Breast Cancer In Caucasian Women Research Articles

CmP Signaling Network Leads to Identification of Prognostic Biomarkers for Triple-Negative Breast Cancer in Caucasian Women.

Objective: Triple-negative breast cancer (TNBC) constitutes ∼15% of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target ER, PR, and HER2 receptors are ineffective. Progesterone (PRG) can induce its effects through either classic, nonclassic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or nonclassic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CCM signaling complex (CSC) can couple both nPRs and mPRs into a CmPn signaling network, which plays an important role during nPR(+) breast cancer tumorigenesis. We recently defined the novel CmP signaling network in African American women (AAW)-derived TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Methods: Under mPR-specific steroid actions, we measured alterations to key tumorigenic pathways in Caucasian American women (CAW)- derived TNBC cells, with RNAseq/proteomic and systems biology approaches. Exemption from ethics approval from IRB: This study only utilized cultured NBC cell lines with publicly available TNBC clinical data sets. Results: Our results demonstrated that TNBCs in CAW share similar altered signaling pathways, as TNBCs in AAW, under mPR-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have deconvoluted the CmP signalosome, using systems biology approaches and CAW-TNBC clinical data, to identify 21 new CAW-TNBC-specific prognostic biomarkers that reinforce the definitive role of CSC and mPR signaling during CAW-TNBC tumorigenesis. Conclusion: This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.

Whole Genome Transcriptome Analysis of the Association between Obesity and Triple-Negative Breast Cancer in Caucasian Women.

Background: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this exploratory study was to investigate the association between obesity and TNBC in premenopausal and postmenopausal Caucasian women using transcription profiling. Methods: We compared gene expression levels of tumor samples drawn from normal weight, overweight, and obese pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. Results: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight, and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways associating obesity with TNBC. The discovered pathways included the unfolded protein response, endoplasmic reticulum stress, B cell receptor, and autophagy signaling pathways in obese premenopausal women; and the integrin, axonal guidance, ERK/MAPK (extracellular-signal-regulated kinase/mitogen activated protein kinase) and glutathione biosynthesis signaling pathways in obese postmenopausal women. Conclusions: The results suggest that both overweight and obese status are associated with TNBC, highlighting the need for conformation of these results in independent studies.

The 811 C/T polymorphism in the 3' untranslated region of the selenoprotein 15-kDa (Sep15) gene and breast cancer in Caucasian women.

The 15-kDa selenoprotein (Sep15) is a selenocysteine-containing oxidoreductase in the endoplasmic reticulum that participates in disulfide-bond formation and protein folding control. The 3'-untranslated region (3'-UTR) contains two exclusively linked, polymorphic sites at positions 811 (C/T) and 1125 (G/A), which result in two functional haplotypes: 811C/1125G or 811T/1125A. The 811T/1125A variant occurs significantly more often in African-Americans as compared to Caucasians and has been linked to increased breast cancer risk in black women. We studied the 811C/T (rs5845) Sep15 gene polymorphism in 182 Caucasian women-83 breast cancer cases and 99 healthy controls-by pyrosequencing and polymerase chain reaction. Associations between allelic variants and clinico-pathological variables (e.g., age, stage of disease, tumor type, grading, and receptor status) were investigated. The genotype distribution in breast cancer patients (CC 63.9%, CT 33.7%, TT 2.4%) and controls (69.7%, CT 28.3%, TT 2%) showed no significant difference (OR 0.77, 95% CI 0.41-1.42, p = 0.4). The overall low prevalence of the T allele was in accordance with that reported for Caucasians in previous studies. There was no significant association between 811C/T Sep15 polymorphism and any of clinico-pathological parameters. In conclusion, we are the first to report on 811C/T SEP 15 polymorphism in white breast cancer patients. Genotype variation within the 3'-UTR of the SEP 15 gene showed no association with breast cancer risk or clinico-pathological parameters in Caucasian women.

CAG repeat polymorphisms in the androgen receptor and breast cancer risk in women: a meta-analysis of 17 studies.

The association between polymorphic CAG repeats in the androgen receptor gene in women and breast cancer susceptibility has been studied extensively. However, the conclusions regarding this relationship remain conflicting. The purpose of this meta-analysis was to identify whether androgen receptor CAG repeat lengths were related to breast cancer susceptibility. The MEDLINE, PubMed, and EMBASE databases were searched through to December 2014 to identify eligible studies. Data and study quality were rigorously assessed by two investigators according to the Newcastle-Ottawa Quality Assessment Scale. The publication bias was assessed by the Begg’s test. Seventeen eligible studies were included in this meta-analysis. The overall analysis suggested no association between CAG polymorphisms and breast cancer risk (odds ratio [OR] 1.031, 95% confidence interval [CI] 0.855–1.245). However, in the subgroup analysis, we observed that long CAG repeats significantly increased the risk of breast cancer in the Caucasian population (OR 1.447, 95% CI 1.089–1.992). Additionally, the risk was significantly increased in Caucasian women carrying two alleles with CAG repeats ≥22 units compared with those with two shorter alleles (OR 1.315, 95% CI 1.014–1.707). These findings suggest that long CAG repeats increase the risk of breast cancer in Caucasian women. However, larger scale case-control studies are needed to validate our results.

Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer

BackgroundAlthough diagnosed less often, breast cancer in African American women (AAW) displays different characteristics compared to breast cancer in Caucasian women (CW), including earlier onset, less favorable clinical outcome, and an aggressive tumor phenotype. These disparities may be attributed to differences in socioeconomic factors such as access to health care, lifestyle, including increased frequency of obesity in AAW, and tumor biology, especially the higher frequency of triple negative breast cancer (TNBC) in young AAW. Improved understanding of the etiology and molecular characteristics of TNBC in AAW is critical to determining whether and how TNBC contributes to survival disparities in AAW.MethodsDemographic, pathological and survival data from AAW (n = 62) and CW (n = 98) with TNBC were analyzed using chi-square analysis, Student’s t-tests, and log-rank tests. Frozen tumor specimens were available from 57 of the TNBC patients (n = 23 AAW; n = 34 CW); RNA was isolated after laser microdissection of tumor cells and was hybridized to HG U133A 2.0 microarrays. Data were analyzed using ANOVA with FDR <0.05, >2-fold difference defining significance.ResultsThe frequency of TNBC compared to all BC was significantly higher in AAW (28%) compared to CW (12%), however, significant survival and pathological differences were not detected between populations. Gene expression analysis revealed the tumors were more similar than different at the molecular level, with only CRYBB2P1, a pseudogene, differentially expressed between populations. Among demographic characteristics, AAW consumed significantly lower amounts of caffeine and alcohol, were less likely to breastfeed and more likely to be obese.ConclusionsThese data suggest that TNBC in AAW is not a unique disease compared to TNBC in CW. Rather, higher frequency of TNBC in AAW may, in part, be attributable to the effects of lifestyle choices. Because these risk factors are modifiable, they provide new opportunities for the development of risk reduction strategies that may decrease mortality by preventing the development of TNBC in AAW.

Does alcohol increase breast cancer risk in African-American women? Findings from a case–control study

Background:Alcohol is an important risk factor for breast cancer in Caucasian women, but the evidence in African-American (AA) women is limited and results are inconclusive.Methods:Associations between recent and lifetime drinking and breast cancer risk were evaluated in a large sample of AA women from a case–control study in New York and New Jersey. Multivariable logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs).Results:There was no association between recent drinking and breast cancer risk, even when stratified by menopausal status or by hormone receptor status. A borderline decreased risk with increased lifetime consumption was found (OR=0.77; 95% CI: 0.58–1.03), which was stronger among women who drank when under 20 years of age (OR=0.65; 95% CI: 0.47–0.89), regardless of menopausal or hormone receptor status.Conclusion:Breast cancer risk associated with recent alcohol consumption was not apparent in AA women, while early age drinking seemed to decrease risk. This is the first investigation on recent and lifetime drinking in subgroups and drinking during different age periods in AA women. If findings are replicated, racial differences in biological pathways involving alcohol and its metabolites should be explored.

Transforming Growth Factor β Signaling Pathway Associated Gene Polymorphisms May Explain Lower Breast Cancer Risk in Western Indian Women

Transforming growth factor β1 (TGFB1) