Cytochrome P450 1A2 (CYP1A2) Activity and Risk Factors for Breast Cancer: A Cross-Sectional Study

Chi-Chen Hong; Bing-Kou Tang; Geoffrey L Hammond; David Tritchler; Martin Yaffe; Norman F Boyd

Disclosures

Breast Cancer Res. 2004;6(4) 

In This Article

Discussion

In the present study we found that CYP1A2 activity, as measured by the CMR, varied 30-fold in premenopausal women and ninefold in postmenopausal women, but as in previous studies mean values did not vary with menopausal status.[6] CYP1A2 activity was found in both menopausal groups, through stepwise and maximum R regression, to be independently associated with a number of covariates, including smoking status, serum levels of SHBG, circulating levels of blood cholesterol, and triglycerides. CYP1A2 activity was also associated with age, BMI, endogenous insulin levels, and caffeine intake in premenopausal women, and with IGF-1 levels and age at menarche in postmenopausal women. These results suggest that CYP1A2 activity is associated with a number of risk factors associated with breast cancer.

In both premenopausal and postmenopausal women, approximately 40% of the variability associated with CYP1A2 activity was explained by the lifestyle, hormonal, and host factors examined in the study. The remaining 60% of variability not explained by our models point to unexamined factors, which may in part be genetic. In a twin study of Caucasians conducted in Denmark,[28] CYP1A2 activity was determined for 49 monozygotic twin pairs and 34 same-sex dizygotic twin pairs concordant for nonsmoking and nonuse of oral contraceptives. A biometrical model for the caffeine ratio including only additive genetic factors and unique environmental factors was the best fitting model and gave a heritability estimate of 0.725 (95% confidence interval 0.577–0.822), suggesting that CYP1A2 activity is mainly under genetic control. Several genetic polymorphisms have been identified to date in the CYP1A2 gene, including one associated with greater inducibility[29] and one associated with decreased inducibility.[8] The extent, however, to which these polymorphisms explain the interindividual variation associated with CYP1A2 activity is unclear, particularly in nonsmokers.[29] Results from this study add to the evidence that CYP1A2 function is related to traits that are in part under genetic control, such as blood levels of IGF-1 and body size.[30,31]

In the present study, CYP1A2 function was positively related to insulin levels in premenopausal women and positively, but weakly, related to IGF-1 levels in postmenopausal women. Because both insulin[32,33] and IGF-1[34] levels have been linked to increased risk for breast cancer and/or recurrence, our findings suggest that CYP1A2 function is associated with increased rather than decreased breast cancer risk as hypothesized.

Given the cross-sectional nature of the study, it is unclear whether CYP1A2 activity is affected by insulin and IGF-1 levels, or vice versa, although there is evidence to suggest that these variables may mutually affect each other. In a recent randomized study of healthy elderly (≥ 70 years) men on the effects of administered recombinant human GH,[35] those given GH had increased IGF-1 levels and increased CMR, as a measure of CYP1A2 activity, compared with those given placebo. There is also some evidence from animal studies that insulin can induce CYP1A2 activity,[36] and obese Zucker rats, which exhibit hyperinsulinemia, hyperglycemia, and hypercholesterolemia compared with lean Zucker rats, also exhibit higher CYP1A2 levels.[37]

In the opposite direction, microarray analysis of CYP1A2-/- knockout mice suggests a role for CYP1A2 in the expression of insulin and IGF-1 genes. CYP1A2-/- mice exhibited downregulation of genes involved in insulin action, including IGFBP-1, glucokinase, and phosphenolpyruvate carboxykinase-1, which catalyzes the rate-limiting step in glucogenesis.[38] These changes in gene expression may be linked to an overall downregulation of cell proliferation, changes in sex steroid and SHBG production, and/or alterations in lipid metabolism.[38]

Increased levels of insulin and/or IGF-1 can potentially increase breast cancer risk through a number of mechanisms. Insulin can decrease SHBG levels,[39] and inverse associations were observed in the present study between SHBG and insulin levels (premenopausal: β = -0.74 ± 0.37, F = 4.07, P = 0.05; postmenopausal: β = -0.91 ± 0.32, F = 7.92, P = 0.006) as well as IGF-1 (in postmenopausal women only: β = -0.22 ± 0.08, F = 8.04, P = 0.005) after adjustment for age, BMI, ethnicity, and WHR. Insulin can also stimulate adrenocortical aromatase P450 mRNA levels[40]; upregulate steroidogenic acute regulatory protein, which increases the rate of cholesterol transport for steroidogenesis[41]; and upregulate transcription of the gene encoding sterol response-binding protein-1c, which is involved in the expression of lipogenic genes.[38]

