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Introduction: The negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020. In this study, the effectiveness of an approved breast cancer DiGA was investigated: The personalized coaching app PINK! Coach supports and accompanies breast cancer patients during therapy and follow-up. Methods: PINK! Coach was specifically designed for breast cancer (BC) patients from the day of diagnosis to the time of Follow-up (aftercare). The app offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT (DRKS00028699) was performed with n = 434 patients recruited in 7 German breast cancer centers from September 2022 until January 2023. Patients with BC were included independent of their stage of diseases, type of therapy and molecular characteristics of the tumor. Patients were randomized into one of two groups: The intervention group got access to PINK! over 12 weeks; the control group served as a waiting-list comparison to "standard of care." The primary endpoint was psychological distress objectified by means of Patient Health Questionnaire-9 (PHQ-9). Subgroups were defined to investigate the app's effect on several patient groups such as MBC vs. EBC patients, patients on therapy vs. in aftercare, patients who received a chemotherapy vs. patients who did not. Results: Efficacy analysis of the primary endpoint revealed a significant reduction in psychological distress (least squares estimate -1.62, 95% confidence interval [1.03; 2.21]; p<0.001) among intervention group patients from baseline to T3 vs, control group. Subgroup analysis also suggested improvements across all clinical situations. Conclusion: Patients with breast cancer suffer from psychological problems including anxiety and depression during and after therapy. Personalized, supportive care with the app PINK! Coach turned out as a promising opportunity to significantly improve psychological distress in a convenient, accessible, and low-threshold manner for breast cancer patients independent of their stage of disease (EBC/MBC), therapy phase (aftercare or therapy) or therapy itself (chemotherapy/other therapy options). The app is routinely available in Germany as a DiGA. Clinical Trial Registration: DRKS Trial Registry (DRKS00028699).
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BACKGROUND: The translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed on reactive glial cells and a biomarker for gliosis in the brain. TSPO ligands have been shown to reduce neuroinflammation in several mouse models of neurodegeneration. Here, we analyzed TSPO expression in mouse and human retinal microglia and studied the effects of the TSPO ligand XBD173 on microglial functions. METHODS: TSPO protein analyses were performed in retinoschisin-deficient mouse retinas and human retinas. Lipopolysaccharide (LPS)-challenged BV-2 microglial cells were treated with XBD173 and TSPO shRNAs in vitro and pro-inflammatory markers were determined by qRT-PCR. The migration potential of microglia was determined with wound healing assays and the proliferation was studied with Fluorescence Activated Cell Sorting (FACS) analysis. Microglial neurotoxicity was estimated by nitrite measurement and quantification of caspase 3/7 levels in 661 W photoreceptors cultured in the presence of microglia-conditioned medium. The effects of XBD173 on filopodia formation and phagocytosis were analyzed in BV-2 cells and human induced pluripotent stem (iPS) cell-derived microglia (iPSdM). The morphology of microglia was quantified in mouse retinal explants treated with XBD173. RESULTS: TSPO was strongly up-regulated in microglial cells of the dystrophic mouse retina and also co-localized with microglia in human retinas. Constitutive TSPO expression was high in the early postnatal Day 3 mouse retina and declined to low levels in the adult tissue. TSPO mRNA and protein were also strongly induced in LPS-challenged BV-2 microglia while the TSPO ligand XBD173 efficiently suppressed transcription of the pro-inflammatory marker genes chemokine (C-C motif) ligand 2 (CCL2), interleukin 6 (IL6) and inducible nitric oxide (NO)-synthase (iNOS). Moreover, treatment with XBD173 significantly reduced the migratory capacity and proliferation of microglia, their level of NO secretion and their neurotoxic activity on 661 W photoreceptor cells. Furthermore, XBD173 treatment of murine and human microglial cells promoted the formation of filopodia and increased their phagocytic capacity to ingest latex beads or photoreceptor debris. Finally, treatment with XBD173 reversed the amoeboid alerted phenotype of microglial cells in explanted organotypic mouse retinal cultures after challenge with LPS. CONCLUSIONS: These findings suggest that TSPO is highly expressed in reactive retinal microglia and a promising target to control microglial reactivity during retinal degeneration.
