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Carcinogenesis Advance Access originally published online on February 14, 2008
Carcinogenesis 2008 29(4):766-771; doi:10.1093/carcin/bgn042
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project

Yu Chen1, Marilie D. Gammon2, Susan L. Teitelbaum3, Julie A. Britton3, Mary Beth Terry4, Sumitra Shantakumar2, Sybil M. Eng5, Qiao Wang6, Irina Gurvich6, Alfred I. Neugut4, Regina M. Santella6 and Habibul Ahsan4,7,*

1 Department of Environmental Medicine and New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA
2 Department of Epidemiology, University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, NC 27599-7435, USA
3 Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
4 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
5 Global Epidemiology, Pfeizer, New York, NY 10017, USA
6 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
7 Departments of Health Studies, Medicine and Human Genetics and Cancer Research Center, The University of Chicago, 5841 South Maryland Avenue, Suite N102, Chicago, IL 60637, USA

* To whom correspondence should be addressed. Tel: +1 773 834 9956; Fax: +1 773 834 0139; Email: habib{at}uchicago.edu


   Abstract
Top
 Abstract
Introduction and background
 Materials and Methods
 Results
 Discussion
 Funding
 References
 
The genes that are involved in estrogen biosynthesis, cellular binding and metabolism may contribute to breast cancer susceptibility. We examined the effect of the CYP17 promoter T -> C polymorphism and its interactions with the reproductive history, exogenous hormone use and selected lifestyle risk factors on breast cancer risk among 1037 population-based incident cases and 1096 population-based controls in the Long Island Breast Cancer Study Project. Overall, there were no associations between the CYP17 genotype and breast cancer risk. Among postmenopausal women, the joint exposure to higher body mass index (BMI) and the variant C allele was associated with an increased risk of breast cancer [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.15–2.22]. The joint exposure to the variant C allele and long-term use of hormone replacement therapy (HRT) (>51 months) was related to an increased risk of breast cancer (OR, 1.51; 95% CI, 0.99–2.31) especially estrogen receptor-positive, progesterone receptor-positive breast cancer (OR, 1.87; 95% CI, 1.08–3.25). Among the control population, the CYP17 variant C allele was inversely associated with long-term use of postmenopausal HRT and a higher BMI in postmenopausal women. In conclusion, the findings suggest that the CYP17 variant C allele may increase breast cancer risk in conjunction with long-term HRT use and high BMI in postmenopausal women.

Abbreviations: BMI, body mass index; CI, confidence interval; HBC, hormonal birth control; HRT, hormone replacement therapy; LIBCSP, Long Island Breast Cancer Study Project; OR, odds ratio


   Introduction and background
Top
 Abstract
 Introduction and background
Materials and Methods
 Results
 Discussion
 Funding
 References
 
Circulating estrogen is considered to be the key element in breast cancer etiology (1–4). The effects of many of the established and suspected risk factors for breast cancer, including reproductive (ages at menarche, first birth and menopause and parity), exogenous hormone use [oral contraceptive and hormone replacement therapy (HRT)] and lifestyle [body mass index (BMI) and alcohol consumption] factors, are mediated through estrogen (5–8). Estrogen biosynthesis, cellular binding and metabolism involve many steps, and the genes controlling these steps may contribute to the inherent variability in breast cancer susceptibility (9,10). Endogenous estrogen is produced predominantly in ovarian theca cells in premenopausal women and in breast stromal adipose cells in postmenopausal women (11). The enzyme cytochrome P450 17{alpha} hydroxylase (CYP17) controls two successive early steps of endogenous estrogen biosynthesis by converting pregnenolone and progesterone to precursors of androgen and estrogen (12,13).

A T -> C single nucleotide polymorphism in the 5’ promoter region of the CYP17 gene has been found to create a Sp1-type (CCACC) promoter site (14), and the C allele is associated with an increased serum estrogen level (15–17). CYP17 C allele has also been inversely associated with HRT use (16,18), earlier age at menarche (19,20) and later age at menopause (20). A recent human genome epidemiology (HuGE) review of CYP17 gene polymorphisms concluded that further investigation is needed of relations between genotype and hormone levels, exogenous hormone use and markers of hormonal status (19).