In both menopausal groups, CYP1A2 phenotype was not associated with total estradiol levels, but it was negatively associated with percentage free estradiol, which in turn is strongly related to SHBG levels. The positive association between CYP1A2 activity and SHBG levels (and inverse associations between CYP1A2 and percentage free estradiol) was independent of the relationship of CYP1A2 with insulin and IGF-1 levels. Because estrogens increase serum SHBG levels presumably through enhanced hepatic synthesis,[42] lower levels of CYP1A2 activity in the liver might have a direct effect on enhancing SHBG production due to an increased level of estrogen activity in the liver, and this would account for a lowering of plasma free estradiol levels.

Inverse associations between CYP1A2 activity and percentage free estradiol are consistent with previous reports that female sex hormones have an inhibitory effect on CYP1A2 activity. CYP1A2 activity is lower in women,[6] reduced by 35–50% during pregnancy,[7] inhibited by oral contraceptives[6] and hormone replacement therapy,[43] and may be lower during the late luteal phase of the menstrual cycle, when estradiol concentrations peak.[44]

CYP1A2 activity varied negatively with total cholesterol levels in premenopausal women and HDL-cholesterol levels in postmenopausal women. Relationships between estrogens and plasma lipids are well documented, and exogenous estrogens are known to reduce serum lipids and lipoproteins.[45] Furthermore, 2-hydroxyestrone, a product of CYP1A2 activity, has been shown in rats to have a serum triglyceride reducing effect as strong as that of 17β-estradiol.[46] Elevated triglyceride levels have been associated with increased breast cancer risk in both premenopausal and postmenopausal women.[47,48] In this study, however, circulating triglyceride levels were positively associated with CYP1A2 activity in premenopausal women, and negatively associated in postmenopausal women. The reason for this is unclear, although findings were independent of BMI and WHR, which were included in the analyses as potential predictors of CYP1A2 function. Findings were not altered when BMI and WHR were forced into the regression models as potential confounders (data not shown).

Recent research shows that several genes involved in fatty acid and cholesterol biosynthetic pathways are downregulated in the CYP1A2 knockout mouse.[38] This may affect breast cancer risk since steroidogenesis is influenced by the provision of cholesterol as a substrate.[49] These findings, however, support a positive association between CYP1A2 activity and lipid and cholesterol biosynthesis, whereas our findings generally showed inverse associations between CYP1A2 activity and circulating cholesterol and triglyceride levels (in postmenopausal women).

As in previous studies, CYP1A2 function was strongly induced by tobacco smoke.[6,7] The effect of smoking on CYP1A2 function may explain why smoking is not an important risk factor for breast cancer and may actually be protective. Cigarette smoking has been observed to increase 2-hydroxylation[50] and reduce the conversion rate of androgens to estrogens.[51] Brunet and coworkers[52] recently reported that smoking reduces risk for breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations.

CYP1A2 activity was found to vary inversely with BMI in premenopausal women after adjusting for other covariates. These findings were similar to that observed in a study of 786 Caucasian women,[6] which was the first to find an inverse association between CYP1A2 activity and BMI. Because increased BMI is associated with reduced risk before the menopause,[53] our findings would suggest that lower CYP1A2 activity (associated with greater BMI) in these women would be associated with lower breast cancer risk. Low 2-hydroxyestrone levels, however, have been associated with higher risk for breast cancer in premenopausal women.[54] Further study is needed to elucidate the relationship between CYP1A2 activity, body size, and breast cancer risk.

CYP1A2 activity was associated with a number of dietary factors in premenopausal women but not in postmenopausal women. After adjusting for body size, age, ethnicity, and smoking status, positive associations were observed with intake of caffeine, total energy, fat, and protein. After adjusting for other covariates through stepwise and maximum R regression, however, only caffeine intake remained significant. The positive association between caffeine intake and CYP1A2 activity in premenopausal women is consistent with results from other studies that suggest that caffeine can induce CYP1A2 activity.[6,7,55] This has been observed in population[12] as well as rat studies.[56]

Limitations of the present study include the small number of participants, particularly after stratification by menopausal status. The research was exploratory in nature, and so novel findings, such as associations observed with insulin and IGF-1 levels, as well as with blood lipids and cholesterol, are more likely due to chance and need replication in future studies.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....