Genome-wide meta-analyses of smoking behaviors in African Americans.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

In vitro and in vivo analysis of B-Myb in basal-like breast cancer.

A defining feature of basal-like breast cancer, a breast cancer subtype with poor clinical prognosis, is the high expression of 'proliferation signature' genes. We identified B-Myb, a MYB family transcription factor that is often amplified and overexpressed in many tumor types, as being highly expressed in the proliferation signature. However, the roles of B-Myb in disease progression, and its mammary-specific transcriptional targets, are poorly understood. Here, we showed that B-Myb expression is a significant predictor of survival and pathological complete response to neoadjuvant chemotherapy in breast cancer patients. We also identified a significant association between the G/G genotype of a nonsynonymous B-Myb germline variant (rs2070235, S427G) and an increased risk of basal-like breast cancer [OR 2.0, 95% CI (1.1-3.8)]. In immortalized, human mammary epithelial cell lines, but not in basal-like tumor lines, cells ectopically expressing wild-type B-Myb or the S427G variant showed increased sensitivity to two DNA topoisomerase IIalpha inhibitors, but not to other chemotherapeutics. In addition, microarray analyses identified many G2/M genes as being induced in B-Myb overexpressing cells. These results confirm that B-Myb is involved in cell cycle control, and that its dysregulation may contribute to increased sensitivity to a specific class of chemotherapeutic agents. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment.

Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.

Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review).

Reproductive factors in relation to breast cancer characterized by p53 protein expression (United States).

OBJECTIVE: To evaluate the potential etiologic heterogeneity of breast cancer by examining whether associations with reproductive and other personal characteristics differed by p53 protein expression status. METHODS: Data from the Carolina Breast Cancer Study, a population-based, case-control study of 861 cases and 790 controls, were utilized. Immunohistochemical staining for the p53 protein was performed on 638 archived tumor specimens; 46% of cases were classified as p53+. Two separate unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for p53+ and p53- breast cancer relative to controls for reproductive and other personal characteristics. Analyses were performed separately for younger (< or = 45 years) and older (>45 years) women. RESULTS: Risk factor profiles largely overlapped for p53+ and p53- breast cancer, with the exception of oral contraceptive (OC) use among younger women and a family history of breast cancer. Prolonged OC use was more strongly associated with p53+ breast cancer [OR 3.1 (95% CI: 1.2-8.1) than p53- breast cancer (OR 1.3 (95% CI: 0.6-3.2)] among younger women only. A first-degree family history of breast cancer was associated with p53+ breast cancer among younger women [OR 1.5 (95% CI: 1.0-2.2)] and older women [OR 1.4 (95% CI: 0.9-2.3)], but not p53- breast cancer in either age-group. CONCLUSIONS: These results provide little evidence of breast cancer heterogeneity as classified by p53 expression status. However, although not statistically significant, OC use among younger women and family history of breast cancer may operate through a pathway involving p53 alterations to increase risk of breast cancer.

Heterocyclic amines, meat intake, and association with colon cancer in a population-based study.

The authors examined the association between colon cancer and meat intake categorized by level of doneness, cooking method, and estimated levels of heterocyclic amines (HCAs), benzo[a]pyrene, and mutagenicity. Data were collected as part of a population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 that included 701 African-American (274 cases, 427 controls) and 957 White (346 cases, 611 controls) participants. Odds ratios were calculated by using unconditional logistic regression, comparing the fifth to the first quintile levels of intake or exposure. Intake of red meat was positively associated with colon cancer (odds ratio (OR) = 2.0, 95% confidence interval (CI): 1.3, 3.2). Associations with meat intake by cooking method were strongest for pan-fried red meat (OR = 2.0, 95% CI: 1.4, 3.0). Associations with meat intake by doneness were strongest for well-/very well done red meat (OR = 1.7, 95% CI: 1.2, 2.5). The strongest association for individual HCAs was reported for 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) across all levels of exposure, with odds ratios of 1.8-2.0. Overall, sophisticated exposure measures were used to report modest, positive associations between red meat intake and colon cancer consistent with the hypothesis that HCAs may be among the etiologically relevant compounds in red meat.

Environmental factors in relation to breast cancer characterized by p53 protein expression.

