RESUMEN
Cancer cells have the ability to undergo an unlimited number of cell divisions, which gives them immortality. Thus, the cancer cell can extend the length of its telomeres, allowing these cells to divide unlimitedly and avoid entering the state of senescence or cellular apoptosis. One of the main effects of photobiomodulation (PBM) is the increase in the production of adenosine triphosphate (ATP) and free radicals, mainly reactive oxygen species (ROS). Existent data indicates that high levels of ROS can cause shortening and dysfunctional telomeres. Therefore, a better understanding of the effects induced by PBM on cancer cell telomere maintenance is needed. This work aimed to evaluate the effects of low-power red laser (658 nm) and blue LED (470 nm) on the TRF1 and TRF2 mRNA levels and telomere length in human breast cancer cells. MCF-7 and MDA-MB-231 cells were irradiated with a low-power red laser (69 J cm-2, 0.77 W/cm-2) and blue LED (482 J cm-2, 5.35 W/cm-2), alone or in combination, and the relative mRNA levels of the genes and telomere length were assessed by quantitative reverse transcription polymerase chain reaction. The results suggested that exposure to certain red laser and blue LED fluences decreased the TRF1 and TRF2 mRNA levels in both human breast cancer cells. Telomere length was increased in MCF-7 cells after exposure to red laser and blue LED. However, telomere length in MDA-MB-231 was shortened after exposure to red laser and blue LED at fluences evaluated. Our research suggests that photobiomodulation induced by red laser and low-power blue LED could alter telomere maintenance and length.
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Neoplasias de la Mama , Terapia por Luz de Baja Intensidad , Telómero , Proteína 1 de Unión a Repeticiones Teloméricas , Proteína 2 de Unión a Repeticiones Teloméricas , Humanos , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Telómero/efectos de la radiación , Terapia por Luz de Baja Intensidad/métodos , Proteína 1 de Unión a Repeticiones Teloméricas/metabolismo , Proteína 1 de Unión a Repeticiones Teloméricas/genética , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Células MCF-7 , Homeostasis del Telómero/efectos de la radiación , Complejo Shelterina , Proteínas de Unión a TelómerosRESUMEN
Pesticide exposure is a risk factor for the development of several diseases, including breast cancer (BC). The enzyme UGT2B7 participate in detoxification of pesticides and the presence rs7438135 (G > A) variant in your gene increases its glucuronidation potential, contributing to oxidative stress metabolites neutralization. Here we investigated the impact of occupational pesticide exposure on the systemic oxidative stress generation from 228 women with BC depending on their UGT2B7 rs7438135 (G > A) status. q-PCR investigated the presence of the rs7438135 variant, and oxidative stress markers (lipid peroxidation levels, total antioxidant capacity-TRAP, and nitric oxide metabolites-NOx) were measured in plasma. Pesticide exposure induced significant augment in the systemic lipid peroxidation in the presence of the variant for several clinicopathological conditions, including tumors with high proliferation index (ki67) and with high aggressiveness. NOx was augmented in high ki67, positive progesterone receptors, high-grade and triple-negative/Luminal B tumors, and low-risk stratified patients. TRAP was depleted in young patients at menopause and those with triple-negative/Luminal B tumors, as well as those stratified as at low risk for death and recurrence. These findings showed that the presence of the variant was not able to protect from pesticide-induced oxidative stress generation in BC patients.
