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AIMS: To identify the multiple mediating effects of resilience and depression between social support and self-care ability among patients with breast cancer during rehabilitation to provide reference for developing and implementing targeted interventions. DESIGN: A cross-sectional study reported according to the STROBE checklist. METHODS: A convenience sample of 320 patients with breast cancer during rehabilitation was recruited from one hospital in China. Data were collected from April to August 2022 using a self-report questionnaire, including the demographic and clinical information, Appraisal of Self-Care Agency Scale-Revised, Multidimensional Scale of Perceived Social Support, Connor-Davidson Resilience Scale-10 item, and Patient Health Questionnaire-9. The mediation analysis was conducted using the SPSS Process macro. RESULTS: Self-care ability was positively associated with social support (ß = .229) and resilience (ß = .290), and negatively associated with depression (ß = -.208). The relationship between social support and self-care ability was mediated by resilience and depression, respectively, and together in serial. The multiple mediating effects accounted for 34.0% of the total effect of social support on self-care ability. CONCLUSION: Our findings identify resilience and depression as multiple mediators between social support and self-care ability and highlight the important roles of social support, resilience and depression in improving self-care ability. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should pay great attention to the underlying mechanisms of how social support affects patients' self-care ability during breast cancer rehabilitation. Integrated intervention programmes targeted at enhancing social support, building resilience and alleviating depression might be beneficial to the improvement of self-care ability. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. REPORTING METHOD: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cross-sectional studies was applied to report the results.
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Background and Objectives. The prognostic role of adjacent nontumor tissue in patients with breast cancer (BC) is still unclear. The activity changes in immunologic and hallmark gene sets in normal tissues adjacent to BC may play a crucial role in predicting the prognosis of BC patients. The aim of this study was to identify BC subtypes and ribosome-associated prognostic genes based on activity changes of immunologic and hallmark gene sets in tumor and adjacent nontumor tissues to improve patient prognosis. Materials and Methods. Gene set variation analysis (GSVA) was applied to assess immunoreactivity changes in the overall sample and three immune-related BC subtypes were identified by non-negative matrix factorization (NMF). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses were after determining the prognostic gene set using the least absolute shrinkage and selection operator (LASSO) method. Ribosome-related genes were identified by PPI (protein-protein interaction) analysis, and finally a prognostic risk model was constructed based on the expression of five ribosomal genes (RPS18, RPL11, PRLP1, RPL27A, and RPL38). Results. A comprehensive analysis of immune and marker genomic activity changes in normal breast tissue and BC tissue identified three immune-related BC subtypes. BC subtype 1 has the best prognosis, and subtype 3 has the worst overall survival rate. We identified a prognostic gene set in nontumor tissue by the least absolute shrinkage and selection operator (LASSO) method. We found that the results of both KEGG and GO analyses were indistinguishable from those of ribosome-associated genes. Finally, we determined that genes associated with ribosomes exhibit potential as a reliable predictor of overall survival in breast cancer patients. Conclusions. Our research provides an important guidance for the treatment of BC. After a mastectomy, the changes in gene set activity of both BC tissues and the nontumor tissues adjacent to it should be thoroughly evaluated, with special attention to changes in ribosome-related genes in the nontumor tissues.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Pronóstico , Mastectomía , Ribosomas/genética , MamaRESUMEN
BACKGROUND AND PURPOSE: Limited information is available regarding the correlations between mammographic calcifications and the epidemiological features of patients with breast cancer living different lifestyles in Western China. Thus, this study aimed to investigate the relationship between mammographic calcifications and the epidemiological characteristics of female patients with breast cancer in Western China. METHODS: This was a hospital-based, retrospective, multi-center epidemiological study of patients with breast cancer. Using the Western China Clinical Cooperation Group (WCCCG) database, we obtained the records of 7317 patients (with mammographic data) diagnosed with breast cancer between March 2011 and June 2016. These patients were divided into Groups I (mass