Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL6/JAK/STAT3 pathway initiated by the binding of IL6 family of cytokines (i.e., IL-6, IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc, Mcl-1), angiogenesis (Hif1α, VEGF), and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9, MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly-interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3’s involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its co-regulatory transcription factors.

Although the ERK pathway has a central role in the response of cells to growth factors, its regulatory structure and dynamics are incompletely understood. To investigate ERK activation in real time, we expressed an ERK-GFP fusion protein in human mammary epithelial cells. On EGF stimulation, we observed sustained oscillations of the ERK-GFP fusion protein between the nucleus and cytoplasm with a periodicity of B15 min. The oscillations were persistent (445 cycles), independent of cell cycle phase, and were highly dependent on cell density, essentially disappearing at confluency. Oscillations occurred even at ligand doses that elicited very low levels of ERK phosphorylation, and could be detected biochemically in both transfected and nontransfected cells. Mathematical modeling revealed that negative feedback from phosphorylated ERK to the cascade input was necessary to match the robustness of the oscillation characteristics observed over a broad range of ligand concentrations. Our characterization of single-cell ERK dynamics provides a quantitative foundation for understanding the regulatory structure of this signaling cascade.

No abstract

The dynamic solvation time correlation function 𝒵(t) is, within linear response, formulated in terms of the intermolecular solute–solvent interactions, without recourse to the intrinsically macroscopic concept of a cavity carved out of a dielectric medium. For interaction site models (ISM) of both the solute and the solvent, the theory relates the fluctuating polarization charge density of the solvent to the fluctuating vertical energy gap that controls 𝒵(t). The theory replaces the factual (or bare) solute charge distribution by a surrogate expressed in terms of the solute–solvent site–site direct correlation functions. Calculations for solute ions in water and in acetonitrile lead to 𝒵(t) and the second moment of the associated spectral density in good agreement with molecular dynamics simulation results in the literature. We also use the theory to calculate 𝒵(t) for model solutes in which the ‘‘sudden’’ change of the charge distribution involves multipoles of higher order. The response is qualitatively similar in the various cases studied here.