Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Blood ; 135(26): 2337-2353, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32157296

RESUMEN

Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.


Asunto(s)
Crisis Blástica/genética , Regulación Leucémica de la Expresión Génica/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Complejo Represivo Polycomb 1/fisiología , Complejo Represivo Polycomb 2/fisiología , Diferenciación Celular , Inmunoprecipitación de Cromatina , Metilación de ADN , Conjuntos de Datos como Asunto , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Dosificación de Gen , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 2/genética , Transcriptoma , Secuenciación del Exoma , Secuenciación Completa del Genoma
2.
J Mammary Gland Biol Neoplasia ; 15(1): 35-47, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20101445

RESUMEN

Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine therapy remains a major challenge in the clinic. A number of possible mechanisms for drug resistance have been described, which include activation of growth factor receptor pathways, overexpression of ER coactivators, and metabolic resistance due to polymorphisms in metabolizing enzymes. While many of these changes are caused by genetic alterations, there is also increasing evidence to implicate epigenetic gene regulatory mechanisms in the development of endocrine resistance. Since epigenetic modifications are easier to reverse than genetic mutations, they are appealing therapeutic targets, and thus future improvements in medical care for breast cancer patients will depend upon a better understanding of the roles epigenetic modifications play in endocrine resistance. In this review we will focus on recent advances made in the understanding of epigenetic gene regulation in estrogen response and endocrine resistance in breast cancer. We will also summarize current clinical-translational advances in epigenetic therapy, and discuss potential future clinical use of epigenetic changes as therapeutic targets, especially with respect to endocrine treatment.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Epigénesis Genética/fisiología , Receptores de Estrógenos/metabolismo , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Resultado del Tratamiento
3.
Horm Cancer ; 6(5-6): 214-24, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26113056

RESUMEN

Acquired resistance to aromatase inhibitors (AIs) remains a major clinical problem in the treatment of estrogen receptor-positive (ER+) breast cancer. We and others have previously reported widespread changes in DNA methylation using breast cancer cell line models of endocrine resistance. Here, we show that the histone variant HIST1H2BE is hypomethylated in estrogen deprivation-resistant C4-12 and long-term estrogen-deprived (LTED) cells compared with parental MCF-7 cells. As expected, this hypomethylation associates with increased expression of HIST1H2BE in C4-12 and LTED cells. Both overexpression and downregulation of HIST1H2BE caused decreased proliferation in breast cancer cell lines suggesting the need for tightly controlled expression of this histone variant. Gene expression analysis showed varied expression of HIST1H2BE in a large panel of breast cancer cell lines, without restriction to specific molecular subtypes. Analysis of HIST1H2BE messenger RNA (mRNA) expression in ER+ AI-treated breast tumors showed significantly higher expression in resistant (n = 19) compared with sensitive (n = 37) tumors (p = 0.01). Using nanostring analysis, we measured expression of all 61 histone variants in endocrine-resistant and endocrine-sensitive tumors. We found significant overexpression of 22 variant histone genes in tumors resistant to AI therapy. In silico The Cancer Genome Atlas (TCGA) analysis showed frequent amplification of the HIST1 locus. In summary, our studies show, for the first time, that overexpression of histone variants might be important in endocrine response in ER+ breast cancer, and that overexpression is at least in part mediated via epigenetic mechanisms and amplifications. Future studies addressing endocrine response should include a potential role of these currently understudied histone variants.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Variación Genética , Histonas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Análisis por Conglomerados , Terapia Combinada , Metilación de ADN , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histonas/química , Histonas/metabolismo , Humanos , Persona de Mediana Edad , Familia de Multigenes , Clasificación del Tumor , Estadificación de Neoplasias , Análisis de Secuencia de ADN
4.
Cancer Prev Res (Phila) ; 8(10): 1000-9, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26290394

RESUMEN

The most effective natural prevention against breast cancer is an early first full-term pregnancy. Understanding how the protective effect is elicited will inform the development of new prevention strategies. To better understand the role of epigenetics in long-term protection, we investigated parity-induced DNA methylation in the mammary gland. FVB mice were bred or remained nulliparous and mammary glands harvested immediately after involution (early) or 6.5 months following involution (late), allowing identification of both transient and persistent changes. Targeted DNA methylation (109 Mb of Ensemble regulatory features) analysis was performed using the SureSelectXT Mouse Methyl-seq assay and massively parallel sequencing. Two hundred sixty-nine genes were hypermethylated and 128 hypomethylated persistently at both the early and late time points. Pathway analysis of the persistently differentially methylated genes revealed Igf1r to be central to one of the top identified signaling networks, and Igf1r itself was one of the most significantly hypermethylated genes. Hypermethylation of Igf1r in the parous mammary gland was associated with a reduction of Igf1r mRNA expression. These data suggest that the IGF pathway is regulated at multiple levels during pregnancy and that its modification might be critical in the protective role of pregnancy. This supports the approach of lowering IGF action for prevention of breast cancer, a concept that is currently being tested clinically.


Asunto(s)
Metilación de ADN/genética , Glándulas Mamarias Animales/metabolismo , Paridad/genética , Receptor IGF Tipo 1/genética , Animales , Neoplasias de la Mama/genética , Femenino , Genoma , Ratones , Parto , Reacción en Cadena de la Polimerasa , Embarazo
5.
Sci Transl Med ; 6(229): 229ra41, 2014 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-24670685

RESUMEN

Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.


Asunto(s)
Neoplasias de la Mama/genética , Reprogramación Celular/genética , Resistencia a Antineoplásicos/genética , Epigénesis Genética/genética , Estrógenos/farmacología , Proteínas de Homeodominio/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Reprogramación Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Células MCF-7 , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Regiones Promotoras Genéticas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Clin Cancer Res ; 17(12): 4177-86, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21459801

RESUMEN

PURPOSE: ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome. EXPERIMENTAL DESIGN: We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively. RESULTS: Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group. CONCLUSIONS: Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/fisiopatología , Metilación de ADN , Regiones Promotoras Genéticas/genética , Receptores de Progesterona/metabolismo , Adulto , Anciano , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Orden Génico , Humanos , Persona de Mediana Edad , Pronóstico , Isoformas de Proteínas/metabolismo , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Análisis de Supervivencia , Tamoxifeno/uso terapéutico , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA