Instruct: Given a scientific claim, retrieve passages that support or refute the claim.
Query: Environmental factors can influence the development of breast cancer.
BACKGROUND Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. METHODS We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). FINDINGS After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). INTERPRETATION Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. FUNDING Cancer Research UK and the UK Medical Research Council.
High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York. In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance. Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure. The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables. There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast. The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables. Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.
Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994-1998). For White, parous premenopausal and postmenopausal women, those who had an interval of > or =16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had < or =5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.
Evaluate known breast cancer risk factors in relation to breast density. We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires. Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer. The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more.
Objective To determine whether risk factors in childhood and early adulthood affect later mammographic breast density. Methods: Subjects were 628 women who attended a medical examination at the University of Glasgow Student Health Service (1948–1968), responded to a questionnaire (2001) and had a screening mammogram in Scotland (1989–2002). Mammograms (median age of 59years) were classified using a six category classification (SCC) of breast density percent. Logistic regression was used to determine associations between risk factors and having a high-risk mammogram (≥25 dense). Results: In multi-variable analyses, high-risk mammograms were associated with parity (adjusted odds ratio (OR) per child: 0.77 (95 confidence interval (CI) 0.61–0.99)), age at first birth, OR per year: 1.05 (0.99–1.11), smoking at university, OR smokers versus non-smokers: 0.58 (0.36–0.92) and body mass index (BMI) while at university, OR per 1kg/m20.75 (0.69–0.82). No associations with SCC were found for age at menarche, birth weight, oral contraceptive (OC) use, height, leg length or exercise at age 20. Conclusions: We confirm previous findings that breast density is affected by reproductive events and some anthropometric measures, however most of the risk factors acting throughout the life course which we examined were not closely related to adult breast density.
Obesity has a complicated relationship to both breast cancer risk and the clinical behavior of the established disease. In postmenopausal women, particularly the elderly, various measures of obesity have been positively associated with risk. However, before menopause increased body weight is inversely related to breast cancer risk. In both premenopausal and postmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have been related to estrogenic activity. Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer. Breast cancer in African-American women, considering its relationship to obesity, exhibits some important differences from those described in white women, although the high prevalence of obesity in African-American women may contribute to the relatively poor prognosis compared with white American women. Despite the emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove to be equally or more important, particularly as they relate to expression of an aggressive tumor phenotype. Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and their relationship to angiogenesis, and transcriptional factors.
Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm(2)/kg was thrice stronger for nondense than dense area. After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality. The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk.
BACKGROUND The prevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoprotein cholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with an increasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome, yet its role in breast cancer is still undefined. METHODS In two population-based screening surveys during 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38,823 Norwegian women aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake, physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco use were also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) of breast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. We performed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausal status. All statistical tests were two-sided. RESULTS During a median follow-up of 17.2 years, we identified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausal breast cancer was inversely related to quartile of HDL-C (P(trend) =.02). Among women with HDL-C above 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was 0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in the heavier subgroup (BMI > or =25 kg/m2), for whom the relative risk of postmenopausal breast cancer in those with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67; P(trend)<.001; P(interaction) =.001). CONCLUSION Low HDL-C, as part of the metabolic syndrome, is associated with increased postmenopausal breast cancer risk.
Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.
Birth weight is a significant predictor of breast cancer risk in adult life and mammary gland mass could be an intermediate stage in this long process. We have studied the association of birth size measurements with mammographic density, a marker of mammary gland mass. For a population-based sample of 893 postmenopausal women without previous cancer in Sweden, we retrieved information on birth size from birth records and their most recent mammography. Film mammograms of the medio-lateral oblique view were digitized and the Cumulus software was used for computer-assisted semi-automated thresholding of mammographic density. Results were analyzed using generalized linear models controlling for possible confounders. Mean percent mammographic density increased when comparing the extreme categories of birth weight (from 15.6% to 18.6%) and head circumference (from 15.5% to 20.4%), and the corresponding linear trends were statistically significant (p values 0.02 and 0.007, respectively). The associations were particularly strong when the cutoff for high versus low mammographic density was set at the relatively high value of 50%. Compared to women weighing 3001-3500 grams at birth, women with birth weights >4000g were at almost 3-fold risk of developing high mammographic density (odds ratio: 2.9, 95% confidence interval 1.1 to 7.9). No association with mammographic density was evident with respect to birth length which, however, is known to be less accurately measured. These results indicate that adult breast density, a powerful predictor of breast cancer risk, has intrauterine roots, as reflected in birth size.
BACKGROUND Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown. METHODS We carried out three nested case-control studies in screened populations with 1112 matched case-control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age. RESULTS As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram. CONCLUSIONS Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.