alone) and II (mass combined with calcification), and their clinical and pathological data were compared. RESULTS: A total of 4211 patients were enrolled in Group I, and 3106 patients were enrolled in Group II. The tumors in Group II were more likely to be larger (P < 0.0001), higher grade (P = 0.0029), estrogen receptor (ER)+/progesterone receptor (PR)- (P = 0.0319), and human epidermal growth factor receptor 2 (HER-2)-positive (P < 0.0001), and to have axillary lymph node metastasis (P = 0.0033) than those in Group I. Regarding treatment, patients in Group II were more likely to have undergone chemotherapy (P = 0.0108) and anti-HER2 therapy (P = 0.0102), whereas patients in Group I were more likely to have undergone endocrine therapy (P < 0.0001). CONCLUSIONS: In conclusion, mammographic calcifications in tumors were associated with distinct clinicopathologic characteristics and aggressive treatments.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Mamografía/métodos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , China , Femenino , Humanos , Estilo de Vida , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: A few retrospective studies have indicated that neoadjuvant chemotherapy (NAC) in breast cancer may change biomarker profiles of the primary tumor. Little is known about the status of HER-2 gene of the synchronous nodal metastases when that of the residual tumor undergoes negative conversion in a neoadjuvant setting. CASE PRESENTATION: We describe a female patient with left breast cancer (T2N2M0) who underwent negative conversion of HER-2 in the primary tumor instead of the synchronous nodal lesions after NAC. Core needle biopsy showed invasive ductal carcinoma with HER2 immunohistochemistry (IHC) (2+) and amplified HER-2 gene determined by fluorescence in situ hybridization (FISH). Then, the patient underwent 4 cycles of anthracycline- and taxane-based NAC and subsequent left modified radical mastectomy. Postoperative pathology showed invasive ductal carcinoma involving 4 of 12 surgically excised axillary lymph nodes with HER2 IHC (1+) and FISH negative (HER2 gene not amplified) in the residual tumor of the breast specimen. Due to the negative genic switch of HER2 after NAC, the patient rejected to accept trastuzumab. Under the patient's consent, the synchronous nodal lesions were further investigated and showed HER2 IHC(-) but FISH positive (HER-2 gene amplified). Therefore, the patient agreed to accept adjuvant trastuzumab treatment every 3 weeks for 1 year. CONCLUSIONS: We propose further assessment of HER2 gene in the synchronous nodal metastases, especially when negative genic switch of HER-2 occurs in the primary tumor after NAC in order to tailor the systemic regimens for breast cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Ganglios Linfáticos/patología , Terapia Neoadyuvante/métodos , Receptor ErbB-2/genética , Antineoplásicos Inmunológicos/uso terapéutico , Axila , Biopsia con Aguja Gruesa , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/terapia , Quimioradioterapia Adyuvante , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Ganglios Linfáticos/cirugía , Metástasis Linfática , Mastectomía , Persona de Mediana Edad , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéuticoRESUMEN
This study aimed to evaluate whether palliative surgery for metastatic lesion could provide a survival benefit in metastatic breast cancer (MBC) patients with solitary metastasis. De novo MBC patients with solitary distant lesions were enrolled utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to form matched pairs of the surgery group and the non-surgery group. The breast cancer-specific survival (BCSS) and overall survival (OS) outcomes between the 2 groups were compared in the following 3 sample models: the entire cohort of MBC (7665 cases); subgroups of patients with different isolated metastatic organs; and subgroups of patients with different molecular subtypes for each isolated metastatic organ. Compared with the Non-surgery group, the surgery group showed better BCSS and OS before PSM (HRâ =â 0.88, 95% CIâ =â 0.79-0.99, Pâ =â .04 and HRâ =â 0.85, 95% CIâ =â 0.76-0.95, Pâ =â .006, respectively). After PSM, palliative surgery still provided an OS benefit in patients with brain metastasis and lung metastasis (HRâ =â 0.59, 95% CIâ =â 0.37-0.95, Pâ =â .01 and HRâ =â 0.64, 95% CIâ =â 0.45-0.90, Pâ =â .02, respectively). Likewise, a better BCSS benefit was also found in the subset of patients with brain metastasis (HRâ =â 0.61, 95% CIâ =â 0.38-1.00, Pâ =â .01). Further stratification analysis indicated that patients with the luminal A subtype with brain metastasis have a better BCSS (HRâ =â 0.36, 95% CIâ =â 0.16-0.79, Pâ =â .04) and OS (HRâ =â 0.37, 95% CIâ =â 0.18-0.75, Pâ =â .03) after undergoing palliative surgery than nonsurgical treatment. Our study originality showed that palliative surgery for metastatic lesion could improve survival prognosis in patients with special single-organ metastasis and specific molecular subtypes. More clinical studies are needed to determine whether palliative surgery should be performed in MBC patients.
