF to predict unknown miRNA-disease associations. SMALF first utilizes a stacked autoencoder to learn miRNA latent feature and disease latent feature from the original miRNA-disease association matrix. Then, SMALF obtains the feature vector of representing miRNA-disease by integrating miRNA functional similarity, miRNA latent feature, disease semantic similarity, and disease latent feature. Finally, XGBoost is utilized to predict unknown miRNA-disease associations. We implement cross-validation experiments. Compared with other state-of-the-art methods, SAMLF achieved the best AUC value. We also construct three case studies, including hepatocellular carcinoma, colon cancer, and breast cancer. The results show that 10, 10, and 9 out of the top ten predicted miRNAs are verified in MNDR v3.0 or miRCancer, respectively. CONCLUSION: The comprehensive experimental results demonstrate that SMALF is effective in identifying unknown miRNA-disease associations.


Asunto(s)
Neoplasias de la Mama , MicroARNs , Algoritmos , Neoplasias de la Mama/genética , Biología Computacional , Humanos , MicroARNs/genética
13.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804289

RESUMEN

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.


Asunto(s)
Amilorida/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Intercambiador 1 de Sodio-Hidrógeno/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Amilorida/síntesis química , Amilorida/química , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Diuréticos/síntesis química , Diuréticos/química , Diuréticos/farmacología , Femenino , Humanos , Modelos Moleculares , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Relación Estructura-Actividad , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores
14.
Nat Commun ; 12(1): 1998, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790302

RESUMEN

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.


Asunto(s)
Benzamidas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Xenoinjertos/efectos de los fármacos , Morfolinas/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Xenoinjertos/metabolismo , Humanos , Células MCF-7 , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento
15.
Medicine (Baltimore) ; 100(16): e25414, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879671

RESUMEN

ABSTRACT: Single-cell RNA-seq has become a powerful tool to understand tumor cell heterogenicity. This study tried to screen prognosis-related genes in basal-like breast tumors and evaluate their correlations with cellular states at the single-cell level.Bulk RNA-seq data of basal-like tumor cases from The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) and single-cell RNA-seq from GSE75688 were retrospectively reviewed. Kaplan-Meier survival curves, univariate and multivariate analysis based on Cox regression model were conducted for survival analysis. Gene set enrichment analysis (GSEA) and single-cell cellular functional state analysis were performed.Twenty thousand five hundred thirty genes with bulk RNA-seq data in TCGA were subjected to screening. Preliminary screening identified 10 candidate progression-related genes, including CDH19, AQP5, SDR16C5, NCAN, TTYH1, XAGE2, RIMS2, GZMB, LY6D, and FAM3B. By checking their profiles using single-cell RNA-seq data, only CDH19, SDR16C5, TTYH1, and RIMS2 had expression in primary triple-negative breast cancer (TNBC) cells. Prognostic analysis only confirmed that RIMS2 expression was an independent prognostic indicator of favorable progression free survival (PFS) (HR: 0.78, 95%: 0.64-0.95, P  = .015). GSEA analysis showed that low RIMS2 group expression had genes significantly enriched in DNA Repair, and MYC Targets V2. Among the 89 basal-like cells, RIMS2 expression was negatively correlated with DNA repair and epithelial-to-mesenchymal transition (EMT).RIMS2 expression was negatively associated with DNA repair capability of basal-like breast tumor cells and might serve as an independent indicator of favorable PFS.


Asunto(s)
Neoplasias de la Mama/genética , Proteínas de la Membrana/genética , Neoplasias Basocelulares/genética , RNA-Seq , Proteínas de Unión al GTP rab3/genética , Adulto , Biomarcadores de Tumor/genética , Simulación por Computador , Reparación del ADN/genética , Bases de Datos Genéticas , Detección Precoz del Cáncer/métodos , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/genética
16.
BMC Bioinformatics ; 22(1): 174, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33794760

RESUMEN

BACKGROUND: Supervised learning from high-throughput sequencing data presents many challenges. For one, the curse of dimensionality often leads to overfitting as well as issues with scalability. This can bring about inaccurate models or those that require extensive compute time and resources. Additionally, variant calls may not be the optimal encoding for a given learning task, which also contributes to poor predictive capabilities. To address these issues, we present HARVESTMAN, a method that takes advantage of hierarchical relationships among the possible biological interpretations and representations of genomic variants to perform automatic feature learning, feature selection, and model building. RESULTS: We demonstrate that HARVESTMAN scales to thousands of genomes comprising more than 84 million variants by processing phase 3 data from the 1000 Genomes Project, one of the largest publicly available collection of whole genome sequences. Using breast cancer data from The Cancer Genome Atlas, we show that HARVESTMAN selects a rich combination of representations that are adapted to the learning task, and performs better than a binary representation of SNPs alone. We compare HARVESTMAN to existing feature selection methods and demonstrate that our method is more parsimonious-it selects smaller and less redundant feature subsets while maintaining accuracy of the resulting classifier. CONCLUSION: HARVESTMAN is a hierarchical feature selection approach for supervised model building from variant call data. By building a knowledge graph over genomic variants and solving an integer linear program , HARVESTMAN automatically and optimally finds the right encoding for genomic variants. Compared to other hierarchical feature selection methods, HARVESTMAN is faster and selects features more parsimoniously.