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Neoplasias de la Mama , Glucuronosiltransferasa , Estrés Oxidativo , Plaguicidas , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estrés Oxidativo/efectos de los fármacos , Plaguicidas/toxicidad , Persona de Mediana Edad , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Adulto , Pronóstico , Exposición Profesional/efectos adversos , Anciano , Alelos , Peroxidación de Lípido/efectos de los fármacos , Polimorfismo de Nucleótido SimpleRESUMEN
In this study, we identified miRNAs and their potential mRNA targets that are intricately linked to primary chemotherapy response in patients with invasive ductal carcinomas. A cohort of individuals diagnosed with advanced invasive breast ductal carcinoma who underwent primary chemotherapy served as the cornerstone of our study. We conducted a comparative analysis of microRNA expression among patients who either responded or did not respond to primary systemic therapy. To analyze the correlation between the expression of the whole transcriptome and the 24 differentially expressed (DE) miRNAs, we harnessed the extensive repository of The Cancer Genome Atlas (TCGA) database. We mapped molecular mechanisms associated with these miRNAs and their targets from TCGA breast carcinomas. The resultant expression profile of the 24 DE miRNAs emerged as a potent and promising predictive model, offering insights into the intricate dynamics of chemotherapy responsiveness of advanced breast tumors. The discriminative analysis based on the principal component analysis identified the most representative miRNAs across breast cancer samples (miR-210, miR-197, miR-328, miR-519a, and miR-628). Moreover, the consensus clustering generated four possible clusters of TCGA patients. Further studies should be conducted to advance these findings.
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Biomarcadores de Tumor , Neoplasias de la Mama , Carcinoma Ductal de Mama , MicroARNs , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , MicroARNs/análisis , Biomarcadores de Tumor/análisis , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Persona de Mediana Edad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Adulto , Anciano , TranscriptomaRESUMEN
Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.
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Proteínas de Unión al ADN , Edición Génica , Neoplasias Ováricas , Humanos , Femenino , Edición Génica/métodos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Neoplasias Ováricas/genética , Neoplasias de la Mama/genética , Alelos , Sistemas CRISPR-Cas/genéticaRESUMEN
BACKGROUND: The molecular system of receptor activator of nuclear factor kappa-ß (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment. METHODS AND RESULTS: We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs. CONCLUSIONS: These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.
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Biomarcadores de Tumor , Neoplasias de la Mama , Fibroblastos Asociados al Cáncer , Estadificación de Neoplasias , Receptor Activador del Factor Nuclear kappa-B , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/genética , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Pronóstico , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Metástasis de la Neoplasia , Persona de Mediana Edad , Microambiente Tumoral , Ligando RANK/metabolismo , Ligando RANK/genética , Adulto , Anciano , Línea Celular TumoralRESUMEN
Receptor tyrosine kinases (RTKs) are involved in cell growth, motility, and differentiation. Deregulation of RTKs signaling is associated with tumor development and therapy resistance. Potential RTKs like TAM (TYRO3, AXL, MERTK), RON, EPH, and MET have been evaluated in many cancers like lung, prostate, and colorectal, but little is known in breast tumors. In this study, 51 luminal breast cancer tissue and 8 triple negative breast cancer (TNBC) subtypes were evaluated by qPCR for the expression of TAM, RON, EPHA2, and MET genes. Statistical analysis was performed to determine the correlation to clinical data. TYRO3 is related to tumor subtype and stage, patient's age, smoking habits, and obesity. MET expression is correlated to EPHA2 and TAM gene expression. EPHA2 expression is also related to aging and smoking habits. The expression levels of the TAM and EPHA2 genes seem to play an important role in breast cancer, being also influenced by the patient's lifestyle.
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Neoplasias de la Mama , Proteínas Tirosina Quinasas Receptoras , Receptor EphA2 , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Efrina-A2/metabolismo , Efrina-A2/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptor EphA2/metabolismo , Receptor EphA2/genéticaRESUMEN
Chromosomal instability (CIN), characterized by fluctuations in chromosome number or structure within cells, stands out as a hallmark of cancer, enabling tumors to thrive in hostile conditions. CIN serves as a driver of genetic diversity, giving rise to clonal heterogeneity (CH). Emerging evidence points to a potential correlation between CIN, CH, and the prognosis of breast cancer (BC) patients, especially in tumors exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2+). However, our understanding of the role of CIN in other subtypes of BC is limited. Furthermore, it remains unclear whether CIN levels above a certain threshold in BC tumors could adversely affect tumor growth, or if lower to moderate levels of CIN might be associated with a more favorable prognosis for BC patients compared to elevated levels. Elucidating these relationships could significantly influence risk assessment and the formulation of future therapeutic approaches targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples obtained from Colombian patients diagnosed with luminal A, luminal B, HER2+, or triple-negative BC, and compare them with established clinicopathological parameters. The findings of this study indicate that BC patients exhibit intermediate CIN, high CH, and stable aneuploidy. All these characteristics were found to be related to clinicopathological features. Our results suggest that the identification of CIN, CH, and aneuploidy could improve cancer risk stratification, which could help to clarify the prediction of clinical outcomes and guide personalized therapeutic strategies for patients with different BC subtypes.