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Neoplasias de la Mama , Cuidados Paliativos , Puntaje de Propensión , Programa de VERF , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/mortalidad , Cuidados Paliativos/métodos , Persona de Mediana Edad , Anciano , Metástasis de la Neoplasia , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/mortalidad , Adulto , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estudios RetrospectivosRESUMEN
Background: Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. Methods: We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. Results: The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Conclusion: Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.
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Neoplasias Encefálicas , Glioma , Inmunoterapia , Humanos , Biomarcadores , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/inmunología , Glioma/terapia , Proteínas Activadoras de GTPasa/genética , Pronóstico , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Breast cancer (BC) ranks as the most prevalent malignancy affecting women globally, with apoptosis playing a pivotal role in its pathological progression. Despite the crucial role of apoptosis in BC development, there is limited research exploring the relationship between BC prognosis and apoptosis-related genes (ARGs). Therefore, this study aimed to establish a BC-specific risk model centered on apoptosis-related factors, presenting a novel approach for predicting prognosis and immune responses in BC patients. METHODS: Utilizing data from The Cancer Gene Atlas (TCGA), Cox regression analysis was employed to identify differentially prognostic ARGs and construct prognostic models. The accuracy and clinical relevance of the model, along with its efficacy in predicting immunotherapy outcomes, were evaluated using independent datasets, Receiver Operator Characteristic (ROC) curves, and nomogram. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were used to predict potential mechanical pathways. The CellMiner database is used to assess drug sensitivity of model genes. RESULTS: A survival risk model comprising eight prognostically relevant apoptotic genes (PMAIP1, TP53AIP1, TUBA3D, TUBA1C, BCL2A1, EMP1, GSN, F2) was established based on BC patient samples from TCGA. Calibration curves validated the ROC curve and nomogram, demonstrating excellent accuracy and clinical utility. In samples from the Gene Expression Omnibus (GEO) datasets and immunotherapy groups, the low-risk group (LRG) demonstrated enhanced immune cell infiltration and improved immunotherapy responses. Model genes also displayed positive associations with sensitivity to multiple drugs, including vemurafenib, dabrafenib, PD-98059, and palbociclib. CONCLUSIONS: This study successfully developed and validated a prognostic model based on ARGs, offering new insights into prognosis and immune response prediction in BC patients. These findings hold promise as valuable references for future research endeavors in this field.