Asunto(s)
Neoplasias de la Mama , Aprendizaje Profundo , Secuenciación Completa del Genoma , Neoplasias de la Mama/genética , Genoma , Genómica , Humanos
17.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809315

RESUMEN

Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for these patients. Bone is among the most frequent sites of metastasis in breast cancer. Once in the bone, disseminated tumor cells can acquire a dormant state and remain quiescent until they resume growth, resulting in overt metastasis. At this stage the disease is characterized by excessive, osteoclast-mediated osteolysis. Cells of the bone microenvironment including osteoclasts, osteoblasts and endothelial cells contribute to the initiation and progression of breast cancer bone metastasis. Direct cell-to-cell contact as well as soluble factors regulate the crosstalk between disseminated breast cancer cells and bone cells. In this complex signaling network interleukins (ILs) have been identified as key regulators since both, cancer cells and bone cells secrete ILs and express corresponding receptors. ILs regulate differentiation and function of bone cells, with several ILs being reported to act pro-osteoclastogenic. Consistently, the expression level of ILs (e.g., in serum) has been associated with poor prognosis in breast cancer. In this review we discuss the role of the most extensively investigated ILs during the establishment of breast cancer bone metastasis and highlight their potential as therapeutic targets in preventing metastatic outgrowth in bone.


Asunto(s)
Neoplasias Óseas/genética , Neoplasias de la Mama/genética , Comunicación Celular/genética , Interleucinas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Huesos/metabolismo , Huesos/patología , Neoplasias de la Mama/patología , Linaje de la Célula/genética , Femenino , Humanos , Metástasis de la Neoplasia
18.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810274

RESUMEN

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Carbazoles/farmacología , Mutágenos/farmacología , Antineoplásicos/química , Neoplasias de la Mama/genética , Carbazoles/química , Daño del ADN , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/metabolismo , Humanos , Células MCF-7 , Mutágenos/química , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo
19.
Pan Afr Med J ; 38: 43, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854672

RESUMEN

Introduction: recent studies show a good relationship between breast cancer (BC) and human papillomaviruses (HPV) wich is responsible for about 18% of BC cases. This study aimed to assess the relationship between different genotypes of HPV and the expression of P53 and retinoblastoma (RB) genes and estrogen and progesterone receptors in BC among Sudanese women. Methods: one hundred and fifty tissue blocks were obtained from females diagnosed with BC. Positive samples were used to determine genotypes with an applied biosystem (ABI 3730XL) genetic analyzer for sequencing and immunohistochemistry. Results: 13/150 samples showed HPV DNA. High-risk HPV-16 was detected in 5 cases, high-risk-HPV-58 was found in four cases, and HPV-18 was detected in three cases. Low-risk-HPV-11 was detected in a single invasive lobular carcinoma (ILC) case. P53 and RB gene mutations were detected in 35 and 30 BC cases, respectively. P53 gene mutation was frequently identified in grade (III) BC while RB gene mutation was positive in grade (II). Grade (II) BC had a higher incidence of HPV-16 and 58. On the other hand, HPV-18 had a higher incidence in grade (III). Estrogen and progesterone receptors were expressed in 94 and 79 HPV cases among the study group, respectively. Conclusion: this study elucidates the associations between HPV genotypes and BC. A statistically significant association was observed among p53 and RB gene mutations and different BC histological types. On the other hand, there was a statistically insignificant association between HPV genotyping and different BC gradings, BC histological types, P53 and RB genes mutations, and estrogen and progesterone receptor expression. Also, there was a statistically insignificant association among estrogen and progesterone receptors expression and BC grading. RB gene mutation was significantly associated with different BC grades. On the other hand, there was a statistically insignificant association between progesterone receptor expression and BC.


Asunto(s)
Alphapapillomavirus/aislamiento & purificación , Neoplasias de la Mama/patología , Infecciones por Papillomavirus/epidemiología , Alphapapillomavirus/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/virología , Estudios Transversales , ADN Viral , Femenino , Regulación Neoplásica de la Expresión Génica , Genes de Retinoblastoma/genética , Genotipo , Humanos , Mutación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Receptores Estrogénicos/genética , Receptores de Progesterona/genética , Sudán , Proteína p53 Supresora de Tumor/genética
20.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806327

RESUMEN

Personalised medicine is the future and hope for many patients, including those with cancers. Early detection, as well as rapid, well-selected treatment, are key factors leading to a good prognosis. MicroRNA mediated gene regulation is a promising area of development for new diagnostic and therapeutic methods, crucial for better prospects for patients. Bladder cancer is a frequent neoplasm, with high lethality and lacking modern, advanced therapeutic modalities, such as immunotherapy. MicroRNAs are involved in bladder cancer pathogenesis, proliferation, control and response to treatment, which we summarise in this perspective in response to lack of recent review publications in this field. We further performed a correlation-based analysis of microRNA and gene expression data in bladder cancer (BLCA) TCGA dataset. We identified 27 microRNAs hits with opposite expression profiles to genes involved in immune response in bladder cancer, and 24 microRNAs hits with similar expression profiles. We discuss previous studies linking the functions of these microRNAs to bladder cancer and assess if they are good candidates for personalised medicine therapeutics and diagnostics. The discussed functions include regulation of gene expression, interplay with transcription factors, response to treatment, apoptosis, cell proliferation and angiogenesis, initiation and development of cancer, genome instability and tumour-associated inflammatory reaction.


Asunto(s)
/genética , MicroARNs/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Sinapsis Inmunológicas/genética , Modelos Genéticos , ARN Mensajero/genética , ARN Neoplásico/genética
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