Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study.

Excess adiposity and hormone replacement therapy (HRT) are important contributors to postmenopausal breast cancer risk. HRT has been shown to modify the association between body weight and breast cancer risk, although few studies are sufficiently large to examine the risk of breast cancer associated with body mass index (BMI) and weight gain separately among current HRT users and nonusers. This study includes 1,934 incident breast cancer cases occurring among 62,756 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort. Age-adjusted incidence rates were calculated, and Cox proportional hazards models were used to examine the association of BMI and adult weight gain (since age 18 years) with breast cancer risk stratified by HRT use. Total adult weight gain strongly predicted breast cancer risk among former and never HRT users (P for trend < 0.0001). Weight gain of 21-30 pounds was associated with a rate ratio of 1.4 (95% confidence interval 1.1-1.8); rates doubled among women gaining >70 pounds compared with women who maintained their weight within 5 pounds of their weight at age 18. After accounting for weight gain, neither recent BMI nor BMI at age 18 were independent predictors of risk. Among current HRT users, no association was seen between breast cancer and either BMI or weight gain. Adult weight gain is strongly associated with postmenopausal breast cancer only among non-HRT users in this study. These data illustrate the importance of examining breast cancer risk factors separately by HRT use; the effects of other risk factors may be attenuated or obscured among women taking HRT.

Glutamine and KGF each regulate extracellular thiol/disulfide redox and enhance proliferation in Caco-2 cells.

Glutamine (Gln) and keratinocyte growth factor (KGF) each stimulate intestinal epithelial cell growth, but regulatory mechanisms are not well understood. We determined whether Gln and KGF alter intra- and extracellular thiol/disulfide redox pools in Caco-2 cells cultured in oxidizing or reducing cell medium and whether such redox variations are a determinant of proliferative responses to these agents. Cells were cultured over a physiological range of oxidizing to reducing extracellular thiol/disulfide redox (Eh) conditions, obtained by varying cysteine (Cys) and cystine (CySS) concentrations in cell medium. Cell proliferation was determined by 5-bromo-2-deoxyuridine (BrdU) incorporation. Gln (10 mmol/l) or KGF (10 microg/l) did not alter BrdU incorporation at reducing Eh (-131 to -150 mV), but significantly increased incorporation at more oxidizing Eh (Gln at 0 to -109 mV; KGF at -46 to -80 mV). Cellular glutathione/glutathione disulfide (GSH/GSSG) Eh was unaffected by Gln, KGF, or variations in extracellular Cys/CySS Eh. Control cells largely maintained extracellular Eh at initial values after 24 h (-36 to -136 mV). However, extracellular Eh shifted toward a narrow physiological range with Gln and KGF treatment (Gln -56 to -88 mV and KGF -76 to -92 mV, respectively; P < 0.05 vs. control). The results indicate that thiol/disulfide redox state in the extracellular milieu is an important determinant of Caco-2 cell proliferation induced by Gln and KGF, that this control is independent of intracellular GSH redox status, and that both Gln and KGF enhance the capability of Caco-2 cells to modulate extremes of extracellular redox.

Dietary glycemic index, glycemic load, and risk of incident breast cancer in postmenopausal women.

Insulin and insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in several studies. Circulating concentrations of insulin increase with dietary consumption of high glycemic index foods, which, in turn, may influence IGF-I levels or activity, but the relevance of such dietary patterns for breast cancer risk is unclear. We investigated whether consumption of carbohydrates with high dietary glycemic index would predict risk of postmenopausal breast cancer among 63,307 United States women in the Cancer Prevention Study II Nutrition Cohort. From baseline in 1992, participants 40-87 years of age and free from cancer and diabetes, were followed for 5 years; 1442 incident breast cancer cases were documented. Diet was assessed at baseline by a validated 68-item food frequency questionnaire from which we calculated dietary glycemic index and glycemic load. Dietary glycemic index and load were not associated with increased risk of postmenopausal breast cancer (rate ratio = 1.03; 95% confidence interval, 0.87-1.22 and rate ratio = 0.90; 95% confidence interval, 0.76-1.08, respectively) after adjustment for multiple breast cancer risk factors. Associations were not modified by body mass index, physical activity, hormone use, or stage of disease. Future evaluations of glycemic index and breast cancer risk may be strengthened by longer follow-up, more complete dietary information, and measurement of plasma insulin and IGF-I levels.

Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort.

Recent studies suggest that the increased risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake. We examined this question among 66,561 postmenopausal women in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. A total of 1,303 incident cases had accrued during the first 5 years of follow-up. Cox proportional hazards models and stratified analysis were used to examine the relationship between alcohol, dietary and total folate intake, multivitamin use, dietary methionine, and breast cancer. We observed an increasing risk of breast cancer with increasing alcohol consumption (P for trend = 0.01). In the highest category of consumption (15 or more grams of ethanol/day), the risk of breast cancer was 1.26 (95% confidence interval, 1.04-1.53) compared with nonusers. We observed this association with higher alcohol consumption for in situ, localized, and regional disease. We found no association between risk of breast cancer and dietary folate, total folate, multivitamin use, or methionine intake. Furthermore, we found no evidence of an interaction between levels of dietary folate (P for interaction = 0.10) or total folate (P for interaction = 0.61) and alcohol. Nor did we find evidence of an interaction between alcohol consumption and recent or long-term multivitamin use (P for interaction = 0.27). Our results are consistent with a positive association with alcohol but do not support an association with folate or methionine intake or an interaction between folate and alcohol intake on risk of breast cancer.

Trefoil peptide expression and goblet cell number in rat intestine: effects of KGF and fasting-refeeding.