Findings from studies of cigarette smoking and low-dose ionizing radiation exposure and breast cancer are unclear. Laboratory studies indicate that both exposures can cause DNA damage, potentially increasing cancer risk if such mutations occur in growth control genes, such as p53. We examined the potential etiologic heterogeneity of breast cancer by evaluating whether associations between cigarette smoking and low-dose ionizing radiation and breast cancer differed by p53 protein expression status. Data were obtained from the Carolina Breast Cancer Study, a population-based, case-control study conducted among African-American and white women ages 20-74 years. Questionnaire data were available from 861 women with incident, primary invasive breast cancer and 790 community-based controls. p53 immunostaining was performed on tissue from 683 women with breast cancer; 46% were classified as p53+. Two separate unconditional logistic regression models were used to calculate odds ratios (ORs) for p53+ and p53- breast cancer, as compared with controls, in relation to smoking and low-dose ionizing radiation exposure. Smoking was not differentially associated with p53+ or p53- breast cancer, even when duration, dose, and passive smoking status were considered. Exposure to individual sources of radiation did not differ for p53+ and p53- breast cancers. However, ORs for combined exposure to chest X-rays and occupational radiation were higher for p53+ [OR, 2.2; 95% confidence interval (CI), 1.0-5.3] than p53- breast cancer (OR, 1.2; 95% CI, 0.5-3.4). Combined exposure to radiation from other medical sources as well as occupational exposure was also higher for p53+ (OR, 3.7; 95% CI, 0.8-16.8) than for p53- breast cancer (OR, 1.7; 95% CI, 0.3-10.5). Although preliminary, our results suggest that exposure to multiple sources of low-dose ionizing radiation may contribute to the development of p53+ breast cancer.

Oral contraceptives and breast cancer among African-american women and white women.

The higher incidence of breast cancer among African-American women younger than 50 as compared to white women points to the need to examine exposures that are common among younger women, including exposure to oral contraceptives (OC). We examined patterns of OC use and their associations with breast cancer in a population-based, case-control study conducted in North Carolina between 1993 and 1996. The study population was comprised of 858 cases and 789 controls, of whom 40% were African-American women. There was little evidence that breast cancer was associated with OC use among older women (age >50) of either race, most of whom discontinued use in the distant past. Among younger women, there was a modest, but nonsignificant, increase in risk associated with ever use of OCs for both African-American and white women. There was a trend of increasing risks with more recent use among African-American women, whereas no such trend was apparent for white women. Overall, we found more substantial age differences than race differences in patterns of OC use and the risk of breast cancer associated with their use. The similarity of the associations between African-American and white women suggest that racial differences in breast cancer incidence are not likely to be attributable to OC use.

Population-based case-control study of occupational exposure to electromagnetic fields and breast cancer.

PURPOSE: This population-based case-control study examined occupational exposure to electromagnetic fields in relation to female breast cancer incidence among 843 breast cancer cases and 773 controls. METHODS: Exposure was classified based on work in the two longest-held jobs, and indices of cumulative exposure to magnetic fields based on a measurement survey. RESULTS: Female breast cancer was not associated with employment as an office or industrial worker. For the total study population, cumulative exposure over the entire career, and in the past 0-10 and 10-20 years generally showed odds ratios (ORs) close to the null. Moderately elevated risks were found for intermediate but not high levels of cumulative exposure accumulated 20 or more years ago (OR = 1.5; 95% CI = 1.1-2.0). Associations were stronger for premenopausal women (OR = 1.7; 95% CI = 1.1-2.7) in the past 10-20 years, and those with estrogen-receptor positive (ER+) breast tumors (OR = 2.06; 95% CI = 1.1-4.0). No consistent dose-response patterns were observed. CONCLUSIONS: These findings give little support to the hypothesis that electromagnetic fields cause cancer of the female breast.

Vitamin supplement use and breast cancer in a North Carolina population.