A number of studies have evaluated the association between the CYP17 polymorphism and breast cancer risk. Feigelson et al. (21) first reported a higher risk of breast cancer in relation to the CYP17 C allele among non-Caucasian women. Although one subsequent study confirmed a significant association between the CYP17 C allele and overall risk of breast cancer (22), others did not find that CYP17 T -> C variant plays a significant role in breast cancer risk (20,23–26). A meta-analysis concluded that the CYP17 T -> C polymorphism is not a significant independent risk factor for breast cancer (27). Nevertheless, many studies reported increased risk in certain subgroups of women studied, e.g. women with early age at menarche (24), women >55 years (17), women who also carry other genetic polymorphisms (28) and nulliparous women (26). Several studies found an association between C allele and breast cancer risk in women <40 (22,23,29). In contrast, two studies reported a tendency of inverse association of breast cancer in relation to C allele among premenopausal women (30,31). In addition, three case–control studies found that the inverse association between later age at menarche and breast cancer risk was more pronounced among women who do not carry the C allele (16,21,30). These findings, although inconsistent, suggest that the influence of CYP17 may be modifiable by other hormone-related risk factors of breast cancer. No studies, to date, have evaluated the association between CYP17 and breast cancer risk by the hormonal receptor status of breast cancer.

In the present large case–control study, we examined whether a woman's genetic status of the CYP17 T -> C polymorphism modifies the effects of ages at menarche, parity, oral contraceptive use, HRT and body size on the risk of breast cancer. We also examined the association between CYP17 genotype and breast cancer risk by hormone receptor status of breast cancer. Although other polymorphisms in the CYP17 gene have been reported, we focused on this polymorphism since it has been studied most extensively both in relation to breast cancer risk and also to circulating estrogens.


   Materials and Methods
Top
 Abstract
 Introduction and background
 Materials and Methods
Results
 Discussion
 Funding
 References
 
The parent case–control study Long Island Breast Cancer Study Project (LIBCSP) is a population-based study designed to identify environmental risk factors of breast cancer, with a particular focus on their potential interactions with host and endogenous factors. The study was undertaken by researchers from most of the major academic and medical institutions in the metropolitan New York area. The details of the study methodologies including the subject identification, selection and recruitment of study participants, collection of questionnaire data and biological samples and their processing have been described elsewhere (32). A brief description of the relevant aspects of study methods is presented here.

Study population
The LIBCSP recruited population-based incident breast cancer cases and controls between 1996 and 1997 among adult female residents of Nassau and Suffolk counties, Long Island, New York. Cases were identified through rapid case ascertainment with frequent contact with the pathology departments of all hospitals in the catchment area. Controls without a history of breast cancer were selected through the use of Waksberg's random digit dialing (for age <65 years) and Health Care Financing Administration rosters (for age ≥65 years), with frequency matching to the expected age distribution of case women by 5 year age groups. Altogether 1102 cases (73% of the total 1508 participating) and 1141 controls (73% of the total 1556 participating) provided blood samples. The blood samples were collected in ethylenediaminetetraacetic acid tubes, which were transported overnight at room temperature on ice to Columbia University and processed and separated into aliquots of plasma and cells within 24 h of collection. The aliquots were stored at –80°C until genomic DNA was isolated (33).

Detailed data on the established and potential risk factors of breast cancer including reproductive, exogenous hormone use and lifestyle factors were collected using a structured questionnaire as described previously (http://epi.grants.cancer.gov/LIBCSP/projects/Questionnaire.html) (32,34). Briefly, to help identify periods of exogenous hormone use, the interviewer used a month-by-month calendar marked earlier in the interview with the participant's reproductive history and other life events (34). Use of HRT was defined as self-reported history of HRT use in the form of pills, shots, skin patch, vaginal cream and suppositories for any period of time prior to the reference date (date of diagnosis for cases, date of identification for controls) (34). Use of hormonal birth control (HBC) was defined as self-reported history of HBC use in the form of pills, shots or implants for any period of time prior to the reference date (34). Self-reported weight and height 1 year prior to the reference date were used to calculate BMI, defined as weight in kilograms divided by height in meters squared (35). Menopausal status was based on self-reported information collected during the baseline interview, including information on a woman's last menstrual period, prior surgical information on hysterectomy or bilateral oophorectomy, cigarette smoking status and HRT use, as described previously (34). Women who answered ‘no’ and ‘yes’ to questions about ever consuming alcoholic beverages such as beer, wine or liquor at least once a month for >6 months were classified as never drinkers and ever drinkers, respectively (36).