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Apoptosis , Neoplasias de la Mama , Nomogramas , Medicina de Precisión , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Femenino , Apoptosis/genética , Pronóstico , Medicina de Precisión/métodos , Genómica/métodos , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Bases de Datos Genéticas , Curva ROC , Medición de Riesgo/métodosRESUMEN
Breast cancer (BC) is one of the major dangerous tumors threatening women's lives. We here aimed to sort out prognostic immune-related genes by univariate Cox regression analysis and build a model of immune-related genes for forecasting the prognosis of BC patients. We identified UL16 binding protein 2 (ULBP2) as a valuable gene for study in the model using related databases and algorithms analysis. We found the stromal and immune cells scores were higher in ULBP2 high expression group and ULBP2 was related to kinds of immune cells, most importantly had negative correlation with CD8+ T cell. Notably, ULBP2 was positively correlated with tumor mutational burden (TMB) and had relationship with many immune checkpoints. Correlation analysis revealed that ULBP2 expression was closely linked to the clinicopathological characters and negatively related to BC patient survival. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed the functional enrichment of differential genes related to ULBP2. Gene Set Enrichment Analysis (GSEA) indicated pathway enrichment in ULBP2 high and low expression groups. In short, this study comprehensively investigated the potential function of ULBP2 in BC, which might make ULBP2 to be an important therapeutic target for BC.
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Deubiquitylases (DUBs) have emerged as promising targets for cancer therapy due to their role in stabilizing substrate proteins within the ubiquitin machinery. Here, we identified ubiquitin-specific protease 26 (USP26) as an oncogene via screening prognostic DUBs in breast cancer. Through in vitro and in vivo experiments, we found that depletion of USP26 inhibited breast cancer cell proliferation and invasion, and suppressed tumor growth and metastasis in nude mice. Further investigation identified co-chaperone Bcl-2-associated athanogene 3 (BAG3) as the direct substrate of USP26, and ectopic expression of BAG3 partially reversed antitumor effect induced by USP26 knockdown. Mechanistically, the lysine acetyltransferase Tip60 targeted USP26 at K134 for acetylation, which enhanced USP26 binding affinity to BAG3, leading to BAG3 deubiquitination and increased protein stability. Importantly, we employed a structure-based virtual screening and discovered a drug-like molecule called 5813669 that targets USP26, destabilizing BAG3 and effectively mitigating tumor growth and metastasis in vivo. Clinically, high expression levels of USP26 were correlated with elevated BAG3 levels and poor prognosis in breast cancer patients. Overall, our findings highlight the critical role of USP26 in BAG3 protein stabilization and provide a promising therapeutic target for breast cancer.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Neoplasias de la Mama , Cisteína Endopeptidasas , Animales , Femenino , Humanos , Ratones , Acetilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Progresión de la Enfermedad , Ratones Desnudos , Pronóstico , Estabilidad Proteica , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Traditional treatments against advanced non-small cell lung cancer (NSCLC) with high morbidity and mortality continue to be dissatisfactory. Given this situation, there is an urgent requirement for alternative modalities that provide lower invasiveness, superior clinical effectiveness, and minimal adverse effects. The combination of photodynamic therapy (PDT) and immunotherapy gradually become a promising approach for high-grade malignant NSCLC. Nevertheless, owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment (TME), the efficacy of this combination therapy approach is less than ideal. In this study, we construct a novel nanoplatform that indocyanine green (ICG), a photosensitizer, loads into hollow manganese dioxide (MnO2) nanospheres (NPs) (ICG@MnO2), and then encapsulated in PD-L1 monoclonal antibodies (anti-PD-L1) reprogrammed exosomes (named ICG@MnO2@Exo-anti-PD-L1), to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities. The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME, thereby activating T cell response. Subsequently, upon endocytic uptake by cancer cells, MnO2 catalyzes the conversion of H2O2 to O2, thereby alleviating tumor hypoxia. Meanwhile, ICG further utilizes O2 to produce singlet oxygen (1O2) to kill tumor cells under 808 nm near-infrared (NIR) irradiation. Furthermore, a high level of intratumoral H2O2 reduces MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further driving T cells. Taken together, the current study suggests that the ICG@MnO2@Exo-anti-PD-L1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.
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BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear. METHODS: Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models. RESULTS: In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8+ T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo. Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8+ T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment. CONCLUSIONS: Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy.
