The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer.

BACKGROUND: Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue. RESULTS: We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing. CONCLUSION: To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.

Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women.

High salt intake is a well-recognized risk factor for osteoporosis because it induces calciuria, but the effects of salt on calcium metabolism and the potential impact on bone health in postmenopausal women have not been fully characterized. This study investigated adaptive mechanisms in response to changes in salt and calcium intake in postmenopausal women. Eleven women completed a randomized cross-over trial consisting of four successive 5-wk periods of controlled dietary intervention, each separated by a minimum 4-wk washout. Moderately low and high calcium (518 versus 1284 mg) and salt (3.9 versus 11.2 g) diets, reflecting lower and upper intakes in postmenopausal women consuming a Western-style diet, were provided. Stable isotope labeling techniques were used to measure calcium absorption and excretion, compartmental modeling was undertaken to estimate bone calcium balance, and biomarkers of bone formation and resorption were measured in blood and urine. Moderately high salt intake (11.2 g/d) elicited a significant increase in urinary calcium excretion (p = 0.0008) and significantly affected bone calcium balance with the high calcium diet (p = 0.024). Efficiency of calcium absorption was higher after a period of moderately low calcium intake (p < 0.05) but was unaffected by salt intake. Salt was responsible for a significant change in bone calcium balance, from positive to negative, when consumed as part of a high calcium diet, but with a low calcium intake, the bone calcium balance was negative on both high and low salt diets.