Details of the descriptive characteristics of the overall LIBCSP cases and controls have been published elsewhere (32). Briefly, in LIBCSP, breast cancer cases were less likely to be highly parous, less likely to have been breast fed, more likely to have a later age at first birth and more likely to have a family history of breast cancer in mother or sister. Cases and controls were comparable in terms of education, age at menarche, body weight and alcohol use (32), although more detailed analyses have found that breast cancer risk is positively associated with postmenopausal obesity (35), use of HRT during the perimenopausal years (34) and lifetime intake of alcohol (37). The racial composition of the study population did not differ from the parent LIBCSP overall population, which consisted of 93.8% White, 4.6% Black and 1.7% others in cases and 91.8% White, 5.5% Black and 2.7% others in controls (32). Medical records were abstracted for case women with signed informed medical record release forms to determine hormone receptor status.

Laboratory analysis
The CYP17 T -> C promoter single nucleotide polymorphism was determined using template-directed primer extension and detection by fluorescence polarization in a 96-microwell-based format (38,39). First, the target DNA was polymerase chain reaction amplified (using forward primer 5'-TTTAAAAGGCCTCCTTGTGC-3’ and reverse primer 5'-TTGGGCCAAAACAAATAAGC-3’) to generate products in the range of 100–200 bp. After polymerase chain reaction amplification, the primers were digested with shrimp alkaline phosphatase and Escherichia coli exonuclease I. Then, single nucleotide extension was carried out in the presence of the appropriate allele specific dideoxy nucleoside triphosphates (Acycloprime FP single nucleotide polymorphism Detection kit labeled with R110 or TAMRA; Perkin Elmer Life Sciences, Boston, MA) and the forward probe (5'-GCCACAGCTCTTCTACTCCAC-3’). Finally, the fluorescence polarization was read on a Perkin Elmer Victor instrument. All laboratory assays were performed with laboratory personnel blinded to the subject's disease status. In addition to assay-specific quality control samples, 10% of samples were reassayed after relabeling to keep laboratory staff blinded to its identity. Kappa statistic, a measure of agreement beyond chance, was 0.96.

Statistical analysis
In the present analysis, we included 1037 cases and 1096 controls with genotyping results, 94 and 96% of cases and controls with blood samples, respectively. Descriptive analysis was first conducted to compare the distributions of CYP17 genotype, reproductive history, exogenous hormone use and lifestyle factors by breast cancer status using t-tests (for continuous variables) and chi-squared tests (for categorical variables).

Odds ratios (ORs) were estimated to evaluate the association between the CYP17 genotype and breast cancer status. Maximum likelihood estimates of OR and associated 95% confidence intervals (CIs) were estimated using unconditional logistic regression models with adjustment for ethnic background and the frequency matching factor age by 5 year age group and other potential confounders (40). We first evaluated the main effects of CYP17 using TT genotype as the reference group. The results did not suggest qualitative differences between the associations of TC and CC genotypes with breast cancer risk. Therefore, to maximize the statistical power for the evaluation of the joint effects of CYP17 and the potential effect modifiers, we treated CYP17 genotype as a categorical variable by classifying the study subjects into two groups according to dominant genetic susceptibility model. Reproductive and lifestyle risk factors of interest were dichotomized according to biological meaningful cut points. For exogenous hormone use and alcohol consumption, long-term (>6 months) users were considered as the exposed group. We estimated ORs for breast cancer according to joint status of CYP17 genotype and each of the hormone-related risk factors using the group with the low-risk genotype and the hypothesized low-risk category of the risk factor as the reference group.