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Neoplasias de la Mama , Inestabilidad Cromosómica , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Persona de Mediana Edad , Adulto , Anciano , Heterogeneidad Genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , PronósticoRESUMEN
Breast cancer (BC) is the leading cause of death from tumors in women worldwide, influenced by various factors, including genetics. The T allele of the single nucleotide variant (SNV) rs3025039 at position +936 of the VEGFA gene has been reported to affect the mRNA regulatory mechanisms, potentially altering VEGFA expression and increasing BC risk. This study aimed to investigate the association between rs3025039 and BC in Mexican women residing in Jalisco, Mexico. The study included 231 women with a confirmed diagnosis of BC and 201 healthy subjects as a reference group (RG). PCR-RFLP was employed for the genotyping of rs3025039, with the visualization of amplified products using polyacrylamide gel electrophoresis. Significant differences were observed in rs3025039 alleles and genotypes between BC cases and the RG (p = 0.0038). The frequency of the T allele and the CT genotype was higher in the BC group compared to the RG, with a significant difference (p = 0.0006). In conclusion, this research suggests that the SNV rs3025039 is associated with a higher risk of BC in Mexican women. These findings enhance our understanding of the genetic underpinnings of BC in this population, offering potential insights for future studies and interventions.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Genotipo , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular , Humanos , Femenino , Neoplasias de la Mama/genética , México/epidemiología , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Factores de Riesgo , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , AncianoRESUMEN
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a new subtype of tumor, for which novel antibody-drug conjugates have shown beneficial effects. Assessment of HER2 requires several immunohistochemistry tests with an additional in situ hybridization test if a case is classified as HER2 2+. Therefore, novel cost-effective methods to speed up the HER2 assessment are highly desirable. METHODS: We used a self-supervised attention-based weakly supervised method to predict HER2-low directly from 1437 histopathological images from 1351 breast cancer patients. We built six distinct models to explore the ability of classifiers to distinguish between the HER2-negative, HER2-low, and HER2-high classes in different scenarios. The attention-based model was used to comprehend the decision-making process aimed at relevant tissue regions. RESULTS: Our results indicate that the effectiveness of classification models hinges on the consistency and dependability of assay-based tests for HER2, as the outcomes from these tests are utilized as the baseline truth for training our models. Through the use of explainable AI, we reveal histologic patterns associated with the HER2 subtypes. CONCLUSION: Our findings offer a demonstration of how deep learning technologies can be applied to identify HER2 subgroup statuses, potentially enriching the toolkit available for clinical decision-making in oncology.
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Biomarcadores de Tumor , Neoplasias de la Mama , Aprendizaje Profundo , Inmunohistoquímica , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Femenino , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica/métodos , Aprendizaje Automático SupervisadoRESUMEN
Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10-3 pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan-Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804-6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.
