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Recent compelling evidence indicates that mutation, aberrant expression, and dysregulation of microRNA (miRNA) biogenesis are implicated in cancer development and progression. Based on the important role of miRNA biogenesis pathway in carcinogenesis, we hypothesized that genetic variations in this pathway genes may play a role as susceptibility factors for breast cancer. To test this hypothesis, we investigated the associations between 41 single nucleotide polymorphisms (SNPs) in 14 genes involved in miRNA biogenesis pathway and breast cancer risk in a case–control study of 559 Korean breast cancer cases and 567 controls frequency-matched by age. In all women, 3 SNPs (AGO1 rs595055, AGO2 rs3864659, and p68 rs1991401) were significantly associated with breast cancer risk. In stratified analysis by menopausal status, altered risk associations were observed for 7 SNPs in postmenopausal breast cancer. When subjects were grouped by the number of high-risk genotypes, we found a progressive increase in gene-dosage effect (P trend = 9.46E−7). The protective effects of AGO2 rs3864659 and HIWI rs11060845 were more pronounced in progesterone receptor-positive (PR+) cancer than in progesterone receptor-negative (PR−) cancer (odds ratio (OR), 0.50; 95% confidence interval (CI), 0.30–0.84 vs. OR, 0.94; 95% CI, 0.60–1.84; P heterogeneity = 0.04 and OR, 0.57; 95% CI, 0.37–0.88 vs. OR, 0.97; 95% CI, 0.65–1.44; P heterogeneity = 0.02, respectively), and the DROSHA rs644236 had stronger association with estrogen receptor-negative (ER−) cancer than for estrogen receptor-positive (ER+) cancer (OR, 1.39; 95% CI, 1.08–1.78 vs. OR, 1.05; 95% CI, 0.85–1.29; P heterogeneity = 0.04). Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer risk, and the modifiable effects might be different according to the menopausal status and hormone receptor status.

This study was conducted to evaluate the potential role of CASP8 genetic polymorphisms in the etiology of breast cancer in a case–control study, Korea. Incident breast cancer cases confirmed histologically (n = 1,599) were recruited from two hospitals in Seoul during 2001–2005. Control subjects (n = 1,536) were selected from the Health Examinee Cohort from Seoul and Gyeonggi Province surrounding Seoul, Korea. Three SNPs (D302H D > H, 5′-UTR C > T, and K337K G > A) were genotyped by the primer extension assay. The CASP8 D302H, which was not polymorphic in 48 samples, was excluded in further genotyping. Odds ratios and 95% confidential intervals (95% CIs) were estimated by unconditional logistic regression model adjusted for age at enrollment, education, age at first full-term pregnancy, cigarette smoking, and family history of breast cancer. The 5′-UTR T allele containing genotypes (CT/TT) were associated with an increased risk of breast cancer, compared with those with the CC genotype (OR = 1.13, 95% CI = 0.95–1.34; and OR = 1.48, 95% CI = 1.04–2.10, respectively; P-trend = 0.02). When stratified by the estrogen and progesterone receptor status, the association between the 5′-UTR T allele and breast cancer risk was prominent in ER(+) and PR(+) cases among pre-menopausal women (OR = 1.31, 95% CI = 1.00–1.72 and OR = 1.40, 95% CI = 1.06–1.85, respectively), whereas the association was found prominent in ER(−) or PR(−) cases (OR = 1.32, 95% CI = 0.93–1.87 and OR = 1.42, 95% CI = 1.04–1.94, respectively) among post-menopausal women. Our results thus suggest that the CASP8 5′-UTR C > T are associated with breast cancer risks and the effect may be modified by estrogen and progesterone receptor status.

To evaluate the potential role of genetic polymorphisms of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) on breast cancer development, a hospital-based case-control study was conducted in Korea.Histologically confirmed breast cancer cases (n = 560) and controls (n = 509) without cancer history were recruited from three teaching hospitals in Seoul between September 1998 and January 2002. Information on risk factors of breast cancer were collected by interviewed questionnaire. Genotypes of IL-1B (-31C/T) and IL-1RN (86 bp variable number tandom repeats in intron 2) were determined by PCR-CTPP (confronting two-pair primers) and PCR, respectively. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression model.The IL-1RN *2-allele was associated with decreased breast cancer risk with marginal significance (OR = 0.7, 95% CI = 0.48-1.05). The IL-1B CC or TC genotype was not associated with decreased risk of breast cancer (OR = 0.9, 95% CI = 0.65-1.16). However, combination of IL-1B C-allele (CT or CC) and IL-1RN *2-allele containing genotypes significantly decreased the risk of breast cancer (OR = 0.6, 95% CI = 0.39-0.99). A moderately decreasing trend of risk was observed as the number of 'putative low risk' allele increased (p for trend = 0.07). Suggestive combined effect on breast cancer risk was also observed between body mass index (BMI) and IL-1RN non-*2 allele: women with higher BMI and IL-1RN non-*2 allele had 1.7-fold higher risk than women with lower BMI and IL-1RN*2 genotypes.Our results suggest that genetic polymorphisms of interleukin-1 may play a role in the individual susceptibility for breast cancer development in Korean women.

Objective. The proliferation of malignant breast epithelial cells is regulated by various stimuli including cytokines and growth factors, thus the variants of those genes may modify the breast cancer risk. To evaluate the potential influences of TGF-β1 T 29C and TNF-β A252G gene polymorphisms on breast cancer risk, a case–control study was conducted in Korea. Methods. Histologically confirmed breast cancer cases (n = 560) and controls (n=509) with no previous history of cancer were recruited from three teaching hospitals in Seoul, Korea. Genotypes were determined by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusting for age, body mass index, education, parity, age at first full-term pregnancy, and family history of breast cancer. Results. The TGF-β1 29C-allele containing genotypes posed an increased risk of breast cancer (OR=1.3, 95% CI=1.02–1.79), especially in postmenopausal women (OR=1.6, 95% CI=1.01–2.44). Similarly, the TNF-β 252G-allele containing genotypes posed an increased risk of postmenopausal breast cancer (OR=1.7, 95% CI=1.09–2.55). The risk of postmenopausal breast cancer increased in parallel with the number of the risk genotypes (p for trend 22.8 kg/m2) (OR=1.9, 95% CI=1.04–3.37). Conclusion. The results of this study therefore suggest that polymorphisms of TGF-β1 and TNF-β genes may modify individual susceptibility to breast cancer in Korean women.

We conducted a hospital-based case-control study to evaluate the interactive effect of reproductive factors and glutathione S-transferase (GST) M1 and T1 genetic polymorphisms in individual susceptibility to breast cancer. The study population consisted of 189 incident breast cancer cases and 189 age-matched controls with no known malignant diseases. GSTM1/T1 genotypes were determined by a multiplex polymerase chain reaction (PCR) method, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression model. The parity factors were grouped as (1) high-risk status defined as nullipara or para with experience of first full-term pregnancy (FFTP) at or over 30 years, and (2) low-risk status defined as para with experience of FFTP under 30 years. A significant multiplicative interaction was observed between GSTM1 and GSTT1 null genotypes and high-risk status of parity factor in all women and in premenopausal women (Por = 0.01), but not in postmenopausal women (P0.05). The interaction between the combined genotypes of GSTM1 and GSTT1 and status of parity factor was also significant in all women and in premenopausal women (P0.01). Our findings suggest that genetic polymorphisms GSTM1/T1 could modify estrogen-related breast cancer risk.

Breast cancer development is related to genes regulating cell cycle progression such as CCND1, CDK7, and ESR1. We conducted a hospital-based case-control study to evaluate the role of genetic polymorphisms in these genes in breast cancer development among Korean women. Questionnaire data and samples were obtained from 864 incident breast cancer cases and 723 controls recruited from 1995 to 2002. Four single nucleotide polymorphisms (SNPs) in three genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry [CCND1 Ex4-1G>A (rs9344), CDK7 Ex2-28C>T (rs2972388), ESR1 P325P Ex4-122G>C (rs1801132), and ESR1 T594T Ex8+229G>A (rs2228480)], and their associations with breast cancer risk were assessed. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis adjusted for age, education, age at the first full-term pregnancy, and family history of breast cancer. Women carrying the CDK7 TT genotype had increased risk of breast cancer (OR, 1.4; 95% CI, 1.1-1.7). There was no significant association between breast cancer risk and the genetic polymorphisms of CCND1 and ESR1. However, when CDK7 and ESR1 P325P were combined, women carrying both the CDK7 TT and ESR1 P325P CC genotypes showed increased breast cancer risk (OR, 1.7; 95% CI, 1.1-2.5; P for trend

Endothelial nitric oxide synthase (NOS3) produces nitric oxide which is a mediator of cytotoxic effects potentially associated with breast cancer. We evaluated the role of genetic polymorphisms of NOS3 in breast cancer etiology, in a case–control study conducted in Korea. We recruited 1,385 eligible patients with histologicaly confirmed incident breast cancer cases and 968 hospital-based controls. Two potentially functional NOS3 polymorphisms in the promoter region (−786T > C) and exon 7 (894G > T, Glu298Asp) were genotyped and individual haplotypes were estimated. Odds ratios (ORs) and 95% confidential intervals (95% CIs) were calculated by unconditional logistic regression, adjusting for age, body mass index, education, family history of breast cancer in first and second degree relatives, age at first full-term pregnancy and parity. There was no overall association between the −786T > C or 894G > T genotype and breast cancer risk. However, the −786C allele was marginally associated with decreased risk for invasive breast cancer with lymph node involvement (OR = 0.76, 95% CI = 0.56–1.04). And, compared to TG-TG carriers, all other haplotype pairs were significantly associated with invasive breast cancer with lymph node involvement (OR = 0.77, 95% CI = 0.59–0.99). Our results suggest that genetic polymorphisms in NOS3 modify individual susceptibility to invasive breast cancer with lymph node involvement in Korean women.

