Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP.

Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.

Magnetic properties of liquid-phase sintered CoFe2O4 for application in magnetoelastic and magnetoelectric transducers.

Cobalt ferrite is a ferrimagnetic magnetostrictive ceramic that has potential application in magnetoelastic and magnetoelectric transducers. In this work, CoFe(2)O(4) was obtained using a conventional ceramic method and Bi(2)O(3) was used as additive in order to obtain liquid-phase sintered samples. Bi(2)O(3) was added to the ferrite in amounts ranging from 0.25 mol% to 0.45 mol% and samples were sintered at 900 °C and 950 °C. It was observed the presence of Bi-containing particles in the microstructure of the sintered samples and the magnetostriction results indicated microstructural anisotropy. It was verified that it is possible to get dense cobalt ferrites, liquid-phase sintered, with relative densities higher than 90% and with magnetostriction values very close to samples sintered without additives.

Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl.

The proto-oncoprotein Cbl is known to control several signaling processes. It is highly expressed in the testis, and because spermatogenesis is androgen dependent, we investigated the androgen dependency expression of Cbl through its testicular sub-localization and its expression levels in rats that were exposed to the antiandrogen flutamide or were hypophysectomized. We report the androgen dependency of Cbl as it localizes in pachytene spermatocytes during androgen-dependent stages, is down-regulated upon flutamide exposure, and is up-regulated with testosterone in hypophysectomized rats. Coculture experiments showed the key control exerted by the Sertoli cell on Cbl activity. As flutamide induces germ cell apoptosis, we investigate members of the Bcl-2 family upon flutamide exposure. We show that the proapoptotic Bcl-2 family member Bim mirrored Cbl expression through a posttranscriptional process. We also show that in Cbl knockout mouse testes, the imbalance between the high expression of Bim and Smac/Diablo and anti-apoptotic factors such as cellular inhibitor of apoptosis 2 favors a survival process, which makes these mice unresponsive to androgen withdrawal and could explain their hypofertility.

The RON receptor tyrosine kinase promotes metastasis by triggering MBD4-dependent DNA methylation reprogramming.

Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo.

Dynamic estrogen receptor interactomes control estrogen-responsive trefoil Factor (TFF) locus cell-specific activities.

Estradiol signaling is ideally suited for analyzing the molecular and functional linkages between the different layers of information directing transcriptional regulations: the DNA sequence, chromatin modifications, and the spatial organization of the genome. Hence, the estrogen receptor (ER) can bind at a distance from its target genes and engages timely and spatially coordinated processes to regulate their expression. In the context of the coordinated regulation of colinear genes, identifying which ER binding sites (ERBSs) regulate a given gene still remains a challenge. Here, we investigated the coordination of such regulatory events at a 2-Mb genomic locus containing the estrogen-sensitive trefoil factor (TFF) cluster of genes in breast cancer cells. We demonstrate that this locus exhibits a hormone- and cohesin-dependent reduction in the plasticity of its three-dimensional organization that allows multiple ERBSs to be dynamically brought to the vicinity of estrogen-sensitive genes. Additionally, by using triplex-forming oligonucleotides, we could precisely document the functional links between ER engagement at given ERBSs and the regulation of particular genes. Hence, our data provide evidence of a formerly suggested cooperation of enhancers toward gene regulation and also show that redundancy between ERBSs can occur.

Physical habitat simulation for small-sized characid fish species from tropical rivers in Brazil

Physical habitat simulation (PHABSIM) is an important step of the instream flow incremental methodology (IFIM), which is applied to establish environmental flow regimes. This study applied the PHABSIM in two reaches of the Velhas river basin, whose long-term discharges are similar but are under different degrees of impact. Suitability curves were obtained for fish species using traditional methods (Astyanax sp., Piabarchus stramineus, Piabina argentea and Serrapinnus heterodon) and generalized additive models for fish density (Astyanax sp., P. argentea and S. heterodon). The results of habitat use depended on the method for curves generation. Applying the suitability curves by traditional methods, different discharge scenarios were simulated. The flow increasing from a dry scenario to a discharge of 1 year of return promotes a possible habitat increase for all species. However, the same hydrological flow percentiles produce different habitat proportions in different rivers. This work demonstrates that regardless of how suitability curves for the Neotropical species are generated, caution should be taken when applying them. However, the PHABSIM method allows more complex analyses than the traditional approaches based on minimal flow estimations, which is usually applied in South America.(AU)

A simulação de habitat para espécies de peixes (PHABSIM) é uma etapa importante do método Instream Flow Incremental Methodology (IFIM), cuja aplicação está relacionada a determinação da vazão ecológica. O presente estudo aplicou PHABSIM em dois trechos da bacia do rio das Velhas, cujas vazões de médio prazo são semelhantes, mas sob condições de conservação ambiental diferente. Curvas de aptidão foram obtidas para Astyanax sp., Piabarchus stramineus, Piabina argentea e Serrapinnus heterodon através do método tradicional e ajustando modelo aditivos generalizados (Astyanax sp., P. argentea e S. heterodon). Os resultados sugerem uso de habitats diferentes dependendo do modelo utilizado para gerar as curvas. Aplicando as curvas obtidas pelo método tradicional no PHABSIM, diferentes cenários de vazão foram simulados. O aumento da vazão para cheia de um ano de retorno aumenta o habitat provável para todas as espécies. Entretanto, mesmo cenário de vazão, fornecido por análise de hidrológica de percentis de ocorrência, fornece diferente proporção de habitat em diferentes rios. O trabalho demonstra que curvas de aptidão para espécies neotropicais, independentemente da forma de geração, devem ser usadas com cautela. Entretanto, o método PHABSIM permite análises mais elaboradas do que as tradicionais estimativas de vazão mínima empregadas na América do Sul.(AU)