Prostate cancer risk and ESR1 TA, ESR2 CA repeat polymorphisms.

BACKGROUND: Experimental evidence has suggested that estrogen receptor alpha (coded by the gene ESR1) might increase prostate cancer risk, whereas estrogen receptor beta (coded by the gene ESR2) might reduce prostate cancer risk. METHODS: We investigated the relationship with prostate cancer risk of both a TA repeat polymorphism in the ESR1 5' region, ESR1 (TA)(n), and with a CA repeat polymorphism in intron 5 of ESR2, ESR2 (CA)(n), in a case-control study (545 cases and 674 controls) nested in the Physicians' Health Study. RESULTS: Prostate cancer risk was highest for carriers of ESR1 (TA)(24) and ESR1 (TA)(25). Replacing one modal ESR1 (TA)(14) allele with one ESR1 (TA)(24) allele yielded an odds ratio of 1.42 (95% confidence interval, 1.00-2.00; P=0.05). Replacing one ESR1 (TA)(14) allele with one ESR1 (TA)(25) allele yielded an odds ratio of 2.10 (95% confidence interval, 1.15-3.84; P=0.02). ESR2 (CA)(n) showed no effects on prostate cancer risk. CONCLUSIONS: The ESR1 (TA)(n) polymorphism might play a role in prostate cancer risk.

Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.

Increased conversion of glucose to lactic acid associated with decreased mitochondrial respiration is a unique feature of tumors first described by Otto Warburg in the 1920s. Recent evidence suggests that the Warburg effect is caused by oncogenes and is an underlying mechanism of malignant transformation. Using a novel approach to measure cellular metabolic rates in vitro, the bioenergetic basis of this increased glycolysis and reduced mitochondrial respiration was investigated in two human cancer cell lines, H460 and A549. The bioenergetic phenotype was analyzed by measuring cellular respiration, glycolysis rate, and ATP turnover of the cells in response to various pharmacological modulators. H460 and A549 cells displayed a dependency on glycolysis and an ability to significantly upregulate this pathway when their respiration was inhibited. The converse, however, was not true. The cell lines were attenuated in oxidative phosphorylation (OXPHOS) capacity and were unable to sufficiently upregulate mitochondrial OXPHOS when glycolysis was disabled. This observed mitochondrial impairment was intimately linked to the increased dependency on glycolysis. Furthermore, it was demonstrated that H460 cells were more glycolytic, having a greater impairment of mitochondrial respiration, compared with A549 cells. Finally, the upregulation of glycolysis in response to mitochondrial ATP synthesis inhibition was dependent on AMP-activated protein kinase activity. In summary, our results demonstrate a bioenergetic phenotype of these two cancer cell lines characterized by increased rate of glycolysis and a linked attenuation in their OXPHOS capacity. These metabolic alterations provide a mechanistic explanation for the growth advantage and apoptotic resistance of tumor cells.

Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer.

Heat shock protein 70 (Hsp70) is a stress-inducible protein that is also known for its inhibitory effects on apoptosis. Increased Hsp70 expression is reported in a variety of tumor tissues. Heat shock protein 70 is detectable in plasma and could potentially be used as a biomarker for diagnosis or disease stratification. The relationship between plasma levels of Hsp70 and prostate cancer status has not been well studied. Our study was designed to test this relationship. One hundred twenty-five patients with localized/untreated or hormone-refractory prostate cancer were identified. Forty-five healthy male blood donors between 50 and 73 years of age served as controls. EDTA plasma was subjected to quantitative sandwich immunoassays for both Hsp70 and prostate-specific antigen (PSA). Wilcoxon rank-sum tests were used to examine differences by category. Maximally selected c2 statistics were used to identify cutoff points to best distinguish between categories. Plasma Hsp70 levels in the patients with localized untreated disease (n = 68; median, 0.8 ng/mL; interquartile range, 0.5-2.0) were significantly higher than those in the control group (n = 45; median, 0.5 ng/mL; interquartile range, 0.3-0.8; P = 0.0037). Although the primary cutoff point (1.15 ng/mL) significantly distinguished the localized untreated patients from the control group, plasma Hsp70 levels did not prove more effective than PSA as a predictor for diagnosis or stratification of patients with prostate cancer in the context of group comparisons. Nonetheless, several patients in the localized untreated group showed higher plasma levels of Hsp70 than the primary cutoff point even though their PSA levels were within normal range (< 4 ng/mL). Heat shock protein 70 is a marker of prostate cancer, although its clinical utility is uncertain. It is possible that when used in conjunction with PSA it might prove useful in identifying patients with early-stage prostate cancer who might otherwise be missed by PSA screening alone.

Cardiac response to progressive cycle exercise in moderately obese adolescent females.

PURPOSE: To assess cardiac responses to exercise and cardiac functional capacity in moderately obese adolescent females. METHODS: Thirteen healthy females (mean age 13.6 +/- 1.5 years) with a body mass index from 30 to 43 kg per m(2) underwent maximal cycle testing. Cardiac responses were measured by Doppler echocardiogram, and gas exchange variables were determined with open circuit spirometry. Data were analyzed by independent Student's t-tests. RESULTS: Peak oxygen uptake relative to height(3.0) was significantly greater in the obese (570 +/- 90 ml m(-3)) compared to the nonobese controls (485 +/- 60 ml m(-3)). This difference was explained by a higher peak cardiac output (4.50 +/- 1.06 L m(-3) vs. 3.81 +/- 58 L m(-3)) and stroke volume (24 +/- 5 ml m(-3) vs. 19 +/- 3 ml m(-3)) in the obese. Maximal cardiac index was similar in the two groups. There was no evidence of myocardial dysfunction during exercise in either group. CONCLUSIONS: Low aerobic fitness in obese adolescents as indicated by depressed peak VO(2) per kg body mass and limited endurance performance does not reflect decreased cardiac functional capacity.