In addition, we assessed the presence of synergy (i.e. interaction on an additive scale) between HRT use and CYP17 genotype by testing whether the joint effect of TC/CC genotypes and HRT use was greater than the sum of their independent effects. We hypothesized a priori a single reference group with the lowest risk of breast cancer (TT genotype and low-risk category of potential effect modifier) and estimated relative excess risk for interaction and the attributable proportion due to interaction using adjusted ORs as surrogates of risk ratios (41,42). CIs of relative excess risk for interaction and attributable proportion due to interaction were estimated for statistical inferences using the standard delta method described by Hosmer et al. (43).

ORs for breast cancer by hormone receptor status of breast cancer were examined using unordered polytomous logistic regression. These models categorized the dependent variable into five groups based on estrogen receptor positivity (ER+) or negativity (ER–) and progesterone receptor positivity (PR+) or negativity (PR–): ER+ PR+, ER+ PR–, ER– PR+, ER– PR– and controls. In addition, we evaluated the relationships between the CYP17 genotype and hormone-related risk factors among the controls.

Since the effects of hormone-related risk factors on breast cancer risk may differ by menopausal status, we conducted stratified analyses by menopausal status. The differences in the effects across menopausal status were assessed by tests for heterogeneity (44). All the analyses were also conducted in White women; however, the results were similar, therefore, were not presented. All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction and background
 Materials and Methods
 Results
Discussion
 Funding
 References
 
Distribution of CYP17 genotype in cases and controls was consistent with Hardy–Weinberg equilibrium (chi-square statistics P > 0.05 in cases and in controls). There was no significant association between CYP17 genotype and breast cancer risk in the overall study population (Table I). CYP17 CC genotype was positively associated with risk of breast cancer in postmenopausal women and was inversely related to breast cancer in premenopausal women. However, the CIs did not exclude unity.


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  		Table I. Breast cancer risk associated with CYP17 genotype: LIBCSP, 1996–1997

 
Table II presents the results on risk estimates for all breast cancer in relation to the joint status of CYP17 genotype and exogenous hormone use (HRT and HBC use), reproductive history (age at menarche and parity) and lifestyle variables (BMI and alcohol consumption) in overall and among pre- and postmenopausal women separately. We observed an increased risk of breast cancer among women who used HRT for ≥6 months and carried the variant C allele, compared with women who used HRT for 0–6 months with TT genotype (OR, 1.38; 95% CI, 1.02–1.87). Among postmenopausal women, as compared with women who were homozygous carriers of the CYP17 T allele with a BMI <25, those who were carriers of the variant C allele with a BMI ≥25 were at an elevated risk of breast cancer (OR, 1.93; 95% CI, 1.32–2.84). In addition, carriers of the variant C allele who used HRT for ≥6 months and who used HRT for >51 months were at a non-significant elevated risk of breast cancer, as compared with women who used HRT for 0–6 months with TT genotype (OR, 1.28; 95% CI, 0.93–1.81 and OR, 1.51; 95% CI, 0.99–2.31, respectively). Long-term HRT users with duration of use 6–51 months and >51 months on average used HRT for 20.5 and 126 months (10.5 years), respectively. There were no consistent associations between the joint status of the genotype and either HBC use, alcohol consumption, parity or age at menarche in overall and in either pre- or postmenopausal women.


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  		Table II. Breast cancer risk associated with CYP17 genotype by hormone-related risk factors of breast cancer: LIBCSP, 1996–1997

