Molecular aspects linking insulin resistance to breast cancer by activation of cell signalling pathways.

Recent findings suggest a connection between obesity and breast cancer. Obesity is linked with higher incidences of insulin resistance as part of the metabolic syndrome, resulting in chronically elevated insulin plasma levels. We examined the effect of high insulin concentrations (100 nM) on estrogen-receptor (ER) negative breast cancer cells (MDA-MB-231) and normal breast epithelial cells (MCF-10a). Treatment with high insulin concentrations increased insulin receptor (IR) phosphorylation significantly in both cell lines. Phosphorylation of protein kinase B (Akt), representative of PI3-kinase cell signalling pathway activation was increased by 101% (p=0.0112) in MDA-MB-231 cells and by 81% (p=0.0031) in MCF-10a cells after 10 min insulin treatment. Phosphorylation of extracellular regulated kinase 1/2 (ERK1/2), representative of MAP-kinase cell signalling pathway activation did not change in both cell lines after 10 min of insulin treatment. Cell proliferation did not change in MDA-MB-231 cells and increased by 75% (p=0.0067) in MCF-10a cells after 24 h insulin treatment. Cell proliferation was decreased in MDA-MB-231 cells by 15% (p=0.0083) after 1 h treatment with PD98059, a MAP-kinase inhibitor. In MCF-10a cells cell proliferation was decreased by 51% (

Molecular aspects of insulin resistance, cell signaling pathways and breast cancer in relation to obesity.

A growing number of clinical studies validate a relation of insulin resistance and breast cancer in obese patients. We hypothesised that high plasma insulin levels cause aberrant insulin signalling in breast epithelial cells which may be responsible for an increase in cell proliferation, indicative of potential carcinogenesis and increased cancer progression. It was of particular interest to determine any differences of high insulin concentrations in activating the phosphoinositide-3 kinase (PI-3 kinase) pathway or the mitogen-activated protein kinase (MAP kinase) pathway, the latter being linked to increased cell proliferation. We used two cell line models to investigate the carcinogenic (MCF-10A, immortalised breast epithelial cells) and cancer progression (MDA-MB-231, ER-negative breast cancer cells) potential of insulin. Insulin treatment (100 nM, 24 h) increased cell proliferation in MCF-10A cells, but had no cell proliferative effect on MDA-MB-231 cells. Additionally expression of PCNA as marker of proliferation was tested. The use of PI-3 kinase and MAP kinase specific inhibitors (Wortmannin and PD98059, respectively) demonstrated both pathways being responsible for the observed increase in cell proliferation (MCF-10A). Simultaneous treatment with both inhibitors eliminated insulin induced cell proliferation entirely. Phosphorylation of ERK1/2 was examined as specific activity measurement of MAP kinase pathway. Insulin induced higher phosphorylation levels in MCF-10A cells than in MDA-MB-231. These preliminary results suggest that insulin may initiate carcinogenesis of breast epithelial cells by increasing cell proliferation rather than increasing cancer progression of existing tumours. These effects may be mediated by insulin activating both the PI-3 kinase and the MAP kinase signalling pathways

Stability of Ferromagnetism in Hubbard models with degenerate single-particle ground states

A Hubbard model with a N_d-fold degenerate single-particle ground state has ferromagnetic ground states if the number of electrons is less or equal to N_d. It is shown rigorously that the local stability of ferromagnetism in such a model implies global stability: The model has only ferromagnetic ground states, if there are no single spin-flip ground states. If the number of electrons is equal to N_d, it is well known that the ferromagnetic ground state is unique if and only if the single-particle density matrix is irreducible. We present a simplified proof for this result.Comment: accepted for publication in J. Phys.

Polarisation Independent Liquid Crystal Lenses and Contact Lenses using Embossed Reactive Mesogens

Liquid crystal lenses have promise in optical systems owing to their tunability combined with low electrical power, cost, and weight. A good example of such a system is switchable contact lenses for the correction of age‐related presbyopia. Sufficiently large phase modulation can be done using nematic liquid crystals in a meniscus lens configuration. However, the birefringent materials are inherently polarisation dependent, usually requiring orthogonal polarisations to be focussed separately. A novel method is presented for producing polarisation independent lenses based on reactive mesogens. Results are presented for a 2‐level and 3‐level diffractive Fresnel lenses, and the promise of the technique for use in refractive lenses such as contact lenses is discussed

Insulin-induced gene expression changes in breast cancer cells and normal breast epithelial cells.

