Alter Breast Cancer Risk Research Articles

Current evidence on the relationship between three polymorphisms in the FGFR2 gene and breast cancer risk: a meta-analysis

In this article, inconsistency of the association of polymorphisms of fibroblast growth factor receptor 2 (FGFR2) with breast cancer is noted. Three commonly studied FGFR2 polymorphisms including rs1219648 (A > G), rs2420946 (C > T), and rs2981582 (C > T) were selected to explore their association with risk of development of breast cancer by meta-analysis of published case-control studies. The results showed that all these three polymorphisms were significantly associated with altered breast cancer risk in any model (co-dominant, dominant, or recessive model) and in stratification based on ethnicity and study design. In the subgroup analyses for postmenopausal women, significantly increased risks were found for rs1219648 and rs2420946 in any model. This meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of breast cancer. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays.

Long-Term Metformin Use Is Associated With Decreased Risk of Breast Cancer

OBJECTIVETo evaluate whether use of oral hypoglycemic agents is associated with an altered breast cancer risk in women.RESEARCH DESIGN AND METHODSUsing the U.K.-based General Practice Research Database, we conducted a nested case-control analysis among 22,621 female users of oral antidiabetes drugs with type 2 diabetes. We evaluated whether they had an altered risk of breast cancer in relation to use of various types of oral hypoglycemic agents. Case and control patients with a recorded diagnosis of type 2 diabetes were matched on age, calendar time, and general practice, and the multivariate conditional logistic regression analyses were further adjusted for use of oral antidiabetes drugs, insulin, estrogens, smoking BMI, diabetes duration, and HbA1c (A1C).RESULTSWe identified 305 case patients with a recorded incident diagnosis of breast cancer. The mean ± SD age was 67.5 ± 10.5 years at the time of the cancer diagnosis. Long-term use of ≥40 prescriptions (>5 years) of metformin, based on 17 exposed case patients and 120 exposed control patients, was associated with an adjusted odds ratio of 0.44 (95% CI 0.24–0.82) for developing breast cancer compared with no use of metformin. Neither short-term metformin use nor use of sulfonylureas or other antidiabetes drugs was associated with a materially altered risk for breast cancer.CONCLUSIONSA decreased risk of breast cancer was observed in female patients with type 2 diabetes using metformin on a long-term basis.

Effect of Flaxseed Consumption on Urinary Levels of Estrogen Metabolites in Postmenopausal Women

Flaxseed is a rich source of dietary lignans. It has been hypothesized that lignans may decrease breast cancer risk through modulation of endogenous hormone levels. The aim of this study was to determine the effect of flaxseed supplementation on urinary levels of estrogen metabolites that may be involved in the development of breast cancer. Forty-three postmenopausal women participated in this 12-wk preintervention–postintervention study. Participants consumed 7.5 g/day of ground flaxseed for 6 wk, followed by 15 g/day for an additional 6 wk. The mean urinary level of 16α –hydroxyestrone (16α -OHE1) was higher at the end of 12 wk compared to baseline (change of 1.32 ug/day, P = 0.02). There was no significant change in 2-OHE1 excretion. The mean urinary level of the 2-OHE1/16α -OHE1 ratio was lower at the end of 12 wk compared to baseline (change of −1.1, P = 0.02). Mean urinary excretion of 2-methoxyestradiol was also lower at 12 wk than at baseline ( P = 0.03). Based on the current paradigm of the effects of estrogen metabolism on breast cancer risk, the regimen of dietary flaxseed intake used in this study did not appear to favorably alter breast cancer risk through shifts in estrogen metabolism pathways in postmenopausal women.

Risk factors for breast cancer in women biopsied for benign breast disease: A nested case-control study