OBJECTIVE: Laboratory data suggest that several different vitamins may inhibit the growth of mammary cancers, however epidemiologic data on the relationship between vitamin supplement use and breast cancer are inconsistent. We examined the association between self-reported vitamin supplement use and breast cancer among black women and white women. DESIGN AND SETTING: The data came from a population-based, case-control study conducted in North Carolina between 1993 and 1996. Logistic regression models were used to calculate adjusted odds ratios (ORs) for breast cancer associated with the use of multivitamins or individual vitamin supplements. SUBJECTS: Eligible cases were aged 20 to 74, and approximately 40% of the study population were black women. The analyses included 861 cases and 790 controls. RESULTS: Among all women, there was little evidence for an association between any vitamin supplement and breast cancer. Modest inverse associations were observed among white women for use of multivitamins 95% confidence interval (CI): 0.59-1.12), vitamin C 95% CI: 0.54-1.14) and vitamin E 95% CI: 0.49-1.13). There was no evidence that vitamin supplements reduced the risk of breast cancer among black women. CONCLUSIONS: This study provided very limited support for the hypothesis that vitamin supplements may reduce the risk of breast cancer. Although dietary factors are likely an important influence in breast cancer aetiology, reductions in risk are most likely to be achieved through dietary modification rather than through vitamin supplementation.

Polymorphisms in the DNA repair gene XRCC1 and breast cancer.

X-ray repair cross complementing group 1 (XRCC1) encodes a protein involved in base excision repair. We examined the association of polymorphisms in XRCC1 (codon 194 Arg-->Trp and codon 399 Arg-->Gln) and breast cancer in the Carolina Breast Cancer Study, a population-based case-control study in North Carolina. No association was observed between XRCC1 codon 194 genotype and breast cancer, and odds ratios (ORs) were not modified by smoking or radiation exposure. A positive association for XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes compared with Arg/Arg was found among African Americans (253 cases, 266 controls; OR = 1.7, 95% confidence interval, 1.1-2.4) but not whites (386 cases, 381 controls; OR =1.0, 95% confidence interval, 0.8-1.4). Among African-American women, ORs for the duration of smoking were elevated among women with XRCC1 codon 399 Arg/Arg genotype (trend test; P < 0.001) but not Arg/Gln or Gln/Gln (P = 0.23). There was no difference in OR for smoking according to XRCC1 codon 399 genotype in white women. ORs for occupational exposure to ionizing radiation were stronger for African-American and white women with codon 399 Arg/Arg genotype. High-dose radiation to the chest was more strongly associated with breast cancer among white women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures. However, interpretation of our results is limited by incomplete knowledge regarding the biological function of XRCC1 alleles.

Reproducibility of reported farming activities and pesticide use among breast cancer cases and controls. A comparison of two modes of data collection.

PURPOSE: Farming is associated with exposure to many potential hazards including pesticides and other agents, but the quality of self-reported data on farm exposures has not been well studied. METHODS: The reproducibility of self-reported farming history was evaluated among women in a population-based, case-control study of breast cancer in North Carolina. Thirty cases and 31 controls were randomly re-interviewed by telephone an average of 13.8 months after the initial interview. The initial interview was based on a farm-by-farm questionnaire, while the repeat interview was based on a shorter ever/never questionnaire. Agreement was estimated using proportions in exact agreement, kappa (kappa), and intraclass correlation coefficients (ICC). RESULTS: In general, group prevalences and means were higher on re-interview. Kappa estimates ranged from 0.15 to 0.84 among cases, and 0.26 to 0.87 among controls, with most estimates falling between 0.5 and 0.8. Moderate to almost perfect agreement (kappa) was observed for questions on crop work (0.47-0.70), crop type (0.56-0.82), pesticide application to tobacco (0.77), and farm residence (0.84). ICC estimates for continuous variables showed fair to substantial agreement (0.30 to 0.69 among cases, 0.38 to 0.69 among controls). Older cases, less educated cases, cases who lived on more than one farm, and cases with longer time intervals between interviews gave lower total agreement than similar groups of controls. CONCLUSIONS: Agreement estimates in this study are similar to those for other types of exposure information typically collected in epidemiologic studies. Nevertheless, a farm-by-farm method of exposure assessment may be preferable to an ever/never determination.

Race, anthropometric factors, and stage at diagnosis of breast cancer.

