Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. A [TCATA] haplotype formed by polymorphisms at positions -3575, -2763, -1082, -819 and -592 in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the -592C > A polymorphism. Aim of the present study was to analyze the role of the IL-10 [TCATA] haplotype for breast cancer. We performed a case-control study including 500 female patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The -592C > A polymorphism was determined by a 5'-nuclease assay (TaqMan). Frequency of the homozygous -592 AA genotype, indicating homozygosity for the [TCATA] haplotype, was 4.2% among patients and 7.3% among controls (p=0.038; odds ratio 0.56; 95% confidence interval 0.32-0.97). IL-10 genotypes were not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. Therefore we conclude that the IL-10 -592C > A promoter polymorphism may be associated with a reduced breast cancer risk.

Purpose: The matrix metalloproteinase 3 (MMP3), also known as stromelysin-I, is a key-player for carcinogenesis and tumor growth. A 5A/6A promoter polymorphism is associated with differences in MMP3 activity and has been linked to cancer susceptibility in some studies. In the present study we evaluated the role of this polymorphism for breast cancer risk.Experimental Design: A case-control study was performed including 500 patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The MMP3 5A/6A polymorphism was determined by a 5-nuclease (TaqMan) assay.Results: Prevalences of 5A/5A, 5A/6A, and 6A/6A genotypes were similar among patients (20.6, 51.8, and 27.6%, respectively) and controls (23.3, 47.3, and 29.4%, P ‫؍‬ 0.34). The odds ratio of carriers of a MMP3 5A allele for breast cancer was 1.09 (95% confidence interval, 0.83-1.44). Patients with the 5A/5A genotype had a higher proportion of lymph-node metastases than those with a 5A/6A or 6A/6A genotype (P ‫؍‬ 0.010).Conclusions: The MMP3 5A/6A promoter polymorphism does not appear to influence breast cancer susceptibility but may be linked to a higher risk for metastasizing among breast cancer patients.

Nicotine increases serotonin release in the brain and symptoms of nicotine withdrawal may be modulated by diminished serotonergic neurotransmission. The promoter region of the serotonin transporter gene, solute carrier family neurotransmitter transporter member 4 (SLC6A4), contains a functional tandem repeat polymorphism. The long (L) variant is more actively transcribed than the short (S) variant and is associated with a higher serotonin uptake. To investigate the potential role of this polymorphism for smoking behavior, SLC6A4 genotypes were determined in two different studies, the SMOKING GENES case-control study (470 current smokers and 419 subjects who had never smoked) and the cross-sectional Ludwigshafen risk and cardiovascular health (LURIC) study (777 current smokers and 1178 subjects who had never smoked). In the SMOKING GENES case-control study, SLC6A4 genotype frequencies were not statistically different between smokers (LL: 30.9%; LS: 46.8%; SS: 16.4%) and non-smokers (LL: 36.3%; LS: 41.8%; SS: 14.3%; P ¼ 0.13). Similar results were obtained in the crosssectional LURIC study (smokers: LL, 36.5%, LS, 45.6%, SS, 17.9%; nonsmokers: LL, 33.6%, LS, 48.9%, SS, 17.6%; P ¼ 0.33). SLC6A4 genotypes were furthermore not associated with Fagerstrom Tolerance Questionnaire score, packyears, number of cigarettes smoked per day or previous attempts to quit smoking. We conclude that the SLC6A4 promoter polymorphism is not a major determinant of smoking behavior in Caucasian.

The aim of this study was to investigate the selectivity of the ATP‐sensitive potassium (KATP) channel inhibitor U‐37883A (4‐morpholinecarboximidine‐N‐1‐adamantyl‐N′‐1‐cyclohexyl). Membrane currents through KATP channels were recorded in single muscle cells enzymatically isolated from rat mesenteric artery, cardiac ventricle and skeletal muscle (flexor digitorum brevis). KATP currents were induced either by cell dialysis with 0.1 mM ATP and 0.1 mM ADP, or by application of synthetic potassium channel openers (levcromakalim or pinacidil). U‐37883A inhibited KATP currents in smooth muscle cells from rat mesenteric artery. Half inhibition of 10 μM levcromakalim‐induced currents occurred at a concentration of 3.5 μM. Relaxations of rat mesenteric vessels caused by levcromakalim were reversed by U‐37883A. 1 μM levcromakalim‐induced relaxations were inhibited at a similar concentration of U‐37883A (half inhibition, 1.1 μM) to levcromakalim‐induced KATP currents. KATP currents activated by 100 μM pinacidil were also studied in single myocytes from rat mesenteric artery, skeletal muscle and cardiac ventricle. 10 μM U‐37883A substantially inhibited KATP currents in vascular cells, but had little effect in skeletal or cardiac myocytes. Higher concentrations of U‐37883A (100 μM) caused a modest decrease in KATP currents in skeletal and cardiac muscle. The sulphonylurea KATP channel antagonist glibenclamide (10 μM) abolished currents in all muscle types. The effect of U‐37883A on vascular inward rectifier (KIR) and voltage‐dependent potassium (KV) currents was also examined. While 10 μM U‐37883A had little effect on these currents, some inhibition was apparent at higher concentrations (100 μM) of the compound. We conclude that U‐37883A inhibits KATP channels in arterial smooth muscle more effectively than in cardiac and skeletal muscle. Furthermore, this compound is selective for KATP channels over KV and KIR channels in smooth muscle cells. British Journal of Pharmacology (1999) 128, 909–916; doi:

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