BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs. Oncogene (2012) 31, 3667-3678; doi:10.1038/onc.2011.531; published online 28 November 2011

Anatomy and physiology of the human eye: effects of mucopolysaccharidoses disease on structure and function - a review

P>The current paper provides an overview of current knowledge on the structure and function of the eye. It describes in depth the different parts of the eye that are involved in the ocular manifestations seen in the mucopolysaccharidoses (MPS). The MPS are a group of rare inheritable lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in cells and tissues all over the body, leading to widespread tissue and organ dysfunction. GAGs also tend to accumulate in several tissues of the eye, leading to various ocular manifestations affecting both the anterior (cornea, conjunctiva) and the posterior parts (retina, sclera, optic nerve) of the eye.

Lipoprotein-associated phospholipase A(2), inflammatory biomarkers, and risk of cardiovascular disease in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

Objective: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammatory biomarker that circulates mainly bound to LDL. We evaluated the association of Lp-PLA(2) with vascular events in the elderly where the importance of LDL is diminished as a risk factor for coronary disease.

The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.

Intra-epithelial T cells in coeliac disease

Coeliac disease is an enteropathy associated with dietary gluten which occurs in individuals with a genetic predisposition. The pathogenesis remains obscure although it is clear that only certain parts of the gliadin molecule are toxic and there is considerable evidence of immunological activity, including antibody production. In this issue of European Journal of Gastroenterology and Hepatology Carton et al. present evidence in favour of an inherent depletion of CD4CD8 T cells, which could result in a loss of oral tolerance to ingested gliadin. Using flow cytometry they also demonstrated that the classic T-cell infiltration of coeliac disease is not due to an increase in T cells but is an apparent increase associated with a relative decrease in enterocytes as a result of the change in architecture of the mucosa. These could be important fundamental observations in helping to unravel the pathogenesis of coeliac disease.

Intestinal permeability tests in coeliac disease

Intestinal permeability tests have been used to screen for a wide range of small intestinal diseases, including coeliac disease and enteric infections. Several probe molecules have been used to investigate intestinal permeability including monosaccharides, disaccharides, 51Cr-EDTA and polyethyleneglycol. While many factors may affect intestinal permeability tests, the use of two probe molecules, for example, lactulose and mannitol, and the expression of the result as a ratio minimises the effects of these extraneous factors. Rendering the test solution hyperosmolar was also found to increase the sensitivity of the test in detecting coeliac disease. Intestinal permeability is characteristically elevated in untreated coeliac disease, with a sensitivity of up to 96% for the dual sugar techniques. The reason for this is a consistent increase in the absorption of lactulose (via the paracellular route) due to increased "leakiness" of the intestine and a reduction in the absorption of mannitol (via the transcellular route) due to a reduction in surface area as a result of villous atrophy. The intestinal permeability test allows subjects to be selected for jejunal biopsy in whom the clinical features are compatible with coeliac disease and in timing a follow-up biopsy. It has been postulated that raised intestinal permeability may be involved in the pathogenesis of coeliac disease. Recently, serum measurements of the probe molecules may have a valuable role, particularly in paediatric patients. Sucrose permeability has also been proposed as an accurate marker of adult coeliac disease and shows promise as a noninvasive test.