A recent study suggested that the greater prevalence of severe obesity among African-American women explained almost one third of the observed differences between African-American and White women in stage at diagnosis of breast cancer. The objective of this investigation was to attempt to replicate these findings in a second, larger population and to expand the analyses by including a measure of body fat distribution, the waist:hip ratio. The authors used data from a population-based study in North Carolina comprising 791 breast cancer cases (302 in African-American women and 489 in White women) diagnosed between 1993 and 1996. African-American women were more likely to have later-stage (TNM stage >/=II) breast cancer (odds ratio (OR) = 2.2; 95% confidence interval (CI): 1.6, 2.9). They also were much more likely to be severely obese (body mass index >/=32.3) (OR = 9.7; 95% CI: 6.5, 14.5) and to be in the highest tertile of waist:hip ratio (OR = 5.7; 95% CI: 3.8, 8.6). In multivariate logistic regression models, adjustment for waist:hip ratio reduced the odds ratio for later-stage disease in African-American women by 20%; adjustment for both waist:hip ratio and severe obesity reduced the odds ratio by 27%. These observations suggest that obesity and body fat distribution, in addition to socioeconomic and medical care factors, contribute to racial differences in stage at breast cancer diagnosis.

Body size and breast cancer risk in black women and white women: the Carolina Breast Cancer Study.

The relation between body size and breast cancer risk was investigated in a population-based, case-control study of Black women (350 cases, 353 controls) and White women (523 cases, 471 controls) from North Carolina, aged 20-74 years in 1993-1996. Logistic regression analyses compared tertiles of each body size variable, adjusting for age and breast cancer risk factors (results shown for highest relative to lowest tertile). Among premenopausal women, body mass index (kg/m2) was inversely associated with breast cancer (odds ratio (OR) = 0.46, 95% confidence interval (CI): 0.26, 0.80) for Whites but not for Blacks. There was essentially no association among postmenopausal women. Higher waist/hip ratio, adjusted for body mass index, increased risk for all women. Odds ratios for Black and White premenopausal women were 2.50 (95% CI: 1.10, 5.67) and 2.44 (95% CI: 1.17, 5.09), respectively; odds ratios for Black and White postmenopausal women were 1.62 (95% CI: 0.70, 3.79) and 1.64 (95% CI: 0.88, 3.07), respectively. Findings for body mass index differed among Black women when stratified by age (<50 years) (OR = 0.50, 95% CI: 0.25, 1.01) instead of menopausal status. Thus, the associations of breast cancer with body mass index and waist/hip ratio among Black women are similar to those documented for Whites, despite different body size profiles on average.

A population-based case-control study of farming and breast cancer in North Carolina.

We examined the role of farming and pesticide exposure among 862 cases and 790 controls in a population-based, case-control study of breast cancer conducted in North Carolina between 1993 and 1996. We obtained exposure information through personal interview. Increasing duration of farming was inversely associated with breast cancer risk; odds ratios (95% confidence intervals) were 1.2 (0.8-1.7), 0.8 (0.5-1.2), 0.7 (0.5-1.1), and 0.6 (0.4-0.9) for 1-10, 11-17, 18-23, and >23 years of farming, respectively, relative to nonfarmers. Inverse associations persisted when farming was restricted to calendar time periods of 2,2-bis(p-chlorophenyl)- 1,1,1-trichloroethane (DDT) use or to farming at ages 9-16. Among women who farmed, odds ratios (ORs) were elevated for those who reported being present in fields during or shortly after pesticide application (OR = 1.8, 95% CI = 1.1-2.8) and for those who reported not using protective clothing while applying pesticides (OR = 2.0; 95% CI = 1.0-4.3), but not among those who reported using protective clothing (OR = 0.8; 95% CI = 0.4-1.8). We conclude that residence or work on farms may be associated with a reduced risk of breast cancer. Nevertheless, our results suggest a possible increased risk of breast cancer among a subgroup of farming women who were most likely to be exposed to pesticides.

Menstrual risk factors and early-onset breast cancer.