 
We examined the association between CYP17 genotype and breast cancer risk by hormone receptor status of the cases (ER+, ER–, PR+ and PR–). In postmenopausal women, the positive association between the variant C allele and breast cancer risk was more evident only for the subgroup of cases with ER+ PR+ tumor (OR, 1.29; 95% CI, 0.93–1.78 for ER+ PR+; OR, 0.85; 95% CI, 0.52–1.39 for ER+ PR–; OR, 0.86; 95% CI, 0.29–2.59 for ER– PR+ and OR, 0.99, 95% CI, 0.61–1.65 for ER–PR–). In premenopausal women, the variant C allele was inversely related to breast cancer risk for the subgroup of cases with ER+ PR– (OR, 0.83; 95% CI, 0.55–1.26 for ER+ PR+; OR, 0.35; 95% CI, 0.12–1.00 for ER+ PR–; OR, 0.61; 95% CI, 0.21–1.71 for ER– PR+ and OR, 0.75, 95% CI, 0.41–1.35 for ER–PR–). We further evaluated joint effect of HRT use and the variant C allele on breast cancer risk by hormone receptor status of cases in postmenopausal women (Table III). Because effect estimates were similar for the three subgroups with at least one negative hormone receptor, we combined the three groups. The variant C allele is positively associated with the risk of ER+PR+breast cancer risk in postmenopausal women with long-term use of HRT compared with those who did not carry variant C allele and did not take HRT long-term. Although there was no statistical evidence of interaction on a multiplicative scale (P = 0.11), the estimates are suggestive of a synergy effect between HRT use >51 months and CYP17 C allele. The relative excess risk for interaction estimate was 1.00 (95% CI, –0.05, 2.07) and the attributable proportion due to interaction estimate was 0.53 (95% CI, 0.11, 0.95), indicating that 53% of estrogen receptor-positive, progesterone receptor-positive breast cancer risk among those with HRT use >51 months and CYP17 C allele was attributable to the synergy between the two factors.


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  		Table III. Relationships between joint status of HRT use and CYP17 genotype on breast cancer risk by hormone receptor status among postmenopausal women

 
In addition to the case–control comparison described above, we also assessed whether the CYP17 genotype was associated with exogenous hormone use (HRT and HBC use) or relevant reproductive (fertility problem, age at menarche and parity) and lifestyle (BMI and alcohol consumption) variables among the population controls. As shown in Table IV, among postmenopausal women, CYP17 CC genotype was inversely related to ever using HRT (OR, 0.62; 95% CI, 0.37–1.02) and positively related to having a BMI ≥25 (OR, 1.77; 95% CI, 1.09–2.87). Finally, because one prior study reported a protective effect of later age at menarche only among the CYP17 variant C allele carriers, we have also examined this association in our study. We did not observe such an effect in this population (results not shown).


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  		Table IV. Relationships of CYP17 genotype with use of HRT and BMI among controls: LIBCSP, 1996–1997

 

   Discussion
Top
 Abstract
 Introduction and background
 Materials and Methods
 Results
 Discussion
Funding
 References
 
In this population-based case–control study on Long Island, New York, we investigated the effect of the CYP17 promoter polymorphism and its interactions with exogenous hormone use (HRT and HBC use), reproductive history (parity and age at first menarche) and lifestyle factors (BMI and alcohol consumption) in breast cancer risk. Our study was conducted in a predominantly Caucasian population. The finding that there was no overall association between the CYP17 variant C allele and breast cancer is similar to what has been reported in prior published case–control studies in Caucasians (20,24–26) and other populations (18) with number of cases ranging from 242 to 1544. The absence of the association was consistent for all genetic susceptibility models, e.g. dominant, additive and recessive models.

Similar to several case–control studies (22,29–31), we found that the association between CYP17 genotype and breast cancer risk differed by menopausal status, although the test for heterogeneity did not reach statistical significance at P < 0.05 level. Our findings in postmenopausal women are consistent with the literature that there is no overall association in postmenopausal women. Evidence on the association between CYP17 genotype and breast cancer risk in premenopausal is inconsistent. A case–control study with women of homogenous Finnish origin (30) and another case–control study in Korean women (31) suggested an inverse association between CYP17 genotype and breast cancer risk in premenopausal women. We also observed a non-significant inverse association in premenopausal women. On the other hand, Bergman-Jungestrom et al. (29) found an increased risk associated with the CYP17 C allele in Swedish young women. Spurdle et al. (22) also observed an increased risk of breast cancer in relation to the CYP17 C allele among young Australian women (age < 40) with family history of breast cancer but not among those without family history of breast cancer (22). We did not find any differences in the association between participants with and without family history of breast cancer in the present study (data not shown). Taken together, the observation of a differential effect of CYP17 genotype on breast cancer risk by menopausal status supports the view that breast cancer etiology may differ by hormone-related factors, although the associated biological explanations are not clear. The inconsistent findings in premenopausal women may also be due to the possible interactions between CYP17 genotype and other hormone-related lifestyle risk factors that may be more variable in younger women and the interactions between CYP17 genotype and other genetic predisposition that may be more frequently present in younger cases of breast cancer.

