RESUMEN
Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Neoplasias de la Mama/genética , MicroARNs/biosíntesis , Proteínas de Unión al ARN/biosíntesis , Receptor ErbB-2/biosíntesis , Factor de Transcripción STAT3/genética , Adolescente , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas de Unión al ARN/genética , Receptor ErbB-2/genética , Transducción de Señal , Activación Transcripcional/genética , TransfecciónRESUMEN
No disponible
Asunto(s)
Humanos , Dermatomiositis/complicaciones , Linfoma no Hodgkin/complicaciones , Factores de RiesgoRESUMEN
Anaerobic sealants are acrylates that polymerize in the absence of oxygen. They are used principally in the engineering and electronic industries. Their use can cause occupational dermatitis in the workers who handle them. In this work, we report our experience with 6 patients who presented with allergic contact dermatitis to these sealants.
Asunto(s)
Acrilatos/efectos adversos , Dermatitis por Contacto/etiología , Dermatitis Profesional/etiología , Metacrilatos/efectos adversos , Adulto , Dermatitis por Contacto/diagnóstico , Dermatitis Profesional/diagnóstico , Humanos , Persona de Mediana Edad , Pruebas del Parche , EspañaAsunto(s)
Dermatitis por Contacto/etiología , Dermatitis Profesional/etiología , Madera , Adulto , Humanos , MasculinoRESUMEN
3 cases of occupational radiodermatitis from Ir192 exposure in personnel handling a gamma ray projector in industrial radiography are presented. The diagnosis was confirmed histologically. The nature and use of the industrial machines are described.
Asunto(s)
Dermatitis Profesional/patología , Iridio/efectos adversos , Radiodermatitis/patología , Radioisótopos/efectos adversos , Adulto , Estudios de Seguimiento , Dermatosis de la Mano/patología , Humanos , Masculino , Persona de Mediana Edad , Piel/patologíaAsunto(s)
Dermatitis Profesional/etiología , Vidrio/efectos adversos , Adulto , Humanos , Masculino , Pruebas del ParcheRESUMEN
A revision of the sensitivities produced by PTBP resin is made, taking into account professional and consumers points of view. Fifteen cases of sensitivity to the resin are reported.