Breast Neoplasms: Park SK

Park SK, Kang D, McGlynn KA, Garcia-Closas M, Kim Y, Yoo KY, Brinton LA. · Department of Preventive Medicine, Seoul National University College of Medicine, Yeongeon-dong, Jongro-gu, Seoul 110-799, Seoul, Republic of Korea. · Breast Cancer Res. · Pubmed #18205956 links to  free full text

Abstract: INTRODUCTION: Various perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status, and parental smoking, have been postulated to affect breast cancer risk in daughters by altering the hormonal environment of the developing fetal mammary glands. Despite ample biologic plausibility, epidemiologic studies to date have yielded conflicting results. We investigated the associations between perinatal factors and subsequent breast cancer risk through meta-analyses. METHODS: We reviewed breast cancer studies published from January 1966 to February 2007 that included data on birth weight, birth order, maternal age, gestational age, twin status, and maternal or paternal smoking. Meta-analyses using random effect models were employed to summarize the results. RESULTS: We found that heavier birth weights were associated with increased breast cancer risk, with studies involving five categories of birth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 g or more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to 2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk. Support for an association with birthweight was also derived from studies based on three birth weight categories (OR 1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to <3,000 g) and two birth weight categories (OR 1.09 [95% CI 1.02 to 1.18] for > or =3,000 g relative to <3,000 g). Women born to older mothers and twins were also at some increased risk, but the results were heterogeneous across studies and publication years. Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk. CONCLUSION: Our findings provide some support for the hypothesis that in utero exposures reflective of higher endogenous hormone levels could affect risk for development of breast cancer in adulthood.

Yoo KY, Kang D, Park SK, Kim SU, Kim SU, Shin A, Yoon H, Ahn SH, Noh DY, Choe KJ. · Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. · J Korean Med Sci. · Pubmed #11850580 links to  free full text

Abstract: Breast cancer ranks second or third to uterine cervix cancer and stomach cancer as a cause of death in women, and as a common site of primary cancer. The large difference in its incidence between Westernized and non-Westernized countries is remarkable. There is a linear increase with age that is observed in Western countries, which are high-incidence areas, on the contrary to the inverted V shape curve seen in Asian countries. Epidemiologic studies conducted in Korea have shown that an older age, a family history of breast cancer, early menarche, late menopause, late full-term pregnancy, and never having had a breast-fed child are primary risk factors in the development of breast cancer. The estrogen-augmented-by-progesterone hypothesis explains the roles of these factors to some extent. On the other hand, recent molecular studies have revealed the existence of novel gene environmental interactions. Epidemiological features suggest that the breast cancer incidence rate in Korea will increase, but the age specific curve would not be changed in keeping with what is observed in Western countries. Strategies aimed at controlling breast cancer that include the screening guidelines and the identification of individual predispositions may give us further insights into both the etiology and the prevention of breast cancer.

Choi JY, Hamajima N, Tajima K, Yoo KY, Yoon KS, Park SK, Kim SU, Lee KM, Noh DY, Ahn SH, Choe KJ, Han W, Hirvonen A, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea. · Breast Cancer Res Treat. · Pubmed #12779082 No free full text.

Abstract: To evaluate the potential association between breast cancer risk and Ser326Cys polymorphism of hOGG1 gene, encoding for an enzyme involved in the base excision repair of 8-hydroxyguanine, hospital based case-control studies were conducted in two Asian populations consisting of 475 breast cancer cases (271 Korean and 204 Japanese) and 500 controls (314 Korean and 186 Japanese). PCR-based methods were employed for the genotyping analyses and the statistical evaluations were performed by unconditional logistic regression model. The frequency of hOGG1 Ser/Ser, Ser/Cys, and Cys/Cys genotypes were 22.5, 48.7, and 28.8% in all cases, and 23.7, 52.1, and 24.1% in the controls. No statistically significant associations between the genotypes and breast cancer risk were observed, neither when the ethnic groups were examined separately nor when the total study population was included. Neither did stratification by menopausal status reveal any association between hOGG1 genotypes and breast cancer. Our novel findings therefore suggest that hOGG1 Ser326Cys polymorphism is unlikely to play a modifying role in individual susceptibility to breast cancer among Asian women.

Son HK, Kam S, Park KS, Kim JR, Kim RB, Park SK. · Department of Preventive Medicine, School of Medicine, Kyungpook National University, Korea. · J Prev Med Public Health. · Pubmed #19349740 links to  free full text

Abstract: OBJECTIVES: This study was performed to evaluate the relationships between psychosocial characteristics and changes in the stage of breast cancer screening behavior. METHODS: The 474 study subjects were randomly sampled from 21,459 women (age range, 40-70 years) who were eligible for the Korean National Cancer Screening Program in 2006 in Jinju, Gyeongsangnam-do. The information, including behaviors and sociodemographic characteristics, attitudes, subjective norms and self-efficacy, was collected by trained interviewers via home visits. The breast cancer screening stages were grouped as precontemplation, contemplation, action, maintenance and relapse, according to Rakowski. RESULTS: Of the 474 women, 18.8% were in the precontemplation stage, 23.3% were in the contemplation stage, 13.1% were in the action stage, 36.6% were in the maintenance stage, and 8.2% were in the relapse stage. The distribution of stages was associated with attitude, subjective norms and self-efficacy (p for trend<0.01). To investigate the overall relationship between the variables, we conducted a linear structural equation model analysis based on the theory of planned behavior. The subjective norms and self-efficacy influenced the stage of the women's screening behavior. CONCLUSIONS: We should target on self-efficacy about the screening behavior of women by performing timely, thoughtful interventions. The support from family members, friends and other people is crucial for women to undergo breast cancer screening and to improve the breast cancer screening rate.

Kim Y, Park SK, Han W, Kim DH, Hong YC, Ha EH, Ahn SH, Noh DY, Kang D, Yoo KY. · Division of Cancer Prevention, National Cancer Control Research Institute, National Cancer Center, Goyang, Korea. · Cancer Epidemiol Biomarkers Prev. · Pubmed #19190159 No free full text.

Abstract: High-density lipoprotein cholesterol (HDL-C) has been suggested to be associated with breast cancer. However, the roles of HDL-C and hypertriglyceridemia on breast cancer still have been controversial. The goal of this study was to investigate the association between HDL-C with breast cancer risk, stratifying by menopausal status, and body mass index. The hormonal receptor status of breast has been proposed to modify the effect of HDL-C on breast cancer. Multicenter hospital-based case-control study was conducted from November 2004 to December 2005 in Korea. After one to two individual matchings by age (+/-5 years) and menopausal status, 690 cases and 1,380 controls were included in the analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by conditional, unconditional, and multinomial logistic regressions. Protective effect of HDL-C on breast cancer was only observed among premenopausal women with an OR (95% CI) of 0.49 (0.33-0.72) for HDL-C > or = 60 versus <50 mg/dL (P(trend) < 0.01). Only nonobese premenopausal women had a significant decreased risk (OR, 0.34; 95% CI, 0.22-0.53). OR (95% CI) of low HDL-C (<50 mg/dL) and high triglyceride (TG; > or = 150 mg/dL) category was 2.20 (1.32-3.67) on estrogen receptor-negative and progesterone receptor-negative breast cancer compared with high HDL-C (> or = 50 mg/dL) and low TG (<150 mg/dL) category. This study suggests that higher level of HDL-C may reduce breast cancer risk among premenopausal women. Estrogen receptor-negative and progesterone receptor-negative breast cancer was associated with dyslipidemia, which implicates that association among HDL-C, TG, and breast cancer may be modified by receptor status.

Kang JS, Kang MR, Han SB, Yoon WK, Kim JH, Lee TC, Lee CW, Lee KH, Lee K, Park SK, Kim HM. · Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea. · Biol Pharm Bull. · Pubmed #19122299 links to  free full text

Abstract: Breast cancer is one of the most frequent female cancers in the Western world. Perturbation of estrogen levels by hormone replacement therapy or pregnancy is associated with a variety of diseases, including breast cancer. Estrogen supplementation is required to establish appropriate animal models for estrogen-related diseases. In this report, we demonstrated that supplementation with high doses of 17beta-estradiol results in deaths in estrogen-dependent MCF-7 tumor xenograft model. Renal damage and bladder stone formation was implicated as a major cause of death. The mortality rate was significantly reduced when mice received a low dose of 17beta-estradiol. We also confirmed that low dose of 17beta-estradiol supplementation can support the growth of tumors in MCF-7 tumor xenograft model. These results suggest that low dose estrogen supplementation may be more appropriate in estrogen-dependent tumor xenograft models.

Yu W, Jia L, Wang P, Lawson KA, Simmons-Menchaca M, Park SK, Sun L, Sanders BG, Kline K. · Division of Nutrition/A2703, University of Texas at Austin, Austin, TX 78712-1097, USA. · Mol Nutr Food Res. · Pubmed #18381678 No free full text.

