Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.Fil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Béguelin, W.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Natalia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guzmán, P.. Universidad de La Frontera; ChileFil: Roa, J.C.. Universidad de La Frontera; ChileFil: O'Brien, N.A.. David Geffen School of Medicine at UCLA; Estados UnidosFil: Charreau, Eduardo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Encoding and maintaining reference in oral discourse.

International audienceThis study deals with information management and reference encoding modes in oral discourse production. Three potentially influential factors were the distance between the first occurrence of an item and its later occurrences, a topic change that takes the focus off that item, and the span of the conceptual information available for verbalization. French-speaking adult subjects were asked to tell stories from comic strips to a listener who was unfamiliar with them. The frames in each strip were presented simultaneously or in succession. Four versions were generated for each comic strip: a given version was either short (three frames) or long (eight frames), and either did or did not have a topic change. The results showed that the target character was usually marked as a given, regardless of the version. This was more often true, however, when the topic did not change. When the character was treated as a given, referent accessibility marking was dependent on (1) topic change alone when the frames were presented simultaneously, and (2) topic change and comic strip length when the frames were presented in succession. The discussion analyzes the results in terms of the allocation of cognitive resources to maintaining coreference and to assisting addressees in their processing

Cryptanalysis of GlobalPlatform Secure Channel Protocols

GlobalPlatform (GP) card specifications are the de facto standards for the industry of smart cards. Being highly sensitive, GP specifications were defined regarding stringent security requirements. In this paper, we analyze the cryptographic core of these requirements; i.e. the family of Secure Channel Protocols (SCP). Our main results are twofold. First, we demonstrate a theoretical attack against SCP02, which is the most popular protocol in the SCP family. We discuss the scope of our attack by presenting an actual scenario in which a malicious entity can exploit it in order to recover encrypted messages. Second, we investigate the security of SCP03 that was introduced as an amendment in 2009. We find that it provably satisfies strong notions of security. Of particular interest, we prove that SCP03 withstands algorithm substitution attacks (ASAs) defined by Bellare et al. that may lead to secret mass surveillance. Our findings highlight the great value of the paradigm of provable security for standards and certification, since unlike extensive evaluation, it formally guarantees the absence of security flaws

Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants

Summary Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models

Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.

Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as javax.xml.bind.JAXBElement@4375628f Using a focused genetic screen, we identified javax.xml.bind.JAXBElement@76a4bdfb as a relevant target of the 6q deletion and demonstrate tumor suppression by javax.xml.bind.JAXBElement@26a2409a in vivo. Moreover, javax.xml.bind.JAXBElement@3203074e is a direct target of the lymphoma-specific javax.xml.bind.JAXBElement@5a0a6a9b gain-of-function mutation ( javax.xml.bind.JAXBElement@9925f44 javax.xml.bind.JAXBElement@3d00687c ). javax.xml.bind.JAXBElement@179321e5 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. javax.xml.bind.JAXBElement@1e44df3e loss represents an alternative to javax.xml.bind.JAXBElement@5b7cbcd mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, javax.xml.bind.JAXBElement@3bca108f javax.xml.bind.JAXBElement@3558921a mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies