Genetic polymorphisms of <Emphasis Type="Italic">NOS3</Emphasis> are associated with the risk of invasive breast cancer with lymph node involvement

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.     

An intron 4 VNTR polymorphism of the endothelial nitric oxide synthase gene is associated with early‐onset colorectal cancer

Endothelial‐derived nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), may play an important role in colorectal carcinogenesis. However, the putative contribution of common eNOS genetic polymorphisms to colorectal cancer risk remains unknown. We genotyped 3 polymorphisms of eNOS (T‐786C, G894T, and intron4b/a) in 727 colorectal adenocarcinoma cases and 736 age‐ and sex‐matched healthy controls in Taiwan. Genotypes of the T‐786C and G894T polymorphisms were determined by fluorescence polarization assays and the 27‐bp variable number of tandem repeat (VNTR) polymorphism in intron 4 (intron4b/a) was analyzed by PCR. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Among younger participants (≤60 yrs), the intron4a variant genotype was associated with a significantly increased risk of colorectal cancer, compared with the intron4bb genotype (OR = 1.60, 95% CI = 1.04–2.46). In addition, those young individuals bearing a greater number of high‐risk genotypes (OR > 1, i.e., CT+TT for T‐786C, ba+aa for intron4b/a, and GG for G894T) of eNOS had a higher colorectal cancer risk (p_trend = 0.039). Compared with younger individuals without any putative high‐risk genotypes, those with 3 high‐risk genotypes had a significantly greater cancer risk (OR = 1.89, 95% CI = 1.04–3.43). Our results suggest that the eNOS intron4b/a polymorphism may contribute to early‐onset colorectal cancer risk in the Taiwanese population. © 2008 Wiley‐Liss, Inc.     

Family history of breast cancer in first-degree relatives and triple-negative breast cancer risk

Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER−/PR−/HER2+, N = 308) breast cancer among women aged 40–84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43–2.09, HR = 1.62, 95% CI: 1.54–1.70, and HR = 1.56, 95% CI: 1.15–2.13, for triple-negative, ER+, and ER−/PR−/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR_{triple-negative} = 2.66, 95% CI: 1.66–4.27, HR_ER+ = 2.05, 95% CI: 1.79–2.36, HR_ER−_/PR−_/HER2+ = 2.25, 95% CI: 0.99–5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER−/PR−/HER2+ breast cancer.     

Effects of obesity and race on prognosis in lymph node-negative, estrogen receptor-negative breast cancer

SummaryBackground Several factors may contribute to poorer prognosis for obese breast cancer patients, including unfavorable disease features, the influence of fat on estrogen availability, co-morbidity, and socio-demographic factors. Both obesity and estrogen receptor negative (ER-) tumors are more prevalent in black women than in whites in North America. We evaluated obesity and race in relation to outcomes in women with ER-breast cancer.Methods Among 4077 women from National Surgical Adjuvant Breast and Bowel Project clinical trials for node-negative, ER-breast cancer, we evaluated disease-free survival (DFS) and its constituents (tumor recurrence, contralateral breast cancer (CBC), second primary cancers, deaths prior to these events) and mortality in relation to body mass index (BMI) and race, using statistical modeling to account for other prognostic factors.Results Compared to those of normal weight (BMI≤24.9), DFS hazard was greater for obese (BMI ≥ 30) women [hazard ratio (HR)=1.16, 95% confidence interval (CI)=1.01–1.33]. Obesity did not increase recurrence hazard, but did influence CBC (HR=2.08, 95% CI=1.22–3.55 in postmenopausal women) and second cancers (HR=1.49, 95% CI=1.06–2.10). Mortality increased with obesity; when partitioned by likely cause, those with BMI ≥ 35.0 had greater risk of non-breast cancer mortality (HR=1.86, 95% CI=1.21–2.84). Relative to whites and adjusted for BMI, black women had greater hazard for DFS (HR=1.17, 95% CI=1.00–1.38), CBC (HR=1.37, 95% CI=0.94–1.99), and non-breast cancer deaths (HR=2.10, 95% CI=1.45–3.03); risk for deaths likely due to breast cancer was closer to that in whites (HR=1.18; 95% CI=0.93–1.50).Conclusions For women with node-negative, ER-breast cancer from clinical trials, obesity did not increase recurrence risk, but was associated with greater risk for second cancers, CBC, and mortality, particularly non-breast cancer deaths. Less favorable prognosis for black women persists in clinical trials, and is in part attributable to non-breast cancer outcomes.     