Abstract: The goal of these studies was to investigate the potential anticancer properties of two naturally occurring plant sources and two manufactured synthetic forms of vitamin E, i. e., RRR-alpha-tocopherol (alphaT), RRR-gamma-tocopherol (gammaT), all-rac-alpha-tocopherol (all-rac-alphaT), and all-rac-alpha-tocopheryl acetate (all-rac-alphaTAc) in breast cancer models. Vitamin E compounds were evaluated in vitro for inhibition of colony formation and induction of apoptosis in human MDA-MB-435 and MCF-7 breast cancer cells and murine 66cl-4 mammary cancer cells and in vivo for ability to reduce tumor growth and lung and lymph node metastases using the transplantable syngeneic BALB/c mouse 66cl-4-GFP mammary cancer model. gammaT inhibited colony formation and induced apoptosis in all three cancer cell lines. alphaT and all-rac-alphaT were less effective and all-rac-alphaTAc was ineffective. gammaT-induced apoptosis was correlated with activation of caspases-8 and -9 and down-regulation of protein expression of c-FLIP and survivin. In vivo study 1 analyses showed that all-rac-alphaT and all-rac-alphaTAc significantly inhibited tumor growth and inhibited both visible and microscopic size lung metastases. In vivo study 2 analyses showed that alphaT and gammaT reduced tumor growth, but only gammaT reduced tumor growth significantly in comparison to control. In conclusion, synthetic, but not natural, vitamin E exhibits promising anti-cancer properties in vivo.

Lee JY, Choi JY, Lee KM, Park SK, Han SH, Noh DY, Ahn SH, Kim DH, Hong YC, Ha E, Yoo KY, Ambrosone CB, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, Jongnoo-Gu, Seoul, South Korea. · Clin Chim Acta. · Pubmed #18160046 No free full text.

Abstract: BACKGROUND: Hypoxia inducible factor 1 alpha (HIF-1A) is activated by low oxygen condition tension, a key regulator of the gene involved in the cellular response to hypoxia. Tumors exhibiting extensive hypoxia are more aggressive than tumors oxygenized better. METHODS: To evaluate the potential role of the polymorphisms of HIF-1A in the etiology of breast cancer, histologically confirmed incident breast cancer cases (n=1599) and control subjects (n=1536) were recruited. RESULTS: Two selected SNPs (Ex15+197C>T and P582S) were not associated with overall breast cancer risk (TT vs. CC: OR=0.9, 95% CI=0.6-1.5, Ser/Ser vs. Pro/Pro: OR=5.5, 95% CI=0.7-45.4, respectively). However, when stratified analyses were performed, significant associations were observed between Ser/Ser genotype at codon 582 and breast cancer risk among women with larger tumor size (>2 cm) (OR=10.1, 95% CI=1.1-91.1) or without lymph node involvement (OR=9.3, 95% CI=1.1-79.4), although confidence intervals were wide. CONCLUSIONS: Our findings support the hypothesis that the HIF-1Alpha P582S variant may confer susceptibility to subgroups of breast cancer in Korean women. However, further study is warranted due to low statistical power caused by very low minor allele frequencies.

Yu W, Park SK, Jia L, Tiwary R, Scott WW, Li J, Wang P, Simmons-Menchaca M, Sanders BG, Kline K. · School of Biological Sciences, University of Texas at Austin, Austin, TX, USA. · Cancer Lett. · Pubmed #18022315 links to  free full text

Abstract: Goal of this study was to investigate the pro-apoptotic properties of RRR-gamma-tocopherol (gammaT) in human breast cancer cells. gammaT was shown to induce cancer cells but not normal cells to undergo apoptosis, sensitize cancer cells to Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis, and increase death receptor 5 (DR5) mRNA, protein and cell surface expression. Knockdown of DR5 attenuated gammaT-induced apoptosis. Investigations of post-receptor signaling showed: caspase-8, Bid and Bax activation, increases in mitochondria permeability, cytochrome c release and caspase-9 activation. Thus, gammaT is a potent pro-apoptotic agent for human breast cancer cells inducing apoptosis via activation of DR5-mediated apoptotic pathway.

Han S, Lee KM, Choi JY, Park SK, Lee JY, Lee JE, Noh DY, Ahn SH, Han W, Kim DH, Hong YC, Ha E, Yoo KY, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, Chongno-Gu, Seoul, Korea. · Breast Cancer Res Treat. · Pubmed #17940865 No free full text.