Aim: Women with a history of benign breast disease are at increased risk of subsequent breast cancer. However, few studies have examined whether established breast cancer risk factors other than histology are associated with an altered risk of breast cancer in women with benign breast disease. We used a nested case-control design within a large, multi-center cohort of women biopsied for benign breast disease (BBD) to estimate odds ratios for breast cancer in association with exposure to a range of personal and lifestyle factors. Methods: Cases were women biopsied for BBD who subsequently developed breast cancer; controls were individually matched to cases on center and age at diagnosis and were women biopsied for BBD who did not develop breast cancer in the same follow-up interval as that for the cases. After excluding women with prevalent breast cancer, 1357 records (661 case records and 696 records) were available for analysis. We used conditional logistic regression to obtain crude and multivariable-adjusted estimates of the association between specific factors and risk of breast cancer. Results: In multivariable analyses age at first live birth, number of pregnancies, and postmenopausal status were inversely associated with risk of breast cancer. The odds ratio for women with age at first birth <25 years and ≥3 pregnancies, relative to nulliparous women, was 0.49, 95% confidence interval 0.13–0.79, and that for postmenopausal women relative to premenopausal women was 0.60, 95% CI 0.37–0.99. Conclusions: Further study of personal factors influencing the risk of breast cancer in women with BBD may help to identify subgroups of the population at increased risk of invasive disease.

Abstract A2: Genetic variation in estrogen receptor genes and mammographic breast density

Abstract Mammographic density is one of the strongest, independent risk factors in the development of breast cancer. Women with mammographically dense breasts, those with greater than or equal to 75% dense tissue, are at a four to six-fold greater risk of developing breast cancer when compared to those with “no measurable dense tissue,” in which the breasts are composed entirely of fat. Many of the established risk factors for breast cancer have been shown to be associated with variations in breast density (i.e., age, menopausal status, parity, BMI, and postmenopausal hormone use). Additionally, twin studies have also shown that heritability accounts for approximately 60% of the variance in mammographic density. Given the established role of estrogens in the development and progression of breast cancer, we have evaluated the role of 17 single-nucleotide polymorphisms (SNPs) in the estrogen receptor 1 and 2 genes (ESR1 and ESR2), and the recently identified G-Protein Coupled Estrogen Receptor 1 (GPER) gene, which has been demonstrated to regulate physiologic responses to estrogens independent of the traditional estrogen receptors. This study population consisted of 370 cancer-free (excluding cancers of the skin) Caucasian, postmenopausal women enrolled in the Mammograms and Masses Study (MAMS). Three different measures of mammographic density were computed: dense breast area, total breast area, and percent breast density, using the classification system developed by Wolfe in 1976, and a compensating polar planimeter, wax pencil, and transparent overlay. Breast density was calculated as the proportion of visibly dense breast to total breast area, expressed as a percentage. DNA was extracted from buffy coat samples, and genotyping was done using the Sequenom iPLEX Gold Assay. Heterozygote and homozygous variant genotypes were collapsed and compared to the common allele genotype for all statistical analyses. General linear models and χ2 analyses were conducted. We arranged our percent density variable into tertiles for further analysis. We observed that three SNPs in ESR2 (rs12435857, rs1256044, and rs1256031) were significantly associated with percent mammographic density. For ESR2 rs1256044 and rs1256031, mean percent mammographic density was significantly higher among women with at least one rare allele compared to women homozygous for the common allele (respectively, P=0.02 and P=0.03). Conversely, mean percent mammographic density was significantly higher among women with ESR2 rs12435857 GG genotype compared to those with GA/AA genotypes, 29.0 and 23.7, respectively (P=0.03). Our results suggest that common genetic variation in ESR2 is associated with percent mammographic density. Since estrogen receptor genes are highly expressed in breast tissue, functional SNPs in these genes may alter breast cancer risk, by altering mammographic density. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A2.

Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.

The Mitochondrial A10398G Polymorphism, Interaction with Alcohol Consumption, and Breast Cancer Risk

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.

Variation in genes required for normal mitosis and risk of breast cancer

The down-regulation of genes involved in normal cell division can cause aberrant mitoses and increased cell death. Surviving cells exhibit aneuploidy and/or polyploidy. Since mitotic disruption has been linked with tumor development and progression, alterations in the expression or activity of these mitotic regulators may contribute to breast tumor formation. We evaluated associations between common inherited variation in these genes and breast cancer risk. Two hundred and five tagging and candidate functional single nucleotide polymorphisms in 30 genes required for normal cell division were genotyped in 798 breast cancer cases and 843 controls from the Mayo Clinic breast cancer study. Two variants in EIF3A (rs10787899 and rs3824830; P < 0.01) and four variants in SART1 (rs660118, rs679581, rs754532, and rs735942; P(trend) < or = 0.02) were significantly associated with an altered risk of breast cancer along with single variants in RRM2, PSCD3, C11orf51, CDC16, SNW1, MFAP1, and CDC2 (P < 0.05). Variation in both SART1 (P = 0.009) and EIF3A (P = 0.02) was also significant at the gene level. Analyses suggested that SART1 SNPs rs660118 and rs679581 accounted for the majority of the association of that gene with breast cancer. The observed associations between breast cancer risk and genetic variation in the SART1 and EIF3A genes that are required for maintenance of normal mitosis suggest a direct role for these genes in the development of breast cancer.

