Jnk2 Effects on Tumor Development, Genetic Instability and Replicative Stress in an Oncogene-Driven Mouse Mammary Tumor Model

Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK) proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2−/− tumors. In vitro, PyV MT/jnk2−/− cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1) and p21Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A) coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms

Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis

Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer

Measurement of safety rods reactivity worth by advanced source jerk method in HWZPR

Accurate measurement of the reactivity worth of safety rods is very important for the safe reactor operation, in normal and emergency conditions. In this paper, the reactivity worth of safety rods in Heavy Water Zero Power Reactor (HWZPR) in the new lattice pitch is measured by advanced source jerk method. The average of the results related to two different detectors is equal to 29.88 mk. In order to verify the result, this parameter was compared to the previously measured value by subcritical to critical approach. Different experiment results are finally compared with corresponding calculated result. Difference between the average experimental and calculated results is equal to2.2%. Keywords: Safety, Reactivity worth, Neutron generator, HWZPR, Advanced source jer

Precision Medicine in Hormone Receptor-Positive Breast Cancer

In recent decades, breast cancer has become largely manageable due to successes with hormone receptor targeting. Hormone receptor-positive tumors have favorable outcomes in comparison to estrogen receptor (ESR1, ER)/progesterone receptor-negative tumors given the targetable nature of these tumors, as well as their inherently less aggressive character. Nonetheless, treatment resistance is frequently encountered due to a variety of mechanisms, including ESR1 mutations and loss of ER expression. A new era of precision medicine utilizes a range of methodologies to allow real-time analysis of individual genomic signatures in metastases and liquid biopsies with the goal of finding clinically actionable targets. Preliminary studies have shown improved progression-free survival and overall survival with implementation of this information for clinical decision making. In this review, we will discuss the opportunities and challenges in integrating precision medicine through next-generation genomic sequencing into the management of breast cancer