Tyrosine phosphorylation profiling reveals the signaling network characteristics of basal breast cancer cells

To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e. g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup. Cancer Res; 70(22); 9391-401. (C) 2010 AACR.</p

Variscan Magmatism

This chapter aims to identify, characterize and locate the main facts/events related to orogenesis in the Iberian Peninsula. Its succession in space and time determines the geodynamic environment of the broader geological phenomenon corresponding to the Variscan cycle. In this sense, this section comprises two parts: I—The Iberian orogenic magmatism seen through a space-time approach of its westernmost region—focus on the enormous complexity of the inherited basement, its nature, age and distribution in space. Establishes a space-time sequence of geodynamic environments correlated with the obtained data and tries to identify the agents responsible for its genesis. Some case studies are presented to illustrated significant regional aspects of the magmatic process and II—An overview of the petrogenesis of the great batholiths and of the basic, intermediate and mantle-related rocks—identify and analyze a great amount of these rocks intruding and extruded from 400 to 280 Ma and to better understanding the large-scale process involving the whole lithosphere during Variscan cycle.publishe