Abstract: OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Kim HM, Hong SH, Kim MS, Lee CW, Kang JS, Lee K, Park SK, Han JW, Lee HY, Choi Y, Kwon HJ, Han G. · Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon 305-333, Republic of Korea. · Bioorg Med Chem Lett. · Pubmed #17904843 No free full text.

Abstract: Novel delta-lactam-based HDAC inhibitors which have various substituted benzyl, bi-aromatic cap groups were prepared using ring closure metathesis reaction, and evaluated their HDAC inhibitory activities and anti-proliferative effects. Among prepared analogues, 11m and 11o have very strong HDAC enzymatic inhibition and showed the most potent growth inhibitory activity to five human tumor cell lines including PC-3, ACHN, NUGC-3, HCT-15, and MBA-MB-231 tumor cell lines. Compounds 11m and 11o also showed good tumor growth inhibition of MDA-MB-231 cells in in vivo xenograft model. Structure-activity relationship study using docking model explained the significance of hydrophobic aromatic cap groups for their in vitro activities.

Shin A, Kang D, Choi JY, Lee KM, Park SK, Noh DY, Ahn SH, Yoo KY. · Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. · Exp Mol Med. · Pubmed #17603290 links to  free full text

Abstract: Cytochrome P450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogen, the hormone that plays a critical role in the etiology of breast carcinoma. We evaluated the associations between two CYP1A1 polymorphisms [MspI (rs4646903); Ile462Val (rs1048943)] and breast cancer in a multicenter case-control study of 513 breast cancer cases and 447 controls in Korea. Women carrying the T allele of the CYP1A1 MspI polymorphism were found to have a 1.72-fold (95% CI 1.11-2.68) greater risk of developing breast cancer. No association was found between any CYP1A1 Ile462Val polymorphism and breast cancer. Haplotype analysis of the two loci showed that the CA haplotype was associated with the lowest risk of breast cancer, and CA/CA diplotypes were associated with a lower risk of breast cancer [OR=0.28 (0.13-0.61)] than others/others diplotypes. Moreover, this reduced risk was more pronounced among women with a lower body mass index (BMI) [OR=0.18 (0.06-0.58)] or with a shorter lifetime exposure to estrogen [OR=0.23 (0.07-0.81)]. The results obtained suggest that the CYP1A1 MspI polymorphisms could affect susceptibility to breast cancer.

Kim Y, Choi JY, Lee KM, Park SK, Ahn SH, Noh DY, Hong YC, Kang D, Yoo KY. · Departments of Preventive Medicine, Seoul National University College of Medicine, Yongon-dong Chongno-gu, Seoul, Republic of Korea. · Eur J Cancer Prev. · Pubmed #17297388 No free full text.

Abstract: Lactation might have a crucial role in an extraordinary increase in breast cancer incidence in Korea, as the proportion of mothers who practised breast-feeding fell dramatically. This hospital-based case-control analysis has been carried out since 1997 to evaluate whether lactation is associated with breast cancer risk in Korean women. Among the eligible study participants, a total of 753 histologically confirmed incident cases and an equal number of controls were included in the analysis. The risk was estimated using unconditional logistic regression models. Family history, older at menopause, more full-term pregnancies increased the risk of breast cancer. Breast cancer risk decreased according to the total months of breast-feeding (P for trend=0.03). Average duration of breast-feeding of 11-12 months reduced risk of breast cancer by 54% compared with the duration of 1-4 months (odds ratio, 0.46; 95% confidence interval, 0.30-0.70). The decreasing risk trend according to average months of breast-feeding was also statistically significant (P for trend=0.02). Moreover, a reduced risk of breast cancer was apparent when analysis was restricted to the first breast-fed child (P for trend=0.006). This study confirms that lactation has an apparent dose-dependent protective effect against breast cancer in Korean women.

Yoo KY, Kim Y, Park SK, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, 410-769, Korea. · Asian Pac J Cancer Prev. · Pubmed #17250452 No free full text.

Abstract: Not only the incidence but the mortality of breast cancer has been steadily increasing in Korea over the last twenty years, and it became the most common female neoplasm in 2002. In fact, the increase in the rate of breast cancer mortality in Korea over the past 10 years has been higher than anywhere else in the world, and it is particularly noteworthy that more than half of the incident cases occur among those younger than 50 years of age. The rapid westernization of dietary habits and changes in reproductive behavior of Korean women presumably played a central role in this extraordinary increase in breast cancer occurrence. A large-scale multi-center case-control analysis showed that an older age, a family history of breast cancer, early menarche, late menopause, late full-term pregnancy, never-having had a breast-fed child, and postmenopausal obesity are breast cancer risk factors in Korea. Environmental and genetic factors are known to play interactive roles in human carcinogenesis and recent studies have shown that genetic polymorphisms may predispose individuals to breast cancer via gene-to-environment or gene-to-gene interactions. Thus research into genetic variation in xenobiotic metabolism, estrogen metabolism, DNA repair, cytokine metabolism, or cell cycle control may give insights into both the etiology and prevention of breast cancer. Epidemiologic evidence obtained from migrant and lifestyle change studies and investigations of main risk factors strongly suggests that breast cancer will further increase in Korea. Future predictions point to a 2- to 3-fold increase in incidence by 2020. Here, we briefly introduce health education programs and breast cancer campaigns, in the broad context of the Korean National Cancer Control Program.

Lee SA, Lee KM, Park SK, Choi JY, Kim B, Nam J, Yoo KY, Noh DY, Ahn SH, Kang D. · Department of Preventive Medicine, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul 110-799, South Korea. · Breast Cancer Res Treat. · Pubmed #17063279 No free full text.

Abstract: 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 (C > T) 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.

Park SK, Garcia-Closas M, Lissowska J, Sherman ME, McGlynn KA, Peplonska B, Pepońska B, Bardin-Mikolajczak A, Bardin-Mikoajczak A, Zatoński W, Szeszenia-Dabrowska N, Brinton LA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Int J Cancer. · Pubmed #16804898 No free full text.

Abstract: High estrogen exposure in utero may increase breast cancer risk later in life. However, studies of the associations between perinatal factors presumed to affect the fetal hormonal environment and breast cancer risk are inconsistent. We used data from a population-based case-control study of 2,386 incident breast cancers and 2,502 controls in Poland to evaluate risks associated with various perinatal characteristics. After adjusting for confounders, we found a significant trend (p = 0.01) of breast cancer risk with birth weight (OR = 1.54, 95% CI 1.08-2.19 for birth weights >4,000 g vs. <2,500 g). Subjects with a high birth order (> or =6) were at reduced risk (OR = 0.81, 0.61-1.06) when compared with first born subjects. Birth weight was somewhat a stronger risk predictor among subjects whose cancers were diagnosed at 50 years of age or older (OR = 1.84, 1.19-2.85) than among those with cancers diagnosed at younger ages (OR = 1.14, 0.61-2.12). Subjects whose mothers smoked during their pregnancies were at slightly higher risk than those who never smoked (OR = 1.21, 0.99-1.47), but the risk was similar to mothers who only smoked at other times (OR = 1.22, 0.81-1.84). Breast cancer risk was not related to paternal smoking, maternal age, gestational age or twin status. Our results add support to the growing evidence that some perinatal exposures may relate to breast cancer risk. Additional studies are needed to confirm associations and clarify the biologic mechanisms underlying these associations.

Lee KM, Park SK, Hamajima N, Tajima K, Choi JY, Noh DY, Ahn SH, Yoo KY, Hirvonen A, Kang D. · Cancer Research Institute, Institute of Environmental Medicine, SNUMRC, and Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, Korea. · Breast Cancer Res Treat. · Pubmed #16319982 No free full text.

Abstract: OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our results suggest that genetic polymorphisms of interleukin-1 may play a role in the individual susceptibility for breast cancer development in Korean women.

Choi JY, Lee KM, Park SK, Noh DY, Ahn SH, Yoo KY, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul 110-799 Korea. · BMC Cancer. · Pubmed #16259637 links to  free full text

Abstract: BACKGROUND: Older paternal age may increase the germ cell mutation rate in the offspring. Maternal age may also mediate in utero exposure to pregnancy hormones in the offspring. To evaluate the association between paternal and maternal age at birth with the risk of breast cancer in female offspring, a case-control study was conducted in Korea. METHODS: Histologically confirmed breast cancer cases (n = 1,011) and controls (n = 1,011) with no present or previous history of cancer, matched on year of birth and menopausal status, were selected from several teaching hospitals and community in Seoul during 1995-2003. Information on paternal and maternal ages and other factors was collected by interviewed questionnaire. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression model adjusting for family history of breast cancer in 1st or 2nd degree relatives, and lifetime estrogen exposure duration. RESULTS: The risk of breast cancer significantly increased as the paternal age increased (p for trend = 0.025). The association was stronger after controlling for maternal age; women whose fathers were aged >or=40 years at their birth had 1.6-fold increased risk of breast cancer compared with fathers aged <30 years. This association was profound in breast cancer cases in premenopausal women (OR = 1.9, 95% CI = 1.12-3.26, for paternal aged >or=40 vs. <30) (p for trend = 0.031). Although the risk of breast cancer increased as maternal age increased up to the intermediate, and then reduced; the risks in women whose mother were aged 25-29, 30-34, and >or=35 yrs at birth compared to women whose mothers were aged <25 years, were 1.2, 1.4, and 0.8, respectively, the trend was not significant (p for trend = 0.998). CONCLUSION: These findings suggest that older paternal age increases the risk of breast cancer in their female offspring.

Lee KM, Choi JY, Kang C, Kang CP, Park SK, Cho H, Cho DY, Yoo KY, Noh DY, Ahn SH, Park CG, Wei Q, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, Chongno-Gu, Seoul, Korea. · Clin Cancer Res. · Pubmed #15958648 links to  free full text

Abstract: PURPOSE: Genetic polymorphisms of DNA repair genes seem to determine the DNA repair capacity, which in turn may affect the risk of breast cancer. To evaluate the role of genetic polymorphisms of DNA repair genes in breast cancer, we conducted a hospital-based case-control study of Korean women. EXPERIMENTAL DESIGN: We included 872 incident breast cancer cases and 671 controls recruited from several teaching hospitals in Seoul from 1995 to 2002. Twelve loci of selected DNA repair genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (XRCC2 Arg188His, XRCC4 921G > T, XRCC6 1796G > T, LIG4 1977T/C, RAD51 135G > C, 172G > T, RAD52 2259C > T, LIG1 551A > C, ERCC1 8092A > C, 354C > T, hMLH1 -93G > A, and Ile219Val). RESULTS: We found that the RAD52 2259 CT or TT, hMLH1 -93 GG, and ERCC1 8092 AA genotypes were associated with breast cancer risk after adjustment for known risk factors [odds ratio (OR), 1.33; 95% confidence interval (95% CI), 1.02-1.75; OR, 1.31; 95% CI, 0.99-1.74; and OR, 0.58; 95% CI, 0.38-0.89, respectively]. When Bonferroni's method was used to correct for multiple comparisons for nine polymorphisms with P = 0.005, all of these associations were not significant. However, the effects of RAD52 2259 CT or TT and ERCC1 354 CT or TT genotypes were more evident for the estrogen/progesterone receptor-negative cases (OR, 2.03; 95% CI, 1.24-3.34 and OR, 1.99; 95% CI, 1.35-2.94, respectively). CONCLUSION: Our findings suggest that genetic polymorphisms of RAD52, ERCC1, and hMLH1 may be associated with breast cancer risk in Korean women.

Choi JY, Lee KM, Park SK, Noh DY, Ahn SH, Chung HW, Han W, Kim JS, Shin SG, Jang IJ, Yoo KY, Hirvonen A, Kang D. · Department of Preventive Medicine, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul 110-799, Korea. · Cancer Epidemiol Biomarkers Prev. · Pubmed #15894657 links to  free full text

Abstract: We examined whether common single nucleotide polymorphisms (SNP) in SULT1A1 (c.779G>A, *14A>G, and *85C>T) and SULT1E1 (IVS1-447C>A, IVS4-1653T>C, and *959G>A) genes influenced the risk and survival of breast cancer. Our study population consisted of 989 histologically confirmed sporadic breast cancer patients and 1,054 controls without history of cancer recruited from three teaching hospitals in Seoul. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression model. In the survival analysis for 529 breast cancer patients with completed treatments, the hazard ratios (HR) were calculated with Cox proportional hazard model. Women with the SULT1E1 *959 GA/AA genotype had a moderately decreased breast cancer risk compared with those with the GG genotypes (OR, 0.8; 95% CI, 0.70-1.00). When the haplotypes were considered, the homozygous *959 AA genotype together with the IVS4-1653 T>C base change (CTA-CCA haplotype) was associated with halved breast cancer risk (OR, 0.5; 95% CI, 0.24-0.88) compared with the wild type CTG-CTG haplotype. No other significant overall association was observed between the SULT1A1 and SULT1E1 SNPs nor haplotypes and breast cancer risk. When stratified by survival, patients with the SULT1E1 IVS4-1653 TC/CC genotypes showed a >3-fold risk of recurrence (HR, 3.2; 95% CI, 1.39-7.48) compared with those with the TT genotype. Moreover, when the haplotypes were considered, the SULT1E1 *959 G>A base change together with the IVS4-1653 T>C base change (CTG-CCA haplotype) was associated with a >4-fold risk of breast cancer (OR, 4.2; 95% CI, 1.15-15.15). These findings suggest that genetic polymorphisms of SULT1E1 are associated with increased risk and a disease free survival of breast cancer in Korean women.

Lee KM, Choi JY, Park SK, Chung HW, Ahn B, Yoo KY, Han W, Noh DY, Ahn SH, Kim H, Wei Q, Kang D. · Department of Preventive Medicine, Cancer Research Institute, Seoul National University, College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul 110-799, Korea. · Cancer Epidemiol Biomarkers Prev. · Pubmed #15824150 links to  free full text

Abstract: To evaluate the role of genetic polymorphisms of ataxia telangiectasia mutated (ATM) in the etiology of breast cancer, a hospital-based case-control study was conducted in Korea. Nine-hundred ninety-six histologically confirmed incident breast cancer cases and 1,181 cancer-free controls were recruited in Seoul between 1995 and 2003. Genotypes of the ATM polymorphisms-5144A > T, IVS21 + 1049T > C, IVS33 - 55T > C, IVS34 + 60G > A, and 3393T > G were determined by the 5'-nuclease assay. Individual haplotypes were estimated from genotype data by a Bayesian method. Five ATM alleles were found to be in strong linkage disequilibrium (D' > 0.82; P < 0.001). Haplotype frequencies were significantly different between cases and controls (chi2 test, P < 0.001). The ATM IVS21 + 1049 TC or CC, IVS34 + 60 GA or AA, and 3393 TG or GG genotypes were associated with increased breast cancer risk, particularly in premenopausal women [odds ratios (OR), 1.51; 95% confidence interval (CI), 1.11-2.05; OR, 1.42; 95% CI, 1.08-1.88; and OR, 1.37; 95% CI, 1.04-1.80, respectively]. Compared with diploid of TCCAG:TCCAG, the most common haplotype, the ATTGT:ATTGT was associated with decreased risk of breast cancer with borderline significance (OR, 0.77; 95% CI, 0.58-1.04) and TCCAG:ATCGT and ATTGT:ACCAG were associated with increased breast cancer risk (OR, 2.30; 95% CI, 1.18-4.48 and OR, 2.43; 95% CI, 1.1.07-5.52, respectively) after adjusting for age, education, age at first full-term pregnancy, parity, family history of breast cancer, alcohol consumption, and smoking. As the number of ATTGT haplotype decreased, the risk of breast cancer increased (P for trend < 0.01). Our results thus suggest that genetic polymorphisms of ATM play an important role in the development of breast cancer in Korean women.

Lee KM, Park SK, Hamajima N, Tajima K, Yoo KY, Shin A, Noh DY, Ahn SH, Hirvonen A, Kang D. · Department of Preventive Medicine, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-799, Korea. · Breast Cancer Res Treat. · Pubmed #15803361 No free full text.

Abstract: 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-beta1 T29C and TNF-beta 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-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 trend <0.01). 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). CONCLUSION: 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.

Shin MH, Lee KM, Yang JH, Nam SJ, Kim JW, Yoo KY, Park SK, Noh DY, Ahn SH, Kim B, Kang D. · Department of Social and Preventive Medicine, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeongi-do 440-746, Korea. · Exp Mol Med. · Pubmed #15761247 links to  free full text

Abstract: CYP17 gene is involved in steroidogenesis and steroid metabolism. Epidemiologic results on the association between the CYP17 polymorphism and breast cancer risk have been inconsistent. We examined the association between the MspAI polymorphism at +27 relative to the start of transcription in the 5'-untranslated region of CYP17 gene and breast cancer risk in Korean women. Four hundred and sixty-two incident cases and 337 controls were recruited from three teaching hospitals in Seoul during 1994-2001. Polymorphism of the CYP17 gene was determined by a single base extension assay. Demographic and lifestyle characteristics were identified using structured questionnaire. Age-adjusted (aOR) and multivariate odds ratios (& mgr;OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression. The proportions of A1/A1, A1/A2 and A2/A2 genotypes among controls were 20.8%, 45.1% and 34.1%, respectively. Compared to the A1/A1 genotype, A1/A2 or A2/A2 genotype was not statistically significantly associated with overall breast cancer risk (i.e., mOR = 1.01, 95% CI = 0.69-1.47 and mOR = 0.76, 95% CI = 0.51-1.14, respectively). However, a significant association between CYP17 A2/A2 genotype and breast cancer was observed among women aged 50 years or less (mOR = 0.58, 95% CI = 0.34-0.99, P =0.04) and leaner women (body mass index < 22 kg/ m2) (mOR = 0.48, 95% CI = 0.23-0.97, P = 0.04). Our results suggest that genetic polymorphism in 5'-untranslated region of CYP17 might play a role in breast cancer development in Korean women among younger women aged less than 50 or leaner women with body mass index less than 22 kg/m2.