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Inflamación/metabolismo , Microglía/metabolismo , Fagocitos/metabolismo , Receptores de GABA/metabolismo , Retina/citología , Anciano , Animales , Proteínas de Unión al Calcio , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Citometría de Flujo , Regulación de la Expresión Génica/fisiología , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Lipopolisacáridos , Masculino , Ratones , Ratones Noqueados , Proteínas de Microfilamentos , Persona de Mediana Edad , Seudópodos/efectos de los fármacos , Purinas/farmacología , Receptores de GABA/genética , Técnicas de Cultivo de Tejidos , Cicatrización de Heridas/inmunologíaRESUMEN
Genetic variations like single nucleotide polymorphisms (SNPs) in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to affect breast cancer susceptibility. In this study we tested the hypothesis that polymorphisms in the promoter of ESR2 gene may be associated with increased risk for breast cancer. We analyzed three SNPs in the promoter region of human ESR2 gene by means of allele-specific tetra-primer PCR. A total of 318 sporadic breast cancer cases and 318 age-matched controls were included in the study. With regard to homozygous genotypes, women with sporadic breast cancer more frequently carried the CC genotype of ESR2 promoter SNP rs2987983 (OR 1.99, p=0.005). Calculation of allele positivity demonstrated that presence of T allele of this SNP was more frequent in healthy women. Our data suggest that a SNP in the promoter region of ESR2 gene might be able to affect breast cancer risk. These results further support the emerging hypothesis that ERbeta is an important factor in breast cancer development.
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Neoplasias de la Mama/genética , Receptor beta de Estrógeno/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana EdadRESUMEN
GHRH antagonists have been shown to inhibit growth of various human cancer cell lines xenografted into nude mice including estrogen receptor negative human breast cancers. Previous observations also suggest that GHRH locally produced in diverse neoplasms including breast cancer might directly affect proliferation of tumor cells. In the present study we demonstrate that a novel highly potent GHRH antagonist JMR-132 strongly inhibits the proliferation of both estrogen receptor negative SKBR 3 and estrogen receptor positive ZR 75 human breast cancer cell lines in vitro. The proliferation in vitro of ZR 75 and SKBR 3 was increased after direct stimulation with GHRH(1-29)NH2. The GHRH antagonist JMR-132 had a significant antiproliferative activity in the absence of GHRH and nullified the proliferative effect of GHRH in these cell lines. SKBR 3 and ZR 75 expressed the GHRH ligand as well as the pituitary type of GHRH-receptor, which likely appears to mediate the antiproliferative mechanisms in these cell lines. These in vitro results suggest that JMR-132 is a potent inhibitor of breast cancer growth, independent of the estrogen receptor status. Further investigations on the combination treatment with endocrine agents affecting the estrogen pathway and GRHR antagonists are needed in order to improve the treatment of breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Sermorelina/análogos & derivados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Hormona Liberadora de Hormona del Crecimiento/biosíntesis , Hormona Liberadora de Hormona del Crecimiento/efectos de los fármacos , Humanos , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sermorelina/farmacologíaRESUMEN
Hormone therapy (HT), in peri- and postmenopause has been associated with a modest increase in the risk of breast cancer. Hormones play a major role in tumorigenesis of breast cancer, and reproductive factors are known to influence breast cancer risk. Female sex steroids are used for contraception or menopause treatment by women of reproductive age and postmenopausal women respectively. This review reports recent published epidemiological evidence and randomised trials which examined the effect of HT on the risk of breast cancer.