Among post-menopausal women, we found that carriers of the CYP17 variant C allele with long-term use of HRT had an elevated risk of breast cancer, especially breast cancer with ER+ PR+. The finding suggests that CYP17 and long-term HRT use may promote breast cancer through the stimulation of both ERs and PRs. We observed that the CYP17 variant C allele is inversely associated with long-term HRT use in postmenopausal women among the controls, confirming the findings from a previous study (18). The functional role of the CYP17 C allele is not completely understood. However, one prior study has shown that the C allele is associated with increased transcription of the gene and elevated serum estradiol level (15). From this perspective, it is plausible that women who carry the CYP17 variant C allele would have less menopausal symptoms, due to an elevated level of endogenous ovarian estradiols, and hence would be less likely to have used HRT. In sum, our results suggest that there is previously unappreciated genetic susceptibility to the effects of long-term HRT use on breast cancer risk in postmenopausal women, consistent with the notion that HRT use for the relief of perimenopausal symptoms should be for the shortest duration possible (45).

HRT use in younger, premenopausal women may be prescribed for primary or secondary amenorrhea and endometriosis as well as other gynecologic issues (46,47). The detailed analyses of the main effects of HRT use in the parent case–control study found that women who used HRT before menopause had elevated risks for breast cancer (OR, 1.81; 95% CI, 1.17, 2.81), emphasizing that timing of exogenous hormone use is important (34). In the present study, we found a joint effect of CYP17 C allele and HRT use among premenopausal women (Table II), further pointing out a genetic susceptibility to the effect of premenopausal HRT use. However, the analyses were limited by the small sample size and future larger studies are warranted.

We found that carriers of the CYP17 variant C allele who were obese had a significantly elevated risk of breast cancer among postmenopausal women. No prior studies, to our knowledge, have reported such joint effect of the CYP17 variant C allele and high BMI in breast cancer. Among the controls, we also observed that the CYP17 variant C allele is positively related to having a BMI ≥25 in postmenopausal women. The results are compatible with the hypothesis that there is an additive effect of CYP17 and a high BMI on breast cancer risk in postmenopausal women, potentially due to the associated increase in estrogens.

Several limitations of the present study need to be considered when interpreting the results. First, although the study included a reasonably large sample size, the statistical power for our analyses, especially the subgroup analyses for the joint exposures, was limited. Second, multiple comparisons were made in this study and, therefore, the possibility of chance associations especially for those that were observed among subgroups cannot be ruled out. Third, the use of self-reported data on BMI may introduce some misclassification. However, we ascertained height and weight values as of 1 year prior to diagnosis date for cases to minimize differential measurement errors by case status. Lastly, the present study examined only one polymorphism in CYP17. It is possible that the observed effects are due to other variants that are in linkage disequilibrium with this promoter variant. Future large-scale genetic association studies using more comprehensive genomic approach with tagging polymorphisms are warranted.

In conclusion, this population-based case–control study observed no overall association between the CYP17 variant C allele and breast cancer. We observed that postmenopausal women carrying the CYP17 C allele were less likely to have had ever used HRT long term in this population. Post-menopausal women who carried the variant C allele and were obese, or had used HRT long-term were at an increased risk of breast cancer. These findings improve our understanding of the hormonal basis of breast cancer etiology, especially the role of exogenous hormones and their interactions with hormone-related constitutional genotypes.


   Funding
Top
 Abstract
 Introduction and background
 Materials and Methods
 Results
 Discussion
 Funding
References
 
This work was supported in part by grants from the Department of Defense, National Cancer Institute and the National Institutes of Environmental Health Sciences (Grants DAMD170010213, UO1CA/ES66572, UO1CA66572, P30ES09089, UO1CA122171, P30CA014599, CA016087, ES000260, and P30ES10126).


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction and background
 Materials and Methods
 Results
 Discussion
 Funding
 References
 

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Received September 19, 2007; revised January 8, 2008; accepted February 2, 2008.


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