Park SK, Yim DS, Yoon KS, Choi IM, Choi JY, Yoo KY, Noh DY, Choe KJ, Ahn SH, Hirvonen A, Kang D. · Department of Preventive Medicine Cancer Research Institute, Konkuk University College of Medicine, Chungju, Korea. · Breast Cancer Res Treat. · Pubmed #15538046 No free full text.

Abstract: Our previous studies suggested that both catechol O-methyl transferase (COMT) and glutathione S-transferase (GST) M1 and T1 genotypes are associated with breast cancer risk. Here we extended the studies to evaluate the potential combined effect of these genotypes in individual breast cancer risk. Incident breast cancer cases (n = 202) and controls (n = 299) with no previous cancer were recruited from three teaching hospitals in Seoul in 1996-1999. Information on putative risk factors was collected by interviewed questionnaire. PCR-based methods were used for the genotyping analyses. Odds ratios (ORs) and 95% confidence (CIs) intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Among pre-menopausal women the low activity associated (COMT *L) allele containing genotypes and the GSTM1 null genotype posed increased risks of breast cancer with ORs of 1.7 (95% CI = 1.0 - 2.8) and 1.7 (95% CI = 1.0-2.8), respectively. A marginally significant effect of GSTT1 null genotype was also observed when the total study population was considered (OR = 1.3, 95% CI = 1.0-2.1). When the combined genotype effects were examined, the concurrent lack of GSTM1 and GSTT1 genes posed a more than 2-fold risk of breast cancer (OR = 2.2, 95% CI = 1.2-3.9); this effect was mainly attributable in pre-menopausal women (OR = 3.2, 95% CI = 1.5-7.2). Moreover, the breast cancer risk increased in parallel with the number of COMT , GSTM1 , and GSTT1 at-risk genotypes (p for trend = 0.003). This association was particularly clear in pre-menopausal women among whom combination of all three high-risk genotypes posed a 4.1-fold breast cancer risk (95% CI = 1.4-12.7) compared with pre-menopausal women without at-risk genotypes (p for trend = 0.001). The trend was more pronounced in women with BMI greater than 22 kg/m2 (p for trend < 0.001) and high-risk status of parity factor (nulliparous or women with the first full term pregnancy at age of over 25-year-old) (p for trend = 0.013). These results suggest the combined effect between reproductive factors and GSTM1, GSTT1 and COMT genotypes in human breast carcinogenesis.

Kim SU, Lee KM, Park SK, Yoo KY, Noh DY, Choe KJ, Ahn SH, Hirvonen A, Kang D. · Department of Preventive Medicine, Seoul National University College of Medicine, Cancer Research Institute, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-799, Korea. · J Biochem Mol Biol. · Pubmed #15479622 links to  free full text

Abstract: To evaluate the potential association between the GSTP1 genotype and the development of breast cancer, a hospital based case-control study was conducted on Korean women. The study population consisted of 171 histologically confirmed incident breast cancer cases and 171 age-matched controls with no present or previous history of cancer. PCR-RFLP was used for the GSTP1 genotyping and statistical evaluations were performed using an unconditional logistic regression model. Postmenopausal women with the GSTP1 Val allele were found to have a reduced risk of breast cancer (OR = 0.3, 95 % CI = 0.10-0.74). A significant interaction was observed between the GSTP1 genotype and alcohol consumption (p for interaction = 0.01); compared with never-drinking women with Ile/Ile genotype, ever-drinking women with the GSTP1 Val allele had almost a three-fold risk of breast cancer (OR = 2.9, 95 % CI = 1.05-7.85), whereas never-drinking women with Val allele had half this risk (OR = 0.5, 95 % CI = 0.27-0.93). Our findings suggest that the GSTP1 polymorphism influences individual susceptibility to breast cancer in the Korean women and this effect may be modified by alcohol consumption.