No association of the <Emphasis Type="Italic">eNOS</Emphasis> gene polymorphisms with survival in patients with colorectal cancer

Endothelial nitric oxide synthase (eNOS)–derived nitric oxide (NO) is involved in numerous physiologic and pathophysiologic process including tumor angiogenesis and apoptosis. Accordingly, the present study analyzed polymorphisms of eNOS gene and their impact on the prognosis for patients with colorectal cancer. Four hundred and forty-four consecutive patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 2 polymorphisms of eNOS gene (eNOS T786C and eNOS G894T) determined using a real-time PCR genotyping assay. The 2 eNOS gene polymorphisms were successfully amplified, and the frequencies of each genotype are as follows [T786C: TT (82.2%), TC (16.9%), CC (0.9%); G894T: GG (82.0%), GT (17.3%), TT (0.7%)]. Multivariate survival analysis including stage, age, site of disease, and CEA level showed that these polymorphisms were not associated with survival. For the clinicopathologic parameters, CEA level and TNM stage were significant prognostic factors in a Cox model for survival. The eNOS gene polymorphisms investigated in this study were not found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer. However, further studies are warranted to clarify the role of the eNOS gene polymorphisms as a prognostic biomarker for colorectal patients with cancer.     

Long-term pattern of disease recurrence among patients with early-stage breast cancer according to estrogen receptor status and use of adjuvant tamoxifen

Purpose Recent studies on the pattern of gene expression in estrogen receptor positive and negative tumours have revealed profound differences according to receptor status. However, it remains unclear if these differences reflect phenotypic traits in addition to sensitivity to endocrine therapy. This paper describes the long-term pattern of disease recurrence among ca. 2,600 pre- and post-menopausal patients with primary breast cancer according to estrogen receptor status. Material and methods The study was based on patients with an operable, invasive breast cancer entered in one of three controlled clinical trials conducted by the Stockholm Breast Cancer Group. We selected those 2,562 patients who had been randomly allocated between adjuvant tamoxifen and no adjuvant systemic therapy. These patients had a known estrogen receptor status. Result Tamoxifen reduced locoregional (8.8% vs. 12.4%, hazard ratio (HR), 0.66; 95% CI, 0.52–0.83; P = 0.001, distant recurrences (17.2% vs. 20.2%, HR, 0.81; CI, 0.68–0.97; P = 0.018, as well as breast cancer death (18.7% vs. 23.7%, HR, 0.78; CI, 0.67–0.92; P = 0.002). Among patients not allocated to tamoxifen there was no significant differences in term of neither locoregional (12.4% vs. 12.4%, HR, 1; CI, 0.72–1.41; P = 0.98), nor distant metastases (18.5% vs. 20.7%, HR, 1.11;CI, 0.85–1.45; P = 0.46) according to ER status. The pattern of metastases was not different in ER positive comparison with ER negative. Conclusion The results showed that the mentioned substantial differences in terms of gene expression appeared mainly to be related to endocrine sensitivity and not to metastatic potential. However, a slight advantage during the first five years for the ER positive versus ER negative patients in terms of cumulative incidence of events, suggested that ER negativity in some cases is correlated with an increased tumour growth rate.     

Promoter polymorphism (-786t>C) in the endothelial nitric oxide synthase gene is associated with risk of sporadic breast cancer in non-Hispanic white women age younger than 55 years

BACKGROUND: Nitric oxide (NO) is constitutively synthesized in the endothelium by endothelial nitric oxide synthase (eNOS) and acts as a pleiotropic regulator involved in carcinogenesis. Most breast cancers develop from mammary epithelial cells; therefore, NO may play a role in their development. It was hypothesized that eNOS polymorphisms are associated with risk of breast cancer. METHODS: In the current hospital-based case-control study of 421 non-Hispanic white women with sporadic breast cancer and 423 frequency-matched control subjects, we genotyped 3 polymorphisms of eNOS (i.e., -786T>C, the 27-base pair [bp] variable number of tandem repeats [VNTR] in intron 4, and 894G>T [Glu298Asp]) and assessed their associations with risk of breast cancer. RESULTS: It was found that, compared with -786TT, the -786C variant genotypes were associated with a significantly increased risk of breast cancer in an allele dose-dependent manner (adjusted odds ratio [OR], 1.33 [95% confidence interval (95% CI)], 0.99-1.77 for -786TC; and OR, 1.79 [95% CI, 1.11-2.87] for -786CC; P(trend) = .007), but 27-bp VNTR and 894G>T genotypes were not. Stratification analysis demonstrated that the risk associated with -786C variant genotypes (-786TC/CC) was more pronounced in smokers and in those 50 years or older (OR, 1.82 [95% CI, 1.19-2.80] and OR, 2.08 [95% CI, 1.25-3.45], respectively), and in the estrogen and progesterone receptor-negative cases (OR, 1.70 [95% CI, 1.10-2.62] and OR, 1.57 [95% CI, 1.07-2.32], respectively). Furthermore, the C4G haplotype derived from the observed genotypes was also associated with a significantly increased risk of breast cancer (OR, 2.16; 95% CI, 1.07-4.36). CONCLUSIONS: The results suggest that eNOS polymorphisms (especially -786T>C) may play a role in the development of sporadic breast cancer.     

Genetic variation in IGF1, IGF-1R,IGFALS, and IGFBP3 in breast cancer survival among Chinese women: a report from the Shanghai Breast Cancer Study

Disruption of the balance of IGF (Insulin like growth factor) pathway constituents has been implicated in the etiology and progression of breast and other cancers. We hypothesized that genetic polymorphisms in IGF system members may be associated with breast cancer survival and evaluated this hypothesis in a cohort of 1,455 women diagnosed with breast cancer between 1996 and 1998 in Shanghai, China. Nineteen functional or potentially functional polymorphisms were evaluated in the IGF-1, IGF-1R, IGFALS, and IGFBP3 genes. Disease recurrence and vital status were obtained with a median follow-up time of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Overall, no significant association was noted between any of the 19 polymorphisms and survival. However, subgroup analyses demonstrated apparent interactions between menopausal status and survival for several (Single nucleotide polymorphism) SNPs in the IGF-1R and IGFBP3 genes. Carriers of the A/G or G/G genotypes (rs951715) in the IGF-1R gene had an increased risk of death among post-menopausal women (HR = 1.7, 95% CI = 1.1–2.7). Significant associations with breast cancer survival in pre-menopausal women were found for two IGFBP3 polymorphisms (rs2854744 and rs3110697), with an additional polymorphism (rs6413441) reaching borderline significance (P = 0.05). Hazard ratios for overall survival among pre-menopausal women were 1.5 (95% CI = 1.1–2.0) for the C/T–T/T genotypes (rs3110697), 1.4 (95% CI = 1.0–1.9) for the A/C–C/C genotypes (rs2854744), and 1.4 (95% CI = 1.0–1.9) for the N/A–A/A genotypes (rs6413441). Taken together, these data suggest that polymorphisms in the IGF-1R and IGFBP3 genes may be associated with altered survival among subgroups of breast cancer patients defined by menopausal status.     

Reproductive history and risk of three breast cancer subtypes defined by three biomarkers

Breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 expression are biologically distinct and thus, may have distinct etiologies. In particular, it is plausible that risk factors operating through hormonal mechanisms are differentially related to risk of such tumor subtypes. Using data from the Breast Cancer Surveillance Consortium, we explored associations between reproductive history and three breast cancer subtypes. Data on parity and age at first birth were collected from 743,623 women, 10,896 of whom were subsequently diagnosed with breast cancer. Cases were classified into three subtypes based on tumor maker expression: (1) ER positive (ER+, N = 8,203), (2) ER negative/PR negative/HER2 positive (ER−/PR−/HER2+, N = 288), or (3) ER-, PR-, and HER2-negative (triple-negative, N = 645). Associations with reproductive history, evaluated using Cox regression, differed significantly across tumor subtypes. Nulliparity was most strongly associated with risk of ER+ breast cancer [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.23–1.39]; late age at first birth was most strongly associated with risk of ER-/PR-/HER2+ disease (HR = 1.83, 95% CI: 1.31–2.56). Neither parity nor age at first birth was associated with triple-negative breast cancer. In contrast to ER+ and ER−/PR−/HER2+ subtypes, reproductive history does not appear to be a risk factor for triple-negative breast cancer.     

Fruits, vegetables, and micronutrient intake in relation to breast cancer survival

SummaryObjective To determine whether fruit, vegetable, and micronutrient intake 1 year prior to breast cancer diagnosis is associated with a reduction in the subsequent risk of all-cause or breast cancer-specific mortality.Methods Follow-up data from 1,235 invasive breast cancer cases age 25–98 years from the Long Island Breast Cancer Study Project were analyzed. At the 1996–1997 case-control interview, respondents completed a food frequency questionnaire, which assessed dietary intake of fruits, vegetables, and vitamin supplement use in the previous 12 months. All-cause mortality (n=186 deaths) and breast cancer-specific mortality status (n=125 deaths, 67.2%) were determined through December 31, 2002.Results Hazard ratios (HRs) for all-cause mortality were insignificantly reduced for intake of any fruits, fruit juices, and vegetables (HR=0.68, 95% CI: 0.42–1.09) and leafy vegetables (HR=0.72, 95% CI: 0.41–1.24) among post-menopausal women only. Both of these associations were more pronounced among those with ER+PR+ tumors (HR=0.54, 95% CI: 0.27–1.10, and HR=0.66, 95% CI: 0.33–1.31, respectively). Similar associations were observed for breast cancer-specific mortality.Conclusions In a cohort of women diagnosed with breast cancer, higher intake of fruits, vegetables, and micronutrients was associated with a non-significant survival advantage in post-menopausal women only.     

The Relationship Between eNOS Polymorphisms With Age,Smoking, Body Mass Index,and Clinicopathologic Parameters in Patients With Breast Cancer in Comparison With a Control Group

IntroductionNitric oxide (NO) is a free radical involved in carcinogenesis and is synthesized by endothelial nitric oxide synthase (eNOS). Genetic changes in the eNOS enzyme affect its activity, and the nitric oxide produced by inhibiting apoptosis can lead to cancer cell proliferation and metastasis. In this study, in addition to investigating the relationship between genetic changes in eNOS gene and the risk of breast cancer, the relationship between genotypes of polymorphisms, age, smoking, body mass index, and clinopathologic parameters was also investigated.Material and MethodsThree functional (Intron 4a/b, T786C, and G894T) and 1 tagging (G10T) polymorphisms of the eNOS gene were examined in 203 patients with breast cancer and 203 control subjects, and their genotypes were identified by restriction fragment length polymorphism polymerase chain reaction.ResultsThe T allele in G10T polymorphism increased the risk of breast cancer by 1.503-fold, whereas allele a in Intron 4, T allele in G894T, and C allele in T786C decreased its risk by 0.678-, 0.440-, and 0.525-fold, respectively. GG, GT (G10T), bb and ab (Intron4), GG and TT (G894T), and TT and CC (T786C) genotypes were significantly correlated with body mass index. There was a significant relationship between age and bb genotype, cigarette smoking and genotype ab (Intron 4), and estrogen receptor and GG (G10T) genotype. Tumor invasion factor was also significantly associated with TT (G10T), bb (Intron 4), and TT (T786C) genotypes.ConclusionGenetic changes in eNOS appear to have a dual role in breast cancer rate owing to changes in NO production and can be introduced as one of the genetic markers involved in breast cancer by evaluating the genotype of different populations.     

The association between two polymorphisms of eNOS and breast cancer risk: a meta-analysis

Breast cancer is one of the most common malignant tumors worldwide. Endothelial nitric oxide synthase (eNOS) plays a key role in breast cancer development. The associations between the two eNOS polymorphisms (E298D rs1799983, −786T>C rs2070744) and breast cancer risk are inconclusive. A meta-analysis was performed in this study. By searching Medline, ISI Web of Knowledge, ScienceDirect, EBSCO, CNKI, and SinoMed database, six case–control studies were collected for the eNOS E298D polymorphism (3,038 cases and 2,508 controls) and three case–control studies were eligible for the eNOS −786T>C polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the two eNOS polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, significantly decreased risk was observed for E298D (for EE vs. DD: OR = 0.74, 95% CI = 0.59–0.94; for ED vs. DD: OR = 0.78, 95% CI = 0.61–0.98; for dominant model: OR = 0.77, 95% CI = 0.61–0.96) and −786T > C (for TT vs. CC: OR = 0.60, 95% CI = 0.42–0.86; for dominant model: OR = 0.66, 95% CI = 0.47–0.94). In the subgroup analysis by ethnicity, significant decreased risks were found for E298D (for EE vs. DD: OR = 0.75, 95% CI = 0.56–0.99) and −786T>C (for TT vs. CC: OR = 0.53, 95% CI = 0.35–0.81; for dominant model: OR = 0.61, 95% CI = 0.41–0.91; for recessive model: OR = 0.70, 95% CI = 0.55–0.91) among Caucasians; significant decreased risks were observed for E298D (for ED vs. DD: OR = 0.12, 95% CI = 0.02–0.96; for dominant model: OR = 0.13, 95% CI = 0.02–1.00) among Asians. In conclusion, this meta-analysis suggests that both eNOS E298D and −786T>C polymorphisms are associated with reduced breast cancer risk.     

Association of single nucleotide polymorphisms (SNPs) in <Emphasis Type="Italic">TNF-LTA</Emphasis> locus with breast cancer risk in Indian population

Purpose Cytokine milieu of tumor microenvironment affects tumorigenesis in breast cancer. The aim of the present study was to investigate the potential association of functional single nucleotide polymorphisms (SNPs) in TNF-LTA locus with breast cancer. Methods The study included 127 individuals comprising 40 breast cancer cases (35 sporadic & 5 familial) and 87 individuals of high risk group (with family history of breast cancer) along with 150 healthy controls. PCR-RFLP was employed to analyze TNFA promoter polymorphisms at −238 G/A, −308 G/A, −857 C/T, −863 C/A and −1031 T/C along with +252 A/G SNP in LTA. The results were further confirmed by direct sequencing. Results Significant association was established for TNFA −308 G/A and LTA +252 A/G polymorphisms with breast cancer versus controls (P < 0.0001; OR, 9.53; 95% CI, 4.11–22.13; P _c < 0.001) and high risk group versus controls (P < 0.0001; OR, 8.27; 95% CI, 4.28–16.0; P _c < 0.001) respectively. GGACCT haplotype was found to be positively associated with breast cancer (P < 0.0001; OR, 12.17; 95% CI = 5.12–28.92; P _c < 0.001) and high risk group (P, 0.03; OR, 2.95; 95% CI, 1.20–7.26; P _c, 0.005) in relation to controls. While GGGCCT haplotype was significantly related with high risk group in comparison to cancer (P, 0.0002; OR, 5.71; 95% CI, 2.18–14.99; P _c, 0.003) and controls (P, 0.0002; OR, 2.48; 95% CI, 1.55–3.96; P _c, 0.003). Conclusion TNF-LTA locus could serve as an important biomarker for breast cancer predisposition in Indian population.     

Pattern of metastatic spread in triple-negative breast cancer

Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.     

Genetic variations in transcription factor 7-like 2 (<Emphasis Type="Italic">TCF7L2)</Emphasis> gene: association of <Emphasis Type="Italic">TCF7L2</Emphasis> rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters

The purpose of the present study was to evaluate the association between TCF7L2 rs12255372(G/T) or rs7903146(C/T) polymorphism and breast cancer risk, and clinico-pathologic characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method in a hospital-based Malaysian population. The allele (P = 0.033) frequency of rs7903146 (T) polymorphism was significantly higher in the cancer patients than normal individuals. No significant association was demonstrated between CT (OR^adj = 1.386; 95% CI, 0.985–1.949) or TT (OR^adj = 1.579; 95% CI, 0.869–2.870) genotype and breast cancer risk. However, women who were carriers of T allele (OR^adj = 1.316; 95% CI, 1.022–1.695) or T allele genotype (OR^adj = 1.419; 95% CI, 1.027–1.960) showed significant increased risk of breast cancer. Women who were GT heterozygotes (OR^adj = 1.329; 95% CI, 0.948–1.862) or TT homozygotes (OR^adj = 1.574; 95% CI, 0.829–2.987), and carriers of T allele genotype (OR^adj = 1.365; 95% CI, 0.989–1.883) or T allele (OR^adj = 1.284; 95% CI, 0.995–1.657) were not associated with breast cancer risk. The rs7903146(T) allele genotype was significantly associated with nodal involvement (P = 0.003) but rs12255372 (T) allele genotype was not associated with the clinico-pathologic characteristics. In conclusion, our findings suggest that rs7903146 (T) variant may elevate the risk of breast cancer, thus could be a potential candidate for breast cancer susceptibility. The variant may also increase the metastatic potential of the tumor.     

The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer

We investigated the association between the risk of locoregional recurrence (LRR) and biological subtypes defined by hormonal receptors (HR) and HER-2 status in women with invasive breast cancer (BC). A total of 618 newly diagnosed BC patients were identified from a cancer registry within a single institution with standardized methods of tumor assessment for estrogen receptor (ER), progesterone receptor (PR), and HER-2. Patients were stratified based on surgical treatment, breast-conserving therapy (BCT) versus modified radical mastectomy (MRM), as well as biological subtypes: HR+/HER-2− (ER-positive or PR-positive, HER-2-negative), HR+/HER-2+ (ER-positive or PR-positive, HER-2-positive), HR−/HER-2+ (ER-negative and PR-negative, HER-2-positive) and TN (ER-negative, PR-negative and HER-2-negative). The association between clinicopathological factors, biological subtype and LRR was evaluated with univariate and multivariate Cox analysis. With a median follow-up of 4.8 years, the rate of LRR was 7.5%. On multivariate analysis, TN, tumor size ≥2 cm and lymph node (LN) positivity were associated with increased risk of LRR (P = 0.023, P = 0.048, and P = 0.0034, respectively). In BCT group, HR−/HER-2+ and LN positivity were associated with increased risk of LRR (HR 11.13; 95% CI 2.78–44.53; P = 0.0007 and HR 5.40; 95% CI 1.67–17.43; P = 0.0048, respectively). In MRM group, TN subtype and LN positivity were associated with increased risk of LRR (HR 4.72; 95% CI 1.53–14.52; P = 0.0069 and HR 3.23; 95% CI 1.44–7.29; P = 0.0047, respectively). Compared to HR+/HER-2−, HR−/HER-2+ treated by BCT and TN treated by MRM showed a significant decrease of 5-year LRR free survival (P = 0.0002 and P = 0.002, respectively). Tumor profiling using ER, PR, and HER-2 biomarkers is a promising tool to identify patients at high risk of LRR based on surgical treatment. Our findings suggest a different follow-up and locoregional treatment for patients with HR−/HER-2+ and TN subtypes.     

Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Women’s Healthy Eating and Living Study

The protective effect of vegetables on the risk of breast cancer recurrence is uncertain. We sought to evaluate the association between breast cancer recurrence and vegetable intake including analyses stratified on tamoxifen use. Experimental evidence of anti-carcinogenic activity of phytochemicals in cruciferous vegetables in combination with tamoxifen led to specific evaluation of this class of vegetables as well. To assess the association between vegetable intake and breast cancer recurrence, vegetable intake from repeat 24-h dietary recalls were examined as a secondary analysis of 3,080 breast cancer survivors enrolled in the Women’s Healthy Eating and Living (WHEL) Study. At the time of enrollment women were, on average, 23.5 months post-diagnosis. The hazard of recurrence, controlling for relevant and significant clinical and demographic variables, with vegetable intake was assessed overall and separately for women taking tamoxifen. WHEL participants reported mean baseline intakes ( [`(\text x)]{\bar{\text {x}}}, SE) of 3.1 ± 0.05 and 0.5 ± 0.02 servings/day of total and cruciferous vegetables, respectively. Baseline vegetable intake in the highest as compared to lowest tertiles was associated with an overall lower adjusted hazard ratios (HR) for recurrence of 0.69, 95% CI 0.55–0.87. Among women taking tamoxifen, the HRs were 0.56, 95% CI 0.41–0.77 for total vegetables and 0.65, 95% CI 0.47–0.89 for cruciferous vegetable intake. The hazard in women using tamoxifen who reported cruciferous vegetable intake above the median and who were within the highest tertile of total vegetable intake was HR 0.48; 95% CI 0.32–0.70. This secondary analysis in over 3,000 breast cancer survivors suggests that baseline vegetable intake may be associated with a reduction in the risk of breast cancer recurrent or new events particularly for those using tamoxifen. Such associations should be explored further as the possibility that vegetable intake is simply a surrogate for other health-promoting behaviors cannot be ruled out.     