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Linfocitos T CD8-positivos , Neoplasias , Animales , Ratones , Aldehído Deshidrogenasa/metabolismo , Aldehídos/metabolismo , Aldehídos/farmacología , Linfocitos T CD8-positivos/metabolismo , FN-kappa B/metabolismo , Nucleótidos , Escape del Tumor , Microambiente TumoralRESUMEN
Breast cancer is the most common malignancy among women, and the abnormal regulation of gene expression serves an important role in its occurrence and development. However, the molecular mechanisms underlying gene expression are highly complex and heterogeneous, and RNA-binding proteins (RBPs) are among the key regulatory factors. RBPs bind targets in an environment-dependent or environment-independent manner to influence mRNA stability and the translation of genes involved in the formation, progression, metastasis and treatment of breast cancer. Due to the growing interest in these regulators, the present review summarizes the most influential studies concerning RBPs associated with breast cancer to elucidate the role of RBPs in breast cancer and to assess how they interact with other key pathways to provide new molecular targets for the diagnosis and treatment of breast cancer.
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Breast cancer is the most common female malignancy, but the mechanisms regulating gene expression leading to its development are complex. In recent years, as epigenetic research has intensified, RNA-binding proteins (RBPs) have been identified as a class of posttranscriptional regulators that can participate in regulating gene expression through the regulation of RNA stabilization and degradation, intracellular localization, alternative splicing and alternative polyadenylation, and translational control. RBPs play an important role in the development of normal mammary glands and breast cancer. Functional inactivation or abnormal expression of RBPs may be closely associated with breast cancer development. In this review, we focus on the function and regulatory mechanisms of RBPs in breast cancer, as well as the advantages and challenges of RBPs as potential diagnostic and therapeutic targets in breast cancer, and discuss the potential of RBPs in clinical treatment.
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Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune "cold" tumor into "hot" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.
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Fibroblastos Asociados al Cáncer , Receptores de Factores de Crecimiento de Fibroblastos , Linfocitos T , Neoplasias de la Mama Triple Negativas , Animales , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/inmunología , Línea Celular Tumoral , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Quinoxalinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Microambiente TumoralRESUMEN
Tumor microenvironment (TME) is vital for the occurrence and development of breast cancer (BRCA). However, it remains challenging to understand the dynamic modulation of the stromal and immune components comprehensively in TME. Herein, we used ESTIMATE and CIBERSORT algorithm to estimate the number of stromal and immune components and the abundance of tumor-infiltrating immune cells (TICs) in 582 BRCA cases from gene expression omnibus (GEO) database. We employed three regression models including univariable Cox proportion, LASSO regression model and multivariate Cox regression, and identified 7 immune-specific genes related to BRCA survival. Of 7 genes, ATPase Secretory Pathway Ca2+ Transporting 2 (ATP2C2) attracts our attention for significantly predicting prognosis of BRCA patients. Further analysis indicated that ATP2C2 expression was closely related to the clinicopathological features (age, T- and N-staging) and negatively correlated with patients' survival in BRCA. Gene Set Enrichment Analysis (GSEA) was performed to reveal pathway enrichment between ATP2C2high and ATP2C2low groups. The low ATP2C2 expression groups' genes were mainly enriched for immune-related activities, while those in the ATP2C2 high-expression group were largely enriched in metabolic-related pathways. Notably, Pearson's correlation analysis identified that ATP2C2 expression was positively correlated with T follicular helper (Tfh) cells, and negatively correlated with gamma delta (γδ) T cell, suggesting that ATP2C2 might be accountable for the maintenance of immune-dominant status for TME. To sum up, this study comprehensively analyzed the TME and shed light on prognostic immune-related biomarkers for BRCA. In particular, ATP2C2 might be helpful for predicting the prognosis of BRCA patients, which provided an extra insight for BRCA treatment.
