Estrogen and its metabolites are believed to play important roles in breast cancer. The influence of genetic polymorphisms in the enzymes responsible for formation and disposition of estrogen on breast cancer risk may shed light on the importance of estrogen metabolites in this disease. However, for such studies to be valid, it is important to correctly identify the enzymes involved in estrogen bioactivation. Therefore, we assessed the human cytochrome P450 -dependent oxidation of estrone using substrate concentrations that more closely approximate the maximum expected concentrations in breast tissue. The in vitro metabolism of estrone by recombinant human cytochrome P450 enzymes and human liver microsomes was studied. The formation of estrone metabolites (2-hydroxyestrone, 4-hydroxyestrone, and 16A-hydroxyestrone) was monitored by high-performance liquid chromatography. 2-Hydroxyestrone formation was catalyzed predominantly by CYP1A2, CYP1A1, and CYP1B1 enzymes; 4-hydroxyestrone formation was catalyzed predominantly by CYP1B1, CYP1A2, and CYP1A1 enzymes; and 16A-hydroxyestrone formation was catalyzed predominantly by CYP2C19, CYP1A1, and CYP3A5. This study confirms the important role of members of the CYP1 family in the 2-hydroxylation and 4-hydroxylation of estrone, but the enzymes identified as responsible for the 16A-hydroxylation of estrone are different from those previously identified. The relative importance of these enzymes in vivo would depend on the specific tissue expression of the enzymes. These enzymes are all known to be genetically variant in the human population, and additional studies to assess the role CYP1A2, CYP2C19, and CYP3A5 in breast cancer risk are indicated. (Cancer Epidemiol Biomarkers Prev 2006;15(3):551 -8)
Purpose
Kidney cancer is one of the fastest rising cancers worldwide. We aimed to examine the trends in incidence, mortality, and survival for this cancer in Canada.MethodsIncidence data for kidney cancer for 1986–2010 were from the Canadian Cancer Registry and the National Cancer Incidence Reporting System. These data were only available up to 2007 for the province of Quebec and consequently for the same year nationally, for Canada. Mortality data for 1986–2009 were from the Canadian Vital Statistics Death Database. Changes in age-standardized rates were analyzed by Joinpoint regression. Incidence rates were projected to 2025 using a Nordpred age-period-cohort model. Five-year relative survival ratios (RSR) were analyzed for 2004–2008 and earlier periods.ResultsBetween 1986 and 2007, the age-standardized incidence rate (ASIR) per 100,000 rose from 13.4 to 17.9 in males and 7.7 to 10.3 in females. Annual increases in ASIR were greatest for age groups <65 years (males) and ≥65 years (females). The ASIRs increased significantly over time in both sexes for renal cell carcinoma (RCC) but not for other kidney cancer types. RCC rates are projected to increase until at least 2025. Mortality rates decreased only slightly in each sex since 1986 (0.4 %/year in males; 0.8 %/year in females). The 5-year RSR for kidney cancer was 68 % but differed largely by morphology and age, and has increased slightly over time.ConclusionsThe incidence rate of kidney cancer in Canada has risen since at least 1986, led largely by RCC. Increasing detection of incidental tumors, and growing obesity and hypertension rates are possible factors associated with this increase. Greater prevention of modifiable risk factors for kidney cancer is needed.
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