BACKGROUND Breast cancer is the most common malignancy in women. There is increasing evidence suggesting that ORAI1, components of store-operated calcium channel, play a pivotal role in breast cancer progression and metastasis. METHODS A total of 384 female patients with breast cancer were included in this study. We selected five representative tagging ORAI1 SNPs from HapMap database with minimum allele frequency (MAF) >10%. Genotyping was performed using TaqMan allelic discrimination assay. Chi-square (χ²) test was used to analyze statistical differences among control and patient groups in genotype and allelic frequencies. RESULTS Two of the ORAI1 SNPs (rs12320939 and rs12313273) were associated with estrogen receptors positive in breast cancer patients under the recessive model. When the Bonferroni correction was performed, the significance still existed. In addition, rs12320939 also associated with the lymph nodal involvement. CONCLUSION We showed that genetic polymorphisms of ORAI1 associated strongly with lymph nodal involvement and estrogen receptors (ERs) positive breast cancer patients in a Taiwanese population.
The association between anthropometric indices and the risk of breast cancer was analyzed using pooled data from seven prospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incident invasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other risk factors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95% confidence interval (CI): 0.96, 1.10) in premenopausal women and 1.07 (95% CI: 1.03, 1.12) in postmenopausal women. Body mass index (BMI) showed significant inverse and positive associations with breast cancer among pre- and postmenopausal women, respectively; these associations were nonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31 kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs did not increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI: 1.09, 1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their data indicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausal women, this relation is less clear. The association between BMI and breast cancer varies by menopausal status. Weight control may reduce the risk among postmenopausal women.
Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.
Mammographic density is a strong risk factor for breast cancer, but the underlying biology for this association is unknown. Studies suggest that vitamin D may reduce breast cancer risk and dietary vitamin D intake has been associated with reduced breast density. We conducted a case-control study nested within the Nurses' Health Study cohort consisting of 463 and 497 postmenopausal cases and controls, respectively. We examined the association between mammographic density and plasma levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. We assessed whether plasma vitamin D metabolites modify the association between breast density and breast cancer. Percent mammographic density was measured from digitized film mammograms. Generalized linear models were used to determine mean percent breast density per quartile of vitamin D metabolite. Logistic regression models were used to calculate relative risks and confidence intervals. All models were adjusted for matching variables and potential confounders. We found no cross-sectional association between circulating levels of 25(OH)D or 1,25(OH)(2)D with mammographic density. Women in the highest tertile of mammographic density and lowest tertile of plasma 25(OH)D had 4 times greater risk of breast cancer than women with the lowest mammographic density and highest plasma 25(OH)D levels (RR = 3.8; 95% CI: 2.0-7.3). The overall interaction between mammographic density and plasma 25(OH)D was nonsignificant (p-het = 0.20). These results indicate that the association between mammographic density and breast cancer is independent of plasma vitamin D metabolites in postmenopausal women. Further research examining vitamin D, mammographic density and breast cancer risk is warranted.
BACKGROUND Lobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk. METHODS To evaluate whether lobular involution and MBD are independently associated with breast cancer risk in women with benign breast disease, we performed a nested cohort study among women (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, and December 31, 1991 and a mammogram available within 6 months of the diagnosis. Women were followed up for an average of 13.3 years to document any breast cancer incidence. Lobular involution was categorized as none, partial, or complete; parenchymal pattern was classified using the Wolfe classification as N1 (nondense), P1, P2 (ductal prominence occupying <25%, or >25% of the breast, respectively), or DY (extremely dense). Hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of lobular involution and MBD with breast cancer risk were estimated using adjusted Cox proportional hazards model. All tests of statistical significance were two-sided. RESULTS After adjustment for MBD, having no or partial lobular involution was associated with a higher risk of breast cancer than having complete involution (none: HR of breast cancer incidence = 2.62, 95% CI = 1.39 to 4.94; partial: HR of breast cancer incidence = 1.61, 95% CI = 1.03 to 2.53; P(trend) = .002). Similarly, after adjustment for involution, having dense breasts was associated with higher risk of breast cancer than having nondense breasts (for DY: HR of breast cancer incidence = 1.67, 95% CI = 1.03 to 2.73; for P2: HR of breast cancer incidence = 1.96, 95% CI = 1.20 to 3.21; for P1: HR of breast cancer incidence = 1.23, 95% CI = 0.67 to 2.26; P(trend) = .02). Having a combination of no involution and dense breasts was associated with higher risk of breast cancer than having complete involution and nondense breasts (HR of breast cancer incidence = 4.08, 95% CI = 1.72 to 9.68; P = .006). CONCLUSION Lobular involution and MBD are independently associated with breast cancer incidence; combined, they are associated with an even greater risk for breast cancer.