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Neoplasias de la Mama/inducido químicamente , Climaterio/efectos de los fármacos , Terapia de Reemplazo de Hormonas/efectos adversos , Adulto , Anciano , Anticonceptivos Hormonales Orales/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
BACKGROUND: Inhibitor of DNA binding/Inhibitor of differentiation 4 (ID4) is a critical factor for cell proliferation and differentiation in normal vertebrate development. ID4 has regulative functions for differentiation and growth of the developing brain. The role of ID1, ID2 and ID3 are expected to be oncogenic due to their overexpression in pancreatic cancer and colorectal adenocarcinomas, respectively. Aside from these findings, loss of ID3 expression was demonstrated in ovarian cancer. The aim of the present study was to reveal the factual role of ID4 in carcinogenesis in more detail, since its role for the pathogenesis of human breast cancer has been discussed controversially, assigning both oncogenic and tumour suppressive functions. METHODS: ID4 promoter methylation, ID4 mRNA expression and ID4 protein expression were analysed in primary human breast cancer specimens using methylation-specific PCR (MSP) (n=170), semiquantitative realtime RT-PCR (n=46) and immunhistochemistry (n=3), respectively. In order to demonstrate a functional association of ID4 promoter methylation with its gene silencing, we performed DNA demethylation analysis with four human breast cell lines using MSP and semiquantitative realtime RT-PCR. In addition, we performed correlations of ID4 promoter methylation with ID4 mRNA and ID4 protein expression in matched samples of breast tumour and corresponding normal tissue. We carried out statistical analyses in order to find correlations between ID4 promoter methylation and clinicopathological parameters. RESULTS: Frequent ID4 promoter methylation was observed in primary breast cancer samples (69%, 117/170). We found a tight correlation (P<0.0001) between ID4 promoter methylation and loss of ID4 expression in primary breast cancer 3 specimens. Demethylating treatment with breast cancer cell lines was associated with clear ID4 mRNA re-expression. Tumours with ID4 promoter methylation showed distinct loss of ID4 expression on both transcription and protein level. Interestingly, ID4 promoter methylation was a factor for unfavourable recurrence-free survival (P=0.036) and increased risk for lymph node metastasis (P=0.030). CONCLUSION: ID4 is indeed a novel tumour suppressor gene in normal human breast tissue and is epigenetically silenced during cancer development, indicating increased risk for tumour relapse. Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer.
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Neoplasias de la Mama/genética , Metilación de ADN , Proteínas Inhibidoras de la Diferenciación/genética , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Genes Supresores de Tumor , Humanos , Proteínas Inhibidoras de la Diferenciación/biosíntesis , Proteínas Inhibidoras de la Diferenciación/deficiencia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
Estrogen receptor beta gene codes for a variety of transcript isoforms resulting from alternative splicing, which are expressed both in mammary gland and in breast cancer cells. We studied the function of two exon-deleted ERbeta isoforms recently identified by our group in comparison to ERbeta1 in regulation of growth, apoptosis and gene expression of two breast cancer cell lines with different ERalpha status. Overexpression of ERbeta1, but not of the exon-deleted variants exerted strong antitumoral effects both on ERalpha-positive MCF-7 and ERalpha-negative SK-BR-3 cells. ERbeta1 overexpression slowed growth of MCF-7 and SK-BR-3 cells in the absence of E2 and also inhibited E2-triggered growth stimulation of MCF-7 cells, but overexpression of the exon-skipped variants did not affect cell growth. Whereas overexpression of ERbeta1 triggered an increased basal and tamoxifen-induced apoptosis of MCF-7 and SK-BR-3 cells, the isoforms ERbetadelta125 or ERbetadelta1256 did not affect cellular tamoxifen response. The observed lack of function of the exon-deleted variants in terms of regulation of proliferation was accompanied both by their inability to affect expression of cyclins D1 and A2, p21 (WAF1) and PR and their disability to modulate estrogen response element (ERE) activation. In contrast, our results demonstrating antitumoral effects of ERbeta1 on breast cancer cells with different ERalpha-status support the hypothesis that ERbeta is able to exert antitumoral actions both on ERalpha-positive and -negative breast cancer cells.
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Apoptosis/fisiología , Neoplasias de la Mama/genética , Proliferación Celular , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Exones , Femenino , Expresión Génica , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/análisis , Elementos de Respuesta/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
An important mechanism of antitumoral targeted therapies is the induction of apoptosis in tumor cells. Tamoxifen and trastuzumab (Herceptin), respectively, are able to trigger apoptosis in human breast cancer cells. But, frequently altered apoptotic signal cascades, for instance through PTEN mutations, help tumor cells to escape antitumoral therapy. We studied to what extent the apoptotic effect of signal-transduction inhibitors is dependent on PTEN expression. PTEN expression was analysed by Western blot analysis in tumor cell lines of the breast (BT-474, MCF-7, MDA-MB-231), ovary (BG-1, SK-OV-3) and endometrium (Ishikawa, HEC-1A). Apoptotic effects of tamoxifen, trastuzumab, ZD1839 (Iressa) and different mitogen-activated protein kinase (MAP) inhibitors were measured after 24 h of treatment. Cellular apoptosis was determined by the detection of cytoplasmic histone-DNA complexes. The tested tumor cell lines exhibited a different PTEN expression, ranging from a high expression (ovarian cancer cell line BG-1 and BT-474 breast cancer cells) to a total absence of PTEN expression (endometrial Ishikawa cells). The apoptotic effect of receptor-targeting drugs (tamoxifen, trastuzumab, ZD1839) was dependent both on receptor expression and PTEN expression. When cells were treated with MAPK inhibitors, no correlation between PTEN expression and the apoptosis rate was observed. Our data underline the importance of PTEN expression regarding the induction of apoptosis through various targeted therapies.