OBJECTIVES: Epidemiologic studies provide evidence for increased breast cancer risk among women with prolonged exposure to endogenous estrogens and progesterone. Menstrual cycle characteristics, such as early menarche, rapid initiation of regular ovulatory cycles, short cycle length, and more days of flow, all potentially contribute to higher cumulative ovarian hormone exposure. METHODS: We assessed the associations between these characteristics and breast cancer risk in a population-based, case-control study of 1505 controls and 1647 newly diagnosed cases, all younger than 45 years of age. RESULTS: Compared to women with menarche at > or =15 years, we observed some increase in risk for women with younger ages at menarche, although those with very early ages were not at particularly high risk [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-1.9 for menarche at age 12 and OR = 1.2, 95% CI = 0.9-1.7 for menarche at age < or =10]. Women who reported having regular menstrual cycles within 2 years of menarche were at increased breast cancer risk (OR = 1.7, 95% CI = 1.2-2.3), compared to those never having regular cycles. Stratification by current body mass index revealed slightly stronger associations with menstrual characteristics among thinner women (< 22.0 kg/m2) compared to heavier women (> 28.8 kg/m2). CONCLUSIONS: These findings suggest that future studies should focus on clarifying how the interrelated effects of body size and menstrual factors, such as age at menarche and cycle regularity, contribute to breast cancer etiology.

Alcohol consumption and breast cancer among black and white women in North Carolina (United States).

OBJECTIVE: The purpose of this study was to investigate the effects of alcohol consumption on breast cancer risk in black and white women. METHODS: We used data from the Carolina Breast Cancer Study, a population-based, case-control study of black and white women in North Carolina. Interviews were conducted with 890 cases and 841 controls frequency-matched on age and race. RESULTS: Overall, the prevalence of moderate to high levels of alcohol consumption was low. Compared with abstainers, the multivariate odds ratio for recent intake of one or two drinks per day was 1.4 (95% CI = 0.9-2.1) and two or more drinks a day was 1.0 (95% CI = 0.6-1.6); increasing consumption was not associated with risk (p for trend = 0.6). The associations were similar, but somewhat weaker, for average lifetime consumption. Among women who consumed 91 g/week or more of alcohol, a nonsignificant increased risk of breast cancer was observed for women reporting binge drinking (OR = 1.5; 95% CI = 0.9-2.3), but not for those who consumed less than 91 g/week reporting binge drinking (OR = 1.0; 95% CI = 0.6-1.5). Odds ratios did not differ meaningfully by race, age, menopausal status, exogenous hormone use, or body mass index. CONCLUSIONS: These data provide little evidence for an association between alcohol consumption and risk of breast cancer among either black or white women.

Menopausal hormones and breast cancer in a biracial population.

OBJECTIVES: This study examined the association between menopausal hormones and breast cancer in a biracial population. METHODS: Logistic regression was used to calculate odds ratios for breast cancer associated with hormone use among 397 cases and 425 controls, all menopausal women. RESULTS: Odds ratios for ever use of hormones were 0.8 (95% confidence interval [CI] = 0.5, 1.2) for White women and 0.7 (95% CI = 0.4, 1.2) for Black women. Risk was not increased with longer duration of use or more recent use. CONCLUSIONS: Breast cancer risk was not increased among White or Black women who used menopausal hormones, despite patterns of use varying considerably between races.

The associations of adolescent cigarette smoking, alcoholic beverage consumption, environmental tobacco smoke, and ionizing radiation with subsequent breast cancer risk (United States).

OBJECTIVES: Studies of breast cancer among survivors of the World War II atomic bomb blasts over Japan suggest that the adolescent breast may be particularly sensitive to carcinogenic insult. To further explore that possibility we examined the relationships of cigarette smoking, alcohol consumption, environmental tobacco smoke (ETS) exposure, and medical treatment with ionizing radiation during adolescence with subsequent breast cancer risk. METHODS: Data from the Carolina Breast Cancer Study, a population-based, case-control study of breast cancer in North Carolina women aged 20-74 years (864 cases, 790 controls), were analyzed. RESULTS: A modest increase in breast cancer risk was suggested for women who began to smoke cigarettes between the ages of 10 and 14 years (OR: 1.5, CI: 0.9-2.5), and for women exposed to ionizing radiation between ages 10 and 19 years to treat or monitor a medical condition (OR: 1.6, CI: 0.5-2.5). Neither exposure to ETS at home prior to age 18 years (OR: 1.1, CI: 0.9-1.3) nor initiation of alcoholic beverage consumption between ages 10 and 15 years (OR: 1.1, CI: 0.6-1.8) appeared to increase risk. CONCLUSIONS: Our results are consistent with previous evidence suggesting that some adolescent exposures could influence future breast cancer risk.