FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer

Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan−Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan−Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk

Prospects For Identifying Dark Matter With CoGeNT

It has previously been shown that the excess of events reported by the CoGeNT collaboration could be generated by elastically scattering dark matter particles with a mass of approximately 5-15 GeV. This mass range is very similar to that required to generate the annual modulation observed by DAMA/LIBRA and the gamma rays from the region surrounding the Galactic Center identified within the data of the Fermi Gamma Ray Space Telescope. To confidently conclude that CoGeNT's excess is the result of dark matter, however, further data will likely be needed. In this paper, we make projections for the first full year of CoGeNT data, and for its planned upgrade. Not only will this body of data more accurately constrain the spectrum of nuclear recoil events, and corresponding dark matter parameter space, but will also make it possible to identify seasonal variations in the rate. In particular, if the CoGeNT excess is the product of dark matter, then one year of CoGeNT data will likely reveal an annual modulation with a significance of 2-3$\sigma$. The planned CoGeNT upgrade will not only detect such an annual modulation with high significance, but will be capable of measuring the energy spectrum of the modulation amplitude. These measurements will be essential to irrefutably confirming a dark matter origin of these events.Comment: 6 pages, 6 figure

CAV1 inhibits metastatic potential in melanomas through suppression of the Integrin/Src/FAK signaling pathway.

Caveolin-1 (CAV1) is the main structural component of Caveolae which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although, evidence has recently accumulated describing the function of CAV1 in several cancer types, its role in melanoma tumor formation and progression remains poorly explored. Here, by employing B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation while it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterpart. An experimental metastasis assay demonstrates that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we demonstrate that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. CAV1 expression also markedly reduces the expression levels of beta3 Integrin in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma

Requirement of transcription factor NFAT in developing atrial myocardium

Nuclear factor of activated T cell (NFAT) is a ubiquitous regulator involved in multiple biological processes. Here, we demonstrate that NFAT is temporally required in the developing atrial myocardium between embryonic day 14 and P0 (birth). Inhibition of NFAT activity by conditional expression of dominant-negative NFAT causes thinning of the atrial myocardium. The thin myocardium exhibits severe sarcomere disorganization and reduced expression of cardiac troponin-I (cTnI) and cardiac troponin-T (cTnT). Promoter analysis indicates that NFAT binds to and regulates transcription of the cTnI and the cTnT genes. Thus, regulation of cytoskeletal protein gene expression by NFAT may be important for the structural architecture of the developing atrial myocardium

593pthe seneca study prognostic role of serum biomarkers in elderly metastatic colorectal cancer patients

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Excess Higgs Production in Neutralino Decays

The ATLAS and CMS experiments have recently claimed discovery of a Higgs boson-like particle at ~5 sigma confidence and are beginning to test the Standard Model predictions for its production and decay. In a variety of supersymmetric models, a neutralino NLSP can decay dominantly to the Higgs and the LSP. In natural SUSY models, a light third generation squark decaying through this chain can lead to large excess Higgs production while evading existing BSM searches. Such models can be observed at the 8 TeV LHC in channels exploiting the rare diphoton decays of the Higgs produced in the cascade decay. Identifying a diphoton resonance in association with missing energy, a lepton, or b-tagged jets is a promising search strategy for discovery of these models, and would immediately signal new physics involving production of a Higgs boson. We also discuss the possibility that excess Higgs production in these SUSY decays can be responsible for enhancements of up to 50% over the SM prediction for the observed rate in the existing inclusive diphoton searches, a scenario which would likely by the end of the 8 TeV run be accompanied by excesses in the diphoton + lepton/MET and SUSY multi-lepton/b searches and a potential discovery in a diphoton + 2b search.Comment: 42 pages, 19 figure