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Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Fosfohidrolasa PTEN/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Línea Celular Tumoral/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Antagonistas de Estrógenos/farmacología , Flavonoides/farmacología , Gefitinib , Humanos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Quinazolinas/farmacología , Tamoxifeno/farmacologíaRESUMEN
Estrogen receptor (ER) beta gene codes for different transcript variants resulting from alternative splicing. In this study, we report identification of the two novel human exon-skipped ERbeta transcript isoforms ERbetaDelta125 and ERbetaDelta1256 in MDA-MD-231 breast cancer cells. Both transcripts could also be detected in a variety of human tissues. We further report the results of an in vitro attempt to characterize their function in regulation of cell growth, motility, apoptosis and gene expression. COS-1 cells stably transfected with the novel ERbeta transcripts exhibited a notably slower growth even in the absence of estradiol when compared to vector-transfected control cells. Like ERbeta1, both novel ERbeta transcript isoforms raised the basal apoptosis rate of COS-1 cells in a ligand-independent manner. Whereas introduction of ERbetaDelta1256 notably increased the sensitivity of COS-1 cells towards lower concentrations of selective estrogen receptor modulator tamoxifen, presence of ERbeta1 and ERbetaDelta125 transcripts further weakened the growth-inhibitory effect of tamoxifen on this cell line. Furthermore, expression of ERbetaDelta1256 variant was demonstrated to reduce transcript levels of estrogen-responsive genes like cyclin A2, IGFBP-4 and fibulin 1c in COS-1 cells in a ligand-independent manner. Though we were not able to detect the predicted 29 and 34kDa proteins by means of western blot analysis, our data strongly suggest the biological functionality of both isoforms on molecular level. With this report increasing the multitude of existing ERbeta mRNA isoforms, we provide further evidence that their synthesis has to be considered as an important level of estrogen signaling.
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Empalme Alternativo , Apoptosis , Estradiol/farmacología , Receptor beta de Estrógeno/biosíntesis , Regulación de la Expresión Génica , Transducción de Señal , Empalme Alternativo/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/genética , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Isoformas de Proteínas/biosíntesis , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
OBJECTIVE: Tamoxifen, which is widely used in the treatment of breast cancer, also has a beneficial effect on cisplatin-refractory ovarian cancer. In this study, we investigated the long-term effects of this drug on estrogen-receptor-positive ovarian cancer cells. METHODS: We performed an in vitro selection process by long-term treatment of BG-1 ovarian cancer cells with 4-hydroxy tamoxifen (4-OH TAM). Drug effects on cell growth were determined by measurement of relative cell numbers (MTS assay), the apoptotic effects of 4-OH TAM were determined by analysis of poly (ADP-ribose) polymerase (PARP) cleavage and by ELISA measurement of DNA-histone complexes in cytoplasm. RESULTS: Analysis of BG-1(LT) ovarian cancer cells isolated after 5 months of long-term treatment with 4-OH TAM revealed both a significantly reduced apoptotic and antiproliferative effect of this drug. Further experiments to examine expression changes of the receptor tyrosine kinases EGFR, HER2 and estrogen receptor alpha did not reveal any alterations in BG-1(LT) if compared to wild-type cells. In contrast, in this cell line, a significant alteration in the expression of estrogen receptor beta was observed. CONCLUSION: Our findings indicate that long-term treatment with 4-OH TAM is able to diminish both the antiproliferative and apoptotic action of this drug on BG-1 ovarian cancer cells. Our data suggest that the responsiveness of ovarian cancer cells to 4-OH TAM decreases after long-term treatment with this drug in vitro like previously observed after long-term treatment of breast cancer cells.