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Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , ATPasas Transportadoras de Calcio/genética , Microambiente Tumoral , Biomarcadores de Tumor , Neoplasias de la Mama/mortalidad , ATPasas Transportadoras de Calcio/metabolismo , Biología Computacional/métodos , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Nomogramas , Pronóstico , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Transcriptoma , Escape del Tumor , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Breast cancer (BC) is the most common tumor in women, and the molecular mechanism underlying its pathogenesis remains unclear. In this study, we aimed to investigate gene modules related to the phenotypes of BC, and identify representative candidate biomarkers for clinical prognosis of BC patients. Using weighted gene co-expression network analysis, we here identified NPY5R as a hub gene in BC. We further found that NPY5R was frequently downregulated in BC tissues compared with adjacent tumor-matched control tissues, due to its aberrant promoter CpG methylation which was confirmed by methylation analysis and treatment with demethylation agent. Higher expression of NPY5R was closely associated with better prognosis for BC patients. Gene set enrichment analysis showed that transcriptome signatures concerning apoptosis and cell cycle were critically enriched in specimens with elevated NPY5R. Ectopic expression of NPY5R significantly curbed breast tumor cell growth, induced cell apoptosis and G2/M arrest. Moreover, NPY5R also promoted the sensitivity of BC cells to doxorubicin. Mechanistically, we found that NPY5R restricted STAT3 signaling pathway activation through interacting with IL6, which may be responsible for the antitumor activity of NPY5R. Collectively, our findings indicate that NPY5R functions as a tumor suppressor but was frequently downregulated in BC.
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PURPOSE: Chemotherapy-related cognitive impairments in breast cancer patients were usually reported through cognitive questionnaires or scales which may be subjective and insensitive. This study is to assess the effect of chemotherapy on cognitive function in breast cancer patients stratified by age using objective electrophysiological measure, the P300 component of event-related potentials (ERPs) with a large sample size. METHODS: Totally, 529 primary breast cancer patients, including 178 cases at initial diagnosis stage and before chemotherapy (Group1), 167 cases during chemotherapy (Group2), and 184 cases post chemotherapy and during follow-up period (Group3), were examined with ERPs (P300 component) to assess the effect of chemotherapy on their cognitive function. RESULTS: There were significant differences of P300 latency in Group2 (364.74 ± 15.73 ms) and Group3 (364.02 ± 17.12 ms, mean follow-up period of 2.42 years) compared with Group1 (355.13 ± 19.47 ms, P < 0.001), respectively. With further age stratification: in patients of < 50 years, P300 latency was significantly prolonged in Group2 and Group3 compared with Group1 (P < 0.001), respectively; in patients of 50-59 years, P300 latency was significantly prolonged in Group2 compared with Group1 (P < 0.05), but without difference in Group1 and Group3 (P>0.05); In patients of ≥ 60 years, there were no differences of P300 latency among three the groups (P>0.05). CONCLUSIONS: It is first suggested by our objective detection data that the side effect of chemotherapy on cognitive functions in breast cancer patients may decrease with age. Electrophysiological cognitive impairments mainly occur in younger breast cancer patients undergoing chemotherapy and would last for years after chemotherapy, which highlights the importance of early intervention for those patients, especially in younger patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Supervivientes de Cáncer/estadística & datos numéricos , Disfunción Cognitiva/patología , Potenciales Relacionados con Evento P300/efectos de los fármacos , Neoplasias de la Mama/patología , Disfunción Cognitiva/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
PHD Finger Protein 2 (PHF2), as a protein code and a transcription regulatory gene, is a member of the Jumonji-C domain (JmjC). PHF2 is located at human chromosome 9q22.31 and is frequently decreased in various malignancies. However, the definite role of PHF2 in breast cancer remains unclear. To detect the expression and function of PHF2 in breast cancer, a q-PCR assay was used to detect the mRNA expression of PHF2 in breast cancer cell lines and paired breast cancer tissues, and immunohistochemistry was used to test the protein expression in breast cancer tissues and adjacent tissues. In addition, an adenovirus vector system was utilized to upregulate the expression of PHF2 in breast cancer cells. In our study, we found that PHF2 was down-expressed in breast cancer on both the mRNA and protein levels and the low expression of PHF2 was significantly associated with lymph node metastasis, Ki67 positive rate, ER negative expression and poor prognosis in breast cancer patients. The ectopic expression of PHF2 obviously inhibited the proliferation of breast cancer cell lines and the growth of xenograft tumors. Due to the tumor suppressor signature of PHF2 in breast cancer, we have reasons to believe that it could be a promoting marker and target for the prognosis and therapy of breast cancer.