Association of Single Nucleotide Polymorphisms in CYP1B1 and COMT Genes with Breast Cancer Susceptibility in Indian Women

Cytochrome P450 1B1 (CYP1B1) and catechol-$O$-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu432Val and/or COMT Val158Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val158Val) in combination with CYP1B1 heterozygous variant (Leu432Val) [OR: 0.21; 95% CI (0.05–0.82), p value; 0.021] and COMT heterozygous variant (Val158Met) in combination with CYP1B1 wild type (Leu432Leu) [OR: 0.29; 95% CI (0.08–0.96), p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.

Association of single nucleotide polymorphisms in CYP1B1 and COMT genes with breast cancer susceptibility in Indian women.

Cytochrome P450 1B1 (CYP1B1) and catechol-$O$-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu432Val and/or COMT Val158Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val158Val) in combination with CYP1B1 heterozygous variant (Leu432Val) [OR: 0.21; 95% CI (0.05–0.82), p value; 0.021] and COMT heterozygous variant (Val158Met) in combination with CYP1B1 wild type (Leu432Leu) [OR: 0.29; 95% CI (0.08–0.96), p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.

The influence of genetic variation in 30 selected genes on the clinical characteristics of early onset breast cancer

IntroductionCommon variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.MethodsWe selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.ResultsWe confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.ConclusionsWe have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient groups.

Breast cancer risk and hysterectomy status: the Multiethnic Cohort study.

The main objective was to examine the association between simple hysterectomy (without bilateral oophorectomy) and breast cancer risk. Because hysterectomy prevalence varies by ethnicity, the secondary objective was to examine whether inclusion of women with hysterectomies affects the estimates of breast cancer risk by ethnicity. The Multiethnic Cohort study was assembled between 1993 and 1996 and included 68,065 women from Hawaii and Los Angeles, aged 45-75 years, without any missing information or bilateral oophorectomy. Hysterectomy status was self-reported. After 7.7 years median follow-up, 1,862 cases of invasive breast cancer were identified. Proportional hazards models were used to estimate relative risks (RR) while controlling for known risk factors. Prevalence of simple hysterectomy varied from 12% to 29% among the ethnic groups (White, African American, Native Hawaiian, Japanese American, and Latina). Overall, hysterectomy was not associated with breast cancer risk (RR = 0.98). Although the RRs were nonsignificantly elevated by 15% in White women and nonsignificantly reduced by 15% in Latinas of non-US origin, the variation by ethnicity was not significant (p(interaction) = 0.48). The breast cancer risk associated with ethnicity was very similar when estimated with and without women with hysterectomies. This study suggests that simple hysterectomy status does not alter breast cancer risk. Therefore, inclusion of women with simple hysterectomies does not substantially change estimated risk of breast cancer by ethnicity.

Low-Fat Dietary Pattern and Risk of Benign Proliferative Breast Disease: A Randomized, Controlled Dietary Modification Trial

Modifiable factors, including diet, might alter breast cancer risk. We used the Women's Health Initiative Dietary Modification trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of, and considered to be on the pathway to, invasive breast cancer. The Women's Health Initiative Dietary Modification trial was a randomized, controlled, primary prevention trial conducted in 40 U.S. clinical centers from 1993 to 2005. A total of 48,835 postmenopausal women, ages 50 to 79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to the dietary modification intervention group or to the comparison group. The intervention was designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit and vegetable intake to > or =5 servings/d and intake of grain products to > or =6 servings/d, but resulted in smaller, albeit significant, changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies free of cancer, obtained the histologic sections, and subjected them to standardized central review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative breast disease were ascertained in the intervention group and 793 in the comparison group. The hazard ratio for the association between dietary modification and benign proliferative breast disease was 1.09 (95% confidence interval, 0.98-1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain intake do not alter the risk of benign proliferative breast disease.

Polymorphisms in Steroid Hormone Biosynthesis Genes and Risk of Breast Cancer and Fibrocystic Breast Conditions in Chinese Women

Common variants in genes encoding for key enzymes involved in steroidogenesis may alter sex steroid hormone levels, thereby influencing susceptibility to breast carcinoma and related conditions. In a case-control study of Chinese women, we examined genotypes of the CYP11A1 pentanucleotide [(TAAAA)n] repeat (D15S520), CYP17A1 rs743572, and HSD17B1 rs605059 polymorphisms in relation to the risk of breast cancer and fibrocystic breast conditions, comparing 615 women with breast cancer and 467 women with fibrocystic breast conditions separately with 879 women without clinical breast disease. We also evaluated whether these relationships differed by the presence of proliferation in the extratumoral epithelium or fibrocystic lesions, menopausal status, or body mass index. Only CYP11A1 genotype was related to breast cancer risk, with women homozygous for the 4-repeat allele, relative to those homozygous for the 6-repeat allele, at reduced risk (age-adjusted odds ratio, 0.58; 95% confidence interval, 0.37-0.91). There was some suggestion of a stronger inverse association for breast cancer with evidence of proliferation in the extratumoral epithelium than for breast cancer without extratumoral proliferation. Breast cancer risk associated with CYP11A1 genotype did not differ by menopausal status or body mass index level. No associations between CYP11A1, CYP17A1, and HSD17B1 genotypes and risk of fibrocystic breast conditions were observed. Our findings support the possibility that common allelic variation at the CYP11A1 D15S520 locus alters breast cancer risk in Chinese women.

Renin‐angiotensin system inhibitors, angiotensin I‐converting enzyme gene insertion/deletion polymorphism, and cancer

Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current epidemiologic study was to investigate whether renin-angiotensin system inhibitors and/or ACE genotypes were associated with an altered risk of colorectal, lung, breast, and prostate cancer. Data were obtained from the Rotterdam Study, a population-based, prospective cohort study with 7983 participants. Participants who had a history of 1 of the cancers of interest (n = 216) or who had a medication history <6 months (n = 88) were excluded, leaving 7679 participants, of whom the ACE genotypes could be assessed in 6670 individuals. The mean follow-up was 9.6 years, during which 730 incident cancers occurred. The effect of medication, ACE I/D genotypes, and their interaction on cancer risk and progression was studied by using Cox proportional hazard models. Carriers of the high-activity genotype DD had an increased risk of breast cancer compared with low-activity II/ID genotype carriers (hazard ratio [HR], 1.47; 95% confidence interval [95% CI], 1.05-2.04), but no association was demonstrated for other cancers. DD carriers who were exposed to long-term and high-dose medication were at lower risk for cancer (HR, 0.28; 95% CI, 0.10-0.79). Short-term, high-dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67-8.79). Renin-angiotensin system-inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE.

Genetic polymorphisms of XRCC1 (codon 399) and susceptibility to breast cancer in Iranian women, a case–control study

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. In the present study, we specifically investigated whether common genetic variant in XRCC1 (exon 10, codon Arg399Gln) was associated with an altered risk of breast cancer. The eligible cases were patients at chemotherapy unit of Nemazi hospital, Shiraz Iran, from October 1999 to August 2000 and from July 2004 to July 2005. The present study included 186 females with breast cancer. Age frequency-matched controls were randomly selected from the healthy females blood donor, according to the age distribution of the cases. A total of 187 healthy females included in the study. Using PCR-based method, the XRCC1 Arg399Gln polymorphism was determined. In control group the 399Gln allele frequency was 32.6%. The genotypic frequencies of the control subjects did not show significant deviation from Hardy-Weinberg equilibrium (chi(2) = 1.683, df = 1, P > 0.05). A statistically significant association was observed in comparison between Gln/Gln and Arg/Arg genotype (OR = 2.01, 95% CI:1.02-3.94, P = 0.041). There was no linear trend for presence of 0, 1, and 2 of the 399Gln allele and risk of breast cancer (chi(2) = 1.212, P = 0.271). In the recessive effect of the Gln allele (comparison between Gln/Gln vs. Arg/Arg+Arg/Gln), Gln/Gln genotype significantly increased the risk of breast cancer (OR = 2.31, 95% CI:1.21-4.35, P = 0.010). In the dominant effect of the Gln allele (comparison between Gln/Gln+Arg/Gln vs. Arg/Arg), Gln/Gln+Arg/Gln genotypes was not associated with the risk of breast cancer (OR = 0.95, 95% CI:0.63-1.42, P = 0.799). It is concluded that 399Gln allele may act as a recessive allele and increase the breast cancer risk.

Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT. We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.

Haplotype-Based Analysis of Common Variation in theAcetyl-CoA Carboxylase αGene and Breast Cancer Risk: A Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition

A key fatty acid synthesis enzyme, acetyl-CoA carboxylase alpha (ACC-alpha), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC-alpha common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotype-tagging polymorphisms efficiently capturing common variation within 325 kb of ACC-alpha and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC-alpha common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis.

C-Reactive Protein Levels, Variation in the C-Reactive Protein Gene, and Cancer Risk: The Rotterdam Study

It remains unclear if inflammation itself may induce cancer, if inflammation is a result of tumor growth, or a combination of both exists. The aim of this study was to examine whether C-reactive protein (CRP) levels and CRP gene variations were associated with an altered risk of colorectal, lung, breast, or prostate cancer. A total of 7,017 participants age > or = 55 years from the Rotterdam Study were eligible for analyses. Mean follow-up time was 10.2 years. High-sensitivity CRP measurements were performed to identify additional values of 0.2 to 1.0 mg/L compared with standard procedures. Genotypes of the CRP gene were determined with an allelic discrimination assay. High levels (> 3 mg/L) of CRP were associated with an increased risk of incident cancer (hazard ratio, 1.4; 95% CI, 1.1 to 1.7) compared with persons with low levels (< 1 mg/L), even after a potential latent period of 5 years was introduced. Although CRP seems to affect several cancer sites, the association was strongest for lung cancer (hazard ratio, 2.8; 95% CI, 1.6 to 4.9). A CRP single nucleotide polymorphism associated with decreased CRP levels was associated with an increased lung cancer risk of 2.6 (95% CI, 1.6 to 4.4) in homozygous carriers. Baseline CRP levels seem to be a biomarker of chronic inflammation preceding lung cancer, even after subtracting a 5-year latent period. Furthermore, CRP gene variation associated with low CRP blood levels was relatively common in patients with lung cancer. Both chronic inflammation and impaired defense mechanisms resulting in chronic inflammation might explain these results.

Association of gene variants in the transforming growth factor beta signalling pathways with invasive breast cancer risk

We are performing comprehensive association studies of single nucleotide polymorphisms (SNPs) in genes in the transforming growth factor beta (TGFβ) signalling pathways in a female breast cancer case-control study. TGFβ acts as a suppressor of primary tumour initiation but is implicated as a promoter of the later malignant stages. A hypothesis explaining this dual action proposes that TGFβ acts through the ubiquitous ALK5/SMADs2&3 signalling pathway to inhibit proliferation of primary tumour cells, but acts through the endothelial-specific ALK1/SMADs1&5 pathway to promote angiogenesis, which is required for progression to malignancy. In a previous study we showed that a SNP generating a leucine to proline substitution in the signal peptide of the TGFB1 protein was associated with a 1.24-fold increase in the risk of invasive breast cancer, with increased levels of the protein in human serum and with a 2.8-fold increase in amount of the protein secreted in vitro. It is also plausible that other genes in the TGFβ signalling pathways might be associated with altered risk of breast cancer. We have initiated systematic breast cancer association studies with SNPs in the genes encoding proteins directly implicated in TGFβ signalling pathways, including the LTBP and TGFβ isoforms, ALK1, ALK5 and TGFBR2 receptors, and SMADs 1–7. A comprehensive SNP tagging approach was used to select variants for genotyping in a staged study design using up to 4,600 cases and 4,600 controls, all from the East Anglian region of the United Kingdom (>98% of northwestern European ancestry). To date, nine genes (TGFB1, TGFB2, TGFB3, ALK1, ALK5, TGFBR2, Endoglin, SMAD2 and SMAD4) have been analysed. From 285 common SNPs (minor allele frequency >0.05), identified from the International HapMap project data, 83 tagging SNPs have been defined and genotyped. Statistically significant associations with cancer susceptibility have been identified with at least one variant in five of the genes. The TGFB2, TGFB3, Endoglin and SMAD4 genes are not associated. A further eight genes will be studied.