RESUMEN
Breast cancers with estrogen receptor α (ERα) expression are often more differentiated histologically than ERα-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ERα determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ERα that can simultaneously block cell proliferation and induce differentiation through global regulation of ERα-regulated genes. CARM1 was evidenced as an ERα coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ERα levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ERα may provide a better biomarker of well-differentiated breast cancer. Furthermore, our findings define an important functional role of this histone arginine methyltransferase in reprogramming ERα-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers.
Asunto(s)
Neoplasias de la Mama/metabolismo , Diferenciación Celular , Proliferación Celular , Receptor alfa de Estrógeno/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Animales , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclo Celular , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína-Arginina N-Metiltransferasas/genética , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , Trasplante HeterólogoRESUMEN
To determine the relationship of the multiple sites of oestrogen receptor alpha (ERalpha) phosphorylation to clinical outcome after tamoxifen therapy, sections from tissue microarrays representing over 300 ER+ breast cancers from patients who were treated with surgery+radiation and then tamoxifen were used for immunohistochemical determination of total ERalpha, p-S104/106-ERalpha, p-S118-ERalpha, p-S167-ERalpha, p-S282-ERalpha, p-S294-ERalpha, p-T311-ERalpha and p-S559-ERalpha. Relationships of phosphorylated ERalpha to overall and relapse-free survival (RFS; breast cancer death or recurrence) were tested using single (univariate) and multiple (multivariate) predictor statistical models. Large tumour size, node positivity, high grade, progesterone receptor (PR) negative status and low levels of p-S282-ERalpha were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P(7) score > or = 3), taking into account all seven p-ERalpha sites, was significantly associated with reduced OS in univariate and multivariate analyses (hazard ratio (HR)=2.24, 95% confidence interval (CI) 1.15-4.34, n=335; P=0.018). Along with tumour size, node status, grade and PR status, a high P(7) score (> or = 3) was significantly associated with reduced RFS in univariate and multivariate analyses (HR=1.71, 95% CI 1.03-2.86, n=332; P=0.039). Since ERalpha is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERalpha phosphorylation score may be a surrogate marker of the balance between oestrogen-dependent and crosstalk-dependent receptor activity, and is potentially a prognostic marker of clinical outcome in a tamoxifen-treated population of patients.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Fosforilación/fisiología , Tamoxifeno/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores de Progesterona/metabolismo , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
A phospho-tyrosine 537-ERα (p-Y537-ERα) antibody was validated for immunohistochemistry of formalin-fixed paraffin-embedded human breast cancer biopsies and used to interrogate multiple ER positive breast cancer cases present on tissue microarrays already constructed by the Manitoba Breast Tumor Bank. Nuclear p-Y537-ERα protein expression was positively associated with positive nodes (Spearman r = 0.20, P = 0.0002) and large tumor size (r = 0.13, P = 0.02). On univariate analysis, high levels of p-Y537 were associated with poor overall survival (HR = 1.65, 95% CI 1.08-2.52, P = 0.02) but not relapse free survival from breast cancer. The association with overall survival was not significant on multivariate analysis. These data support the relevance of phosphorylation at p-Y537-ERα in human breast cancers and add further support to the presence of a phosphorylation code for ERα in human breast cancer in vivo.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Tamoxifeno/uso terapéutico , Tirosina/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Análisis Multivariante , Fosforilación , Receptor ErbB-2/metabolismo , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
Estrogen receptor (ER)alpha activity is regulated by phosphorylation at several sites. Recently several antibodies specific for individual phosphorylated sites within ERalpha have became available. Validation and use of these antibodies suggests that several forms of phosphorylated ERalpha can be detected in multiple ER+ human breast tumor samples, thus providing relevance for investigating the regulation and function of phosphorylated ERalpha in human breast cancer. Generally, the phosphorylated ERalpha isoforms are associated with parameters that suggest that they are markers of an intact estrogen dependent signaling pathway and better clinical outcome with respect to tamoxifen therapy. Profiling of phosphorylated ERalpha may provide better biomarkers of endocrine therapy response over and above those currently available.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Isoformas de Proteínas/metabolismo , Biopsia , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Fosforilación , Isoformas de Proteínas/genética , Transducción de Señal/fisiologíaRESUMEN
Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.