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Biomarcadores de Tumor , Neoplasias de la Mama , Epóxido Hidrolasas , Humanos , Epóxido Hidrolasas/metabolismo , Epóxido Hidrolasas/genética , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/genética , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/metabolismo , Anciano , Adulto , Núcleo Celular/metabolismo , Regulación hacia Arriba , Regulación Neoplásica de la Expresión Génica , Curva ROC , Anciano de 80 o más Años , Estimación de Kaplan-MeierRESUMEN
Luminal breast cancer has a high incidence worldwide and poses a severe health threat. Estrogen receptor alpha (ER-α) is activated by 17ß-estradiol (E2), and its overexpression promotes cancerous characteristics. Luminal breast cancer is an epithelial type; however, the cytokine IL-6, secreted by cells within the tumor microenvironment, stimulates the epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Also, IL-6 decreases ER-α levels, favoring the tamoxifen (TMX) resistance development. However, genes under E2 regulation continue to be expressed even though this receptor is absent. GPR30 is an alternative E2 receptor present in both luminal and aggressive triple-negative breast cancer and is related to TMX resistance and cancer progression. The roles of GPR30 and IL-6 in metastasis have been individually established; however, their interplay remains unexplored. This study aims to elucidate the role of GPR30 in IL-6-induced metastatic properties of MCF-7 luminal breast cancer cells. Results showed that GPR30 contributes to the E2-induced MCF-7 proliferation because its inhibition with the antagonist G15 and the Pertussis toxin (PTX) reduced it. Besides, GPR30 upregulated vimentin and downregulated E-cadherin levels in MCF-7 and TMX-resistant (R-TMX) cells and is also involved in the IL-6-induced migration, invasion, and TMX resistance in MCF-7 cells. In addition, in MDA-MB-231 triple-negative cells, both basal and IL-6-induced metastatic properties were related to GPR30 activity. These results indicate that the GPR30 receptor regulates the EMT induced by IL-6 in breast cancer cells.
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Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Interleucina-6 , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Humanos , Interleucina-6/metabolismo , Interleucina-6/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Femenino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Células MCF-7 , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tamoxifeno/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
OBJECTIVES: To identify somatic mutations in tumors from young women with triple-negative or luminal breast cancer, through targeted sequencing and to explore the cancer driver potential of these gene variants. METHODS: A customized gene panel was assembled based on data from previous sequencing studies of breast cancer from young women. Triple-negative and luminal tumors and paired blood samples from young breast cancer patients were sequenced, and identified gene variants were searched for their driver potential, in databases and literature. Additionally, the authors performed an exploratory analysis using large, curated databases to evaluate the frequency of somatic mutations in this gene panel in tumors stratified by age groups (every 10 years). RESULTS: A total of 28 young women had their tumoral tissue and blood samples sequenced. Using a customized panel of 64 genes, the authors could detect cancer drivers in 11/12 (91.7 %) TNBC samples and 11/16 (68.7 %) luminal samples. Among TNBC patients, the most frequent cancer driver was TP53, followed by NF1, NOTCH1 and PTPN13. In luminal samples, PIK3CA and GATA3 were the main cancer drivers, and other drivers were GRHL2 and SMURF2. CACNA1E was involved in both TN and luminal BC. The exploratory analysis also indicated a role for SMURF2 in luminal BC development in young patients. CONCLUSIONS: The data further indicates that some cancer drivers are more common in a specific breast cancer subtype from young patients, such as TP53 in TNBC and PIK3CA and GATA3 in luminal samples. These results also provide additional evidence that some genes not considered classical cancer-causing genes, such as CACNA1E, GRHL2 and SMURF2 might be cancer drivers in this age group.
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Mutación , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama Triple Negativas/genética , Adulto , Neoplasias de la Mama/genética , Brasil , Adulto Joven , Persona de Mediana Edad , Factores de Edad , Biomarcadores de Tumor/genéticaRESUMEN
Small nucleolar RNAs (snoRNAs) have robust potential functions and therapeutic value in breast cancer. Herein, we investigated the role SNORA5A in breast cancer. Samples from The Cancer Genome Atlas (TCGA) were reviewed. The transcription matrix and clinical information were analyzed using R software and validated in clinical tissue samples. SNORA5A was significantly down-regulated in breast cancer, and high expression of SNORA5A correlated with a favorable prognosis. High expression of SNORA5A induced a high concentration of tumor-associated macrophages M1 and a low concentration of tumor-associated macrophages M2. Moreover, SNORA5A were clustered in terms related to cancer and immune functions. Possible downstream molecules of SNORA5A were identified, among which TRAF3IP3 was positively correlated with M1 and negatively correlated with M2. The function of TRAF3IP3 in tumor inhibition and its relationship with macrophages in clinical tissue samples were in accordance with bioinformatics analysis results. SNORA5A could regulate macrophage phenotypes through TRAF3IP3 and serves as a potential prognostic marker for breast cancer patients.