RESUMEN
Premenopausal and postmenopausal breast cancers are considered different types. Thus, this study aimed to explore differences in risk factors, epidemiological features, clinicopathological features, and treatment modes of premenopausal breast cancer compared to postmenopausal patients in western China. This was a hospital-based, retrospective, multicenter epidemiological study of patients with breast cancer. Using the Western China Clinical Cooperation Group database, we obtained the records of 15,389 female breast cancers between January 2010 and April 2017. These patients were divided into premenopausal and postmenopausal groups, and their risk factors, epidemiological feature, clinicopathological features, and treatment modes were compared. Chi-square tests, t-test, and the multivariate logistic regression analysis were applied for statistical analysis. A total of 8395 patients were categorized as premenopausal, and 6994 patients were categorized as postmenopausal. Their risk factors, epidemiological features, clinicopathological features, and treatment modes were compared. Premenopausal patients with breast cancer had a greater tumor diameter at diagnosis (P = 0.008); higher rates of estrogen receptor (ER) expression (P < 0.0001), progesterone receptor (PR) expression (P < 0.0001), negative human epidermal growth factor receptor 2 (HER2) expression (P = 0.015), and negative P53 expression (P < 0.0001); and higher proportions of receiving breast-conserving surgery and breast reconstruction (P < 0.0001), chemotherapy (P < 0.0001), radiotherapy (P < 0.0001), and endocrine therapy (P < 0.0001). The ethnicity, age at menarche, marital status, number of pregnancies, and number of births were the risk factors for age at diagnosis of breast cancer before or after menopause in western China. We found that the fall in the fertility rate, early menarche age, married, and less breastfeeding might have increased the possibility of premenopausal breast cancer. Significant differences exist in the tumor size, hormone receptor state, HER2 expression, epidemiological features, and treatment modes between premenopausal and postmenopausal female breast cancer patients in western China. Its further implementation requires prospective clinical testing.
Asunto(s)
Neoplasias de la Mama/epidemiología , Adulto , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/terapia , Neoplasias de la Mama Masculina/epidemiología , China/epidemiología , Terapia Combinada , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Menopausia , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Vigilancia de la Población , Embarazo , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
Recent studies suggest that nucleotide-binding domain leucine-rich repeat protein 1 (NLRP1) is a pivotal factor in the inflammatory process. However, the role of NLRP1 in breast cancer pathogenesis remains unclear. The aim of this study was to examine the expression and function of NLRP1 in breast cancer. We found that NLRP1 was widely expressed in 83% (60/72) of primary breast cancer tissue. NLRP1 expression level was higher in primary breast cancer tissue than in adjacent noncancerous tissue (p < 0.001) and NLRP1 expression was associated with lymph node metastasis (p = 0.003), TNM stage (p = 0.003), and Ki-67 levels (p < 0.001). Overexpression of NLRP1 in the breast cancer cell line MCF-7 promotes proliferation, migration, invasion, and tumorigenicity in nude mice. Restoration of NLRP1 expression resulted in the EMT occurrence that downregulation of epithelial marker E-cadherin and upregulation mesenchymal marker vimentin, C-myc, MMP-9, and snail. In summary, NLRP1 promotes cell line MCF-7 the proliferation, migration, and invasion through inducing EMT.