Pre-diagnosis body mass index,post-diagnosis weight change,and prognosis among women with early stage breast cancer

Objective  We examined the association between body mass index (BMI) around the time of diagnosis, weight change post-diagnosis, and breast cancer prognosis in a prospective cohort study of 1,692 breast cancer survivors. Methods  Pre-diagnosis weight, weight at study entry, and height was obtained from mailed questionnaires and then weight change and BMI were calculated. After approximately seven years of follow-up, 207 recurrences, 99 deaths due to breast cancer, and 162 deaths due to any cause were reported. Delayed entry Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), controlling for treatment and known prognostic factors. Results  Being obese one year before diagnosis was associated with an increased risk of death from any cause (HR = 1.6; 95% CI: 1.1–2.3) and a suggestion of increased risk of death from breast cancer (HR = 1.6; 95% CI: 0.9–2.7). However, weight gain up to four years after a breast cancer diagnosis was not associated with an increased risk of recurrence or death from any cause nor did moderate weight loss (5–10%) decrease risk of these outcomes. There was some evidence that women who had larger weight losses (≥10%) between pre-diagnosis and study entry had an increased risk of recurrence (HR = 1.7; 95% CI 1.0–2.6) and death due to any cause (HR = 2.1; 95% CI 1.3–3.4) compared to being weight stable. This elevated risk was more pronounced among women who were obese before diagnosis (BMI ≥ 30 kg/m²) or who had ER− or PR− tumors. Conclusion  We found that being obese before breast cancer diagnosis was associated with increased risk of recurrence and poorer survival, corroborating results from previous studies. However, weight gain after diagnosis did not confer additional risk. Body weight pre-diagnosis appears to be the strongest predictor of an adverse breast cancer prognosis.     

Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression

The importance of matrix metalloproteinases and their inhibitors in tumor progression is well documented. We wanted to investigate if single nucleotide polymorphisms (SNPs) in the promoter regions of these genes are associated with susceptibility to or progression of breast cancer. In this, so far largest case–control study, we genotyped eight SNPs in the MMP1, MMP2, MMP3, MMP9, MMP13, RECK and TIMP3 genes in a well-characterized breast cancer series of 959 cases and 952 controls from Sweden. Even though we did not correct for multiple comparisons, only a few associations were noted. We observed a moderately increased risk for the TT homozygotes of the MMP9−1562 C/T SNP (OR 1.88, 95% CI 0.97–3.63) and for the C allele carriers of the TIMP3−1296 T/C SNP (OR 1.25, 95% CI 1.05–1.50). In the survival analysis, only the TC heterozygotes of the RECK−420 T/C SNP showed a better survival compared to the TT homozygotes (P = 0.02 in all cases and P = 0.03 in lymph node negative cases). None of the other SNPs conferred an increased breast cancer risk, nor did they correlate with survival. A combination of the −585 TT homozygosity in the RECK gene and the −1296 TT homozygosity in the TIMP3 gene correlated with estrogen and progesterone receptor status (OR 1.81, 95% CI 1.03–3.21 and OR 2.10, 95% CI 1.18–3.86, respectively), and a combination of the −1306 TT homozygosity in the MMP2 gene and the −1562 CC homozygosity in the MMP9 gene with progesterone receptor status (OR 2.34, 95% CI 1.08–5.08). Although our study suggests some correlations between the studied SNPs and the progression of breast cancer, the rarity of the risk genotypes limits their usefulness in the clinic. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Differential Roles of Angiotensinogen and Angiotensin Receptor type 1 Polymorphisms in Breast Cancer Risk

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1–1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1–2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.