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Neoplasias de la Mama , Fenotipo , Macrófagos Asociados a Tumores , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: In this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. METHODS: Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. RESULTS: Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. CONCLUSION: BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.
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Proteína BRCA2 , Neoplasias de la Mama , Quinasa de Punto de Control 2 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteína BRCA2/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Brasil , Persona de Mediana Edad , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Predisposición Genética a la EnfermedadRESUMEN
Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches.
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Neoplasias de la Mama , Receptor alfa de Estrógeno , Estrógenos , Inflamación , Radiación Ionizante , Femenino , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Estrógenos/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Inflamación/metabolismo , Humanos , Ratones , Regulación Neoplásica de la Expresión Génica , Microambiente TumoralRESUMEN
lncRNAs are noncoding transcripts with tissue and cancer specificity. Particularly, in breast cancer, lncRNAs exhibit subtype-specific expression; they are particularly upregulated in luminal tumors. However, no gene signature-based laboratory tests have been developed for luminal breast cancer identification or the differential diagnosis of luminal tumors, since no luminal A- or B-specific genes have been identified. Particularly, luminal B patients are of clinical interest, since they have the most variable response to neoadjuvant treatment; thus, it is necessary to develop diagnostic and predictive biomarkers for these patients to optimize treatment decision-making and improve treatment quality. In this study, we analyzed the lncRNA expression profiles of breast cancer cell lines and patient tumor samples from RNA-Seq data to identify an lncRNA signature specific for luminal phenotypes. We identified an lncRNA signature consisting of LINC01016, GATA3-AS1, MAPT-IT1, and DSCAM-AS1 that exhibits luminal subtype-specific expression; among these lncRNAs, GATA3-AS1 is associated with the presence of residual disease (Wilcoxon test, p < 0.05), which is related to neoadjuvant chemotherapy resistance in luminal B breast cancer patients. Furthermore, analysis of GATA3-AS1 expression using RNA in situ hybridization (RNA ISH) demonstrated that this lncRNA is detectable in histological slides. Similar to estrogen receptors and Ki67, both commonly detected biomarkers, GATA3-AS1 proves to be a suitable predictive biomarker for clinical application in breast cancer laboratory tests.
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Biomarcadores de Tumor , Neoplasias de la Mama , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Terapia Neoadyuvante , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Resistencia a Antineoplásicos/genética , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Perfilación de la Expresión Génica , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , TranscriptomaRESUMEN
The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.
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Neoplasias de la Mama , Estadificación de Neoplasias , Proteómica , Humanos , Femenino , Proteómica/métodos , Persona de Mediana Edad , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adulto , Anciano , Lipoproteínas HDL/sangre , Lipoproteínas HDL/metabolismo , Anciano de 80 o más Años , Proteoma/metabolismo , Adolescente , Adulto JovenRESUMEN
Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment.
Asunto(s)
Neoplasias de la Mama , Proteína 1 Similar a ELAV , Glutaminasa , Glutaminasa/metabolismo , Glutaminasa/genética , Glutaminasa/antagonistas & inhibidores , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/genética , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , ARN Mensajero/metabolismo , ARN Mensajero/genética , Regulación Neoplásica de la Expresión Génica , Empalme Alternativo , Proliferación Celular , Glutamina/metabolismo , Estabilidad del ARNRESUMEN
Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A>I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A>I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A>I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A>I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A>I(G) RNA-edited sites. We gathered databases related to A>I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A>I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A>I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients' A>I(G) RNA-editing profiles.