To evaluate the relationship of genetic polymorphism in XRCC3 Thr(241)Met and the risk of breast cancer, a hospital-based case-control study was conducted in Korea. Histologically confirmed breast cancer cases (n = 574) and controls (n = 502) with no present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2001. Information on demographic characteristics and other information were collected by interviewed questionnaire. Genetic polymorphisms of XRCC3 Thr(241)Met (CT) was determined by single base extention assay. The frequency of Thr/Thr, Thr/Met, and Met/Met genotype were 89.4, 10.4, 0.2% in cases and 92.3, 7.7, 0.0% in controls, respectively. Genotype distribution in controls fit well to the Hardy-Weinberg equilibrium (P = 0.74). XRCC3 codon 241 Thr/Met or Met/Met genotype moderately increased the risk of breast cancer (OR = 1.4, 95% CI: 0.87-2.33), but not significant in this study. In the results of meta-analysis using twelve reports, however, Thr/Met or Met/Met genotype increased the risk of breast cancer (OR = 1.08, 95%CI: 1.00-1.17). In conclusion, although the genetic polymorphism of XRCC3 Thr(241)Met was unlikely to have a substantial overall association in Korean women, the meta-analysis of studies, including ours, provided that Thr/Met and Met/Met was weakly increased the risk of breast cancer compare to Thr/Thr genotype.

The endothelial cell-specific form of nitric oxide synthase (eNOS) may play an important role in tumor progression via angiogenesis or apoptosis. We studied eNOS -786T > C and 894G > T (Glu298Asp), two functionally significant SNPs, in relation to hazard of breast cancer recurrence or death in 873 women with incident, non-metastatic breast cancer, recruited from two teaching hospitals in Seoul, Korea, 1995-2002. Hazards were estimated by Cox proportional hazard models, in relation to genotype, adjusting for hormone receptor status, lymph node involvement, and tumor size. Women carriers of the eNOS -786C allele had significantly increased hazards of breast cancer recurrence or death, compared with women having the TT genotype (HR = 2.1, 95% CI = 1.03-4.33); risks increased up to 3-fold in ER positive cases (HR = 3.2, 95% CI = 0.95-10.50). The hazard was also increased in eNOS 894T carriers, however, it did not reach statistical significance (HR = 1.8, 95% CI = 0.85-3.93). The combined genotypes containing -786C or 894T was associated with a 2.5-fold risk, compared to the TT-GG genotypes, the most dominant genotype combination (95% CI = 1.29-4.68), with the greatest risks in ER positive cases (HR = 4.9, 95% CI = 1.31-18.36). These results indicate that the eNOS -786C polymorphism, and possibly the 894T polymorphism, are associated with breast cancer recurrence and death, particularly in women with ER positive tumors.

The proliferation of malignant breast epithelial cells is regulated by various stimuli including cytokines and growth factors, thus the variants of those genes may modify the breast cancer risk. To evaluate the potential influences of TGF-beta1 T29C and TNF-beta A252G gene polymorphisms on breast cancer risk, a case-control study was conducted in Korea.Histologically confirmed breast cancer cases (n=560) and controls (n=509) with no previous history of cancer were recruited from three teaching hospitals in Seoul, Korea. Genotypes were determined by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusting for age, body mass index, education, parity, age at first full-term pregnancy, and family history of breast cancer.The TGF-beta1 29C-allele containing genotypes posed an increased risk of breast cancer (OR=1.3, 95% CI=1.02-1.79), especially in postmenopausal women (OR=1.6, 95% CI=1.01-2.44). Similarly, the TNF-beta 252G-allele containing genotypes posed an increased risk of postmenopausal breast cancer (OR=1.7, 95% CI=1.09-2.55). The risk of postmenopausal breast cancer increased in parallel with the number of the risk genotypes (p for trend0.01). When data were stratified by the presumed non-genetic risk factors, TGF-beta1 C-allele containing genotypes were found to increase breast cancer risk almost two-fold in postmenopausal women with greater than median body mass index (22.8 kg/m2) (OR=1.9, 95% CI=1.04-3.37).The results of this study therefore suggest that polymorphisms of TGF-beta1 and TNF-beta genes may modify individual susceptibility to breast cancer in Korean women.