OBJECTIVE To compare the incidence of cancer among women with and without a history of pre-eclampsia. DESIGN Cohort study. SETTING Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalem during 1964-76. PARTICIPANTS 37 033 women. MAIN OUTCOME MEASURES Age adjusted and multivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who were primiparous at study entry. RESULTS Cancer developed in 91 women who had pre-eclampsia and 2204 who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancers was increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence of cancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women at study entry who had a history pre-eclampsia. CONCLUSIONS A history of pre-eclampsia is associated with increases in overall risk of cancer and incidence at several sites. This may be explained by environmental and genetic factors common to the development of pre-eclampsia and cancer in this population.
A classification of risk for developing breast cancer has been devised based solely on the appearance of the breast parenchyma by mammography. Four groups of patients were isolated. The study encompassed a five-year period and was done by reviewing the mammograms of all women over the age of 30 who had been examined at Hutzel Hospital, Detroit. The average time of followup would be approximately 2 1/2 years. Four groups had an incidence of developing breast cancer of 0.1, 0.4, 1.7, and 2.2. These parenchymal patterns are described and criteria for their identification are given.
Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell–enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
BACKGROUND It has been suggested that identified risk factors for endometrial cancer operate through a single etiologic pathway, i.e., exposure to relatively high levels of unopposed estrogen (estrogen in the absence of progestins). Only a few studies, however, have addressed this issue directly. PURPOSE We assessed the risk of developing endometrial cancer among both premenopausal and postmenopausal women in relation to the circulating levels of steroid hormones and sex hormone-binding globulin (SHBG). The independent effect of hormones was assessed after adjustment for other known risk factors. METHODS The data used in the analysis are from a case-control study conducted in five geographic regions in the United States. Incident cases were newly diagnosed during the period from June 1, 1987, through May 15, 1990. The case patients, aged 20-74 years, were matched to control subjects by age, race, and geographic region. The community control subjects were obtained by random-digit-dialing procedures (for subjects 20-64 years old) and from files of the Health Care Financing Administration (for subjects > or = 65 years old). Additional control subjects who were having a hysterectomy performed for benign conditions were obtained from the participating centers. Women reporting use of exogenous estrogens or oral contraceptives within 6 months of interview were excluded, resulting in 68 case patients and 107 control subjects among premenopausal women and 208 case patients and 209 control subjects among postmenopausal women. The hormone analyses were performed on blood samples obtained from case patients or from hysterectomy control subjects before surgery. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of an unconditional logistic regression analysis after we controlled for matching variables and potential confounders. All P values were two-sided. RESULTS High circulating levels of androstenedione were associated with 3.6-fold and 2.8-fold increased risks among premenopausal and postmenopausal women, respectively, after adjustment for other factors (P for trend = .01 and < .001, respectively). Risks related to other hormone fractions varied by menopausal status. Among postmenopausal women, a reduced risk was associated with high SHBG levels and persisted after adjustment was made for obesity and other factors (OR = 0.51; 95% CI = 0.27-0.95). High estrone levels were associated with increased risk (OR = 3.8; 95% CI = 2.2-6.6), although adjustment for other risk factors (particularly body mass index) diminished the effect (OR = 2.2; 95% CI = 1.2-4.4). Albumin-bound estradiol (E2), a marker of the bioavailable fraction, also remained an important risk factor after adjustment was made for other factors (OR = 2.0; 95% CI = 1.0-3.9). In contrast, high concentrations of total, free, and albumin-bound E2 were unrelated to increased risk in premenopausal women. In both premenopausal and postmenopausal groups, risks associated with obesity and fat distribution were not affected by adjustment for hormones. CONCLUSION High endogenous levels of unopposed estrogen are related to increased risk of endometrial cancer, but their independence from other risk factors is inconsistent with being a common underlying biologic pathway through which all risk factors for endometrial cancer operate. IMPLICATIONS Further research should focus on alternative endocrinologic mechanisms for risk associated with obesity and body fat distribution and for the biologic relevance of the increased risk associated with androstenedione in both premenopausal and postmenopausal disease.
Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.
To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.
Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p. S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p. F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p. S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.
Excessive exposure to estradiol represents the main risk factor for endometrial cancer. The abnormally high estradiol levels in the endometrium of women with endometrial cancer are most likely due to overproduction by the tumour itself. Endometrial cancer cells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis. Here we used RT-PCR and Western blot to show that the nuclear receptors SF1 and LRH1, two well-known regulators of steroidogenic gene expression in gonadal and adrenal cells, are also expressed in endometrial cancer cell lines. By transient transfections, we found that SF1 and LRH1, but not the related nuclear receptor NUR77, can activate the promoters of three human steroidogenic genes: STAR, HSD3B2, and CYP19A1 PII. Similarly, forskolin but not PMA, could activate all three promoters. In addition, we found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. All together, our data provide novel insights into the mechanisms of steroidogenic gene expression in endometrial cancer cells and thus in the regulation of estradiol biosynthesis by tumour cells.