RESUMEN
The transmembrane tyrosine kinase HER2 (ErbB2, neu) is a prototypical biomarker for breast cancers and a therapeutic target. Although anti-HER2 therapies are remarkably effective, HER2-positive tumors are heterogeneous and some subtypes do not respond or develop resistance to these therapies. Here we show that H2NTF, a novel N-terminal fragment of HER2, is expressed at variable levels in 60% of the breast cancer samples analyzed. Characterization of H2NTF shows that it is devoid of the tyrosine kinase domain but it readily interacts with full-length HER2 and other HER receptors. As a consequence, H2NTF acts as a dominant-negative, attenuating the signaling triggered by full-length HER receptors. Expression of H2NTF results in resistance to the treatment with low concentrations of trastuzumab in vitro. However, cells expressing H2NTF and non-expressing cells have similar sensitivity to trastuzumab in vivo, indicating that H2NTF/trastuzumab complexes trigger antibody-dependent cell-mediated cytotoxicity.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma/genética , Receptor ErbB-2/química , Receptor ErbB-2/genética , Secuencia de Aminoácidos , Animales , Neoplasias de la Mama/epidemiología , Carcinoma/epidemiología , Femenino , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genes Dominantes , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Modelos Biológicos , Datos de Secuencia Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estructura Terciaria de Proteína/genética , Estructura Terciaria de Proteína/fisiología , Receptor ErbB-2/metabolismo , Células Tumorales CultivadasRESUMEN
The objective of this study is to describe the seasonal differences in SO2 ground-level fumigations from a power plant situated on very complex terrain in the Iberian Peninsula within the Western Mediterranean Basin (WMB). The study area extends more than 80 km around the power plant on very complex semi-arid terrain. Considering different plume-rise schemes, by experimentation and modelling this study attempts to characterise the seasonal differences in both the plume footprint 80 km around the power plant and the turbulent regime (diurnal or nocturnal) driving the main contribution to the accumulated plume footprints at different distances from the power plant within a complex terrain region. Two markedly different SO2 ground-level distributions around the power plant are presented for the typical summer and winter dispersive scenarios in the area. Simulations show that the SO2 footprint of a plume being advected more than 450 m above ground level in complex terrain is highly dependent on the prevailing meteorological conditions and on the mesoscale perturbations of the synoptic flows within the lower layers of the troposphere. The results obtained show how on complex terrain, despite seasonal meteorological differences and under stable dispersive conditions, the simulated mechanical turbulence leeward of the mountain ranges reproduces highly concentrated SO2 fumigations on the ground more than 50 km away from the power plant. Besides, under summer convective activity, plume fumigations have been successfully simulated less than 15 km from the power plant. In conclusion, this study shows how measurements from air quality networks together with information obtained from atmospheric transport and diffusion models are able to characterise different transport scenarios. This is a clear advantage for the end-users and decision-makers who manage and optimise the regional air quality networks.