Obesity increases breast cancer incidence rates in postmenopausal women. Chronic high levels of insulin, present in the majority of obese and insulin resistant patients, may provide the growth promoting stimulus to explain this connection. In this work, the cancer progression and cancer initiating properties of high insulin levels were examined in breast cancer cells (MDA-MB-231) and breast epithelial cells (MCF-10a), respectively. High insulin levels (100 nM) induced differential changes in cell proliferation in the two cell lines used. Human Cancer PathwayFinder DNA Microarrays (SABiosciences) were used to examine gene expression changes after insulin treatment. High insulin levels increased expression of genes involved in cell cycle control (e.g. cyclin D1) and DNA damage repair (e.g. ATM) in MDA-MB 231 cells and in MCF-10a cells (e.g. cyclin E1, CDC25a). Expression of genes responsible for mediating apoptosis and cell senescence (e.g. APAF, BAD, bcl-X) was decreased after insulin treatment in MDA-MB 231 cells but the expression of the same group of genes did not change in MCF-10a cells. High insulin levels increased expression of genes encoding for signal transduction molecules (e.g. AKT1) and transcription factors (e.g. FOS, JUN, MYC), and of genes responsible for invasion and metastasis (e.g. MMP2) in MCF-10a cells whereas gene expression of the same groups of genes did not change or was decreased in MDA-MB 231 cells. These results suggest a role for insulin resistance in breast cancer initiation and progression, aggravating the potential of breast cancer to evade apoptosis, to metastasise and may promote carcinogenesis of healthy epithelial cells

Polarisation Independent Liquid Crystal Lenses using Embossed Reactive Mesogens

Liquid crystal lenses have promise in optical systems owing to their tunability combined with low electrical power, cost and weight. A good example of such a system is switchable contact lenses for the correction of age‐related presbyopia. Large phase modulation can be done using nematic liquid crystals. However, the birefringent materials are inherently polarisation dependent, usually requiring orthogonal polarisations to be focused separately. A novel method is presented for producing polarisation independent lenses based on reactive mesogens

Graanrijk voer voor vleesvarkens

Belangstelling voor de grondstofsamenstelling van het voer voor vleesvarkens is voortgekomen uit de veronderstelling, dat de grote hoeveelheden graanbijproducten en tapioca een negatief effect op de vlees- en eetkwaliteit zouden kunnen hebben

Olive oil phenolics: effects on DNA oxidation and redox enzyme mRNA in prostate cells

J.L.Q. was supported by the University of Granada, Spain (Becas de Perfeccionamiento de Doctores Programme). D.K.S. was supported by a grant from World Cancer Research Fund (WCRF) and the other authors were supported by the Scottish Executive Rural and Agricultural Department (SERAD).Hydroxytyrosol, tyrosol and caffeic acid effects on hydrogen peroxide-induced DNA damage, hydroperoxide generation and redox enzyme gene expression were studied in oxidative-stress-sensitive human prostate cells (PC3). Hydroxytyrosol led to lower levels of hydroperoxides, DNA damage, and mRNA levels of classic glutathione peroxidase (GPx) for all the studied concentrations. Only hydroxytyrosol was effective at low concentrations (10 μM). TYROSOL REDUCED DNA OXIDATION ONLY AT HIGH (>50 Μm) concentrations and increased hydroperoxides, GPx and phospholipid hydroperoxide GPx mRNA levels. Caffeic acid elicited effects between those of the other two phenolics. Results indicate that hydroxytyrosol is the only significant antioxidant phenolic in olive oil and may be the major component accounting for its beneficial properties. Tyrosol appeared to exhibit pro-oxidant effects (only at high concentrations) and caffeic acid was neutral. Both number and position of hydroxyl groups appear to play a role in the cellular effects of hydroxytyrosol.University of Granada, Spain (Becas de Perfeccionamiento de Doctores Programme)World Cancer Research Fund (WCRF)Scottish Executive Rural and Agricultural Department (SERAD