The trefoil factor family peptides TFF1, TFF2, and TFF3 are important for gut mucosal protection and restitution. Keratinocyte growth factor (KGF) stimulates proliferation and differentiation of epithelial cells with potent effects on goblet cells. To investigate interactions between food intake and KGF, rats were fed ad libitum (control), fasted for 72 h, or fasted for 72 h and then refed for 72 h with or without KGF (3 mg. kg(-1). day(-1)). With fasting, goblet cell number in duodenum increased, TFF3 mRNA in duodenum and jejunum decreased, and TFF3 protein did not change or increased. KGF during fasting stimulated colonic growth, normalized TFF3 mRNA in duodenum and jejunum, and broadly upregulated gut goblet cell number and TFF3 protein expression. With fasting-refeeding, KGF increased small bowel and colonic mucosal growth, goblet cell number, and TFF3 protein but had variable effects on TFF3 mRNA. KGF induced TFF2 mRNA and protein in duodenum and jejunum with both nutritional regimens. We conclude that nutrient availability modifies rat intestinal goblet cell number, TFF3 mRNA, and the gut-trophic effects of KGF in a region-specific manner. KGF enhances TFF2 expression in proximal small bowel and increases goblet cell number and TFF3 protein content throughout the intestine independent of food intake.

Extracellular thiol/disulfide redox state affects proliferation rate in a human colon carcinoma (Caco2) cell line.

Redox mechanisms function in regulation of cell growth, and variation in redox state of plasma thiol/disulfide couples occurs in various physiologic conditions, including diabetes, chemotherapy, and aging. The present study was designed to determine whether a systematic variation in extracellular thiol/disulfide redox state (E(h)) over a range (0 mV to -150 mV) that occurs in human plasma altered proliferation of cultured cells. Experiments were performed with a human colon carcinoma cell line (Caco2), which grows slowly in the absence of serum and responds to peptide growth factors with increased rate of cell division. The extracellular redox states were established by varying concentrations of cysteine and cystine, maintaining constant pool size in terms of cysteine equivalents. Incorporation of 5-bromo-2-deoxyuridine (BrdU) was used to measure DNA synthesis and was lowest at the most oxidized extracellular E(h) (0 mV). Incorporation increased as a function of redox state, attaining a 100% higher value at the most reduced condition (-150 mV). Addition of insulin-like growth factor-1 (IGF-1) or epidermal growth factor (EGF) increased the rate of BrdU incorporation at more oxidizing redox conditions (0 to -80 mV) but had no effect at -150 mV. Cellular GSH was not significantly affected by variation in extracellular E(h). In the absence of growth factors, extracellular E(h) values were largely maintained for 24 h. However, IGF-1 or EGF stimulated a change in extracellular redox to values similar to that for cysteine/cystine redox in plasma of young, healthy individuals. The results show that extracellular thiol/disulfide redox state modulates cell proliferation rate and that this control interacts with growth factor signaling apparently independently of cellular glutathione.

Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women.

Some epidemiologic studies suggest that use of vitamin C or vitamin E supplements, both potent antioxidants, may reduce the risk of bladder cancer. The authors examined the association between use of individual vitamin C and vitamin E supplements and bladder cancer mortality among 991,522 US adults in the Cancer Prevention Study II (CPS-II) cohort. CPS-II participants completed a self-administered questionnaire at enrollment in 1982 and were followed regarding mortality through 1998. During follow-up, 1,289 bladder cancer deaths occurred (962 in men and 327 in women). Rate ratios were adjusted for age, sex, cigarette smoking, education, and consumption of citrus fruits and vegetables. Regular vitamin C supplement use (>or=15 times per month) was not associated with bladder cancer mortality, regardless of duration (rate ratio (RR) = 0.91, 95% confidence interval (CI): 0.68, 1.20 for <10 years' use; RR = 1.25, 95% CI: 0.91, 1.72 for >or=10 years' use). Regular vitamin E supplement use for >or=10 years was associated with a reduced risk of bladder cancer mortality (RR = 0.60, 95% CI: 0.37, 0.96), but regular use of shorter duration was not (RR = 1.04, 95% CI: 0.77, 1.40). Results support the hypothesis that long-duration vitamin E supplement use may reduce the risk of bladder cancer mortality.

Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort.

Supplementation with antioxidant vitamins has been associated with decreased risk of stomach cancer or regression of precancerous lesions in high-risk areas of China and Colombia. We examined the association between stomach cancer mortality and regular use (> or =15 times per month) of individual vitamin C supplements, individual vitamin E supplements, and multivitamins among 1,045,923 United States adults in the Cancer Prevention Study II (CPS-II) cohort. CPS-II participants completed a questionnaire at enrollment in 1982 and were followed for mortality through 1998. During follow-up, there were 1,725 stomach cancer deaths (1,127 in men and 598 in women). After adjustment for multiple potential stomach cancer risk factors, vitamin C use at enrollment was associated with reduced risk of stomach cancer mortality [rate ratio (RR), 0.83; 95% confidence interval (CI), 0.68-1.01]. However, this reduction in risk was observed only among participants with short duration use at enrollment (RR, 0.68; 95% CI, 0.51-0.91 for <10 years of use; RR, 1.00; 95% CI, 0.73-1.38 for > or =10 years of use). There was no association between stomach cancer mortality and regular use of vitamin E (RR, 1.02; 95% CI, 0.82-1.27) or multivitamins (RR, 0.89; 95% CI, 0.77-1.03), regardless of duration of use. Our results suggest that the use of vitamin C, vitamin E, or multivitamin supplements may not substantially reduce risk of stomach cancer mortality in North American populations in which stomach cancer rates are relatively low. Our results do not rule out effects of vitamin supplementation in areas in which stomach cancer rates are high and stomach cancer etiology may differ.