OBJECTIVE -Coffee consumption is associated with reduced risk of type 2 diabetes, but the mechanism is not clearly understood. Elevated C-peptide, as a marker of insulin secretion, has been linked to insulin-resistant type 2 diabetes. In this study, we examined consumption of caffeinated and decaffeinated coffee and total caffeine in relation to concentrations of plasma C-peptide.RESEARCH DESIGN AND METHODS -Plasma C-peptide concentrations were measured in a cross-sectional setting among 2,112 healthy women from the Nurses' Health Study I who provided blood samples in 1989 -1990. Consumption of caffeinated and decaffeinated coffee and total caffeine was assessed using a semiquantitative food-frequency questionnaire in 1990.RESULTS -Intakes of caffeinated and decaffeinated coffee and caffeine in 1990 were each inversely associated with C-peptide concentration in age-adjusted, BMI-adjusted, and multivariable-adjusted analyses. In multivariable analysis, concentrations of C-peptide were 16% less in women who drank Ͼ4 cups/day of caffeinated or decaffeinated coffee compared with nondrinkers (P Ͻ 0.005 for each). Women in the highest quintile compared with the lowest quintile of caffeine intake had 10% lower C-peptide levels (P ϭ 0.02). We did not find any association between tea and C-peptide. The inverse association between caffeinated coffee and C-peptide was considerably stronger in obese (27% reduction) and overweight women (20% reduction) than in normal weight women (11% reduction) (P ϭ 0.005).CONCLUSIONS -Our findings suggest a potential reduction of insulin secretion by coffee in women. This reduction may be related to other components in coffee rather than caffeine. Diabetes Care 28:1390 -1396, 2005C offee intake has been associated with a reduction in the risk of type 2 diabetes (1-4). Because of its widespread consumption, understanding the relationship between coffee intake and insulin secretion may have implications in the prevention and treatment of diabetes.In contrast, short-term studies have consistently shown that acute administration of caffeine induces insulin resistance and impairs glucose tolerance (3,5,6). Longterm effects of caffeine and other components of coffee, which may be more relevant on insulin secretion, have been less well studied. In a recent crosssectional study of 936 elderly men without diabetes, coffee was associated with increased insulin sensitivity but not with decreased secretion (7). However, this study did not distinguish between caffeinated and decaffeinated coffee, did not study women, and measured only the early insulin response under glucose stimulation.C-peptide is cleaved from proinsulin and released into the bloodstream in equivalent amounts with insulin (8). Increased C-peptide has been associated with insulin resistance and diabetes (9), cardiovascular disease (10), and colon cancer (11). According to the National Coffee Association, 54% of adults in the U.S. drank coffee in 2000, with average per capita daily consumption of 1.9 cups for men and 1.4 cups for women...

Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer.

Background:Prostate-specific antigen (PSA) screening has low specificity. Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity.Method:The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase–π (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions). We conducted a comprehensive literature search on Medline (Pubmed). We included studies if they met all four of the following criteria: (1) measurement of DNA methylation in body fluids; (2) a case-control or case-only design; (3) publication in an English journal; and (4) adult subjects. Reviewers conducted data extraction independently using a standardised protocol. Twenty-two studies were finally included in this paper. Primer sequences and methylation method in each study were summarised and evaluated using meta-analyses. This paper represents a unique cross-disciplinary approach to molecular epidemiology.Results:The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95% CI, 0.80–0.95). Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location). The pooled sensitivity was 0.52 (95% CI, 0.40–0.64).Conclusions:The pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA. The sensitivity of GSTP1 was modest, no higher than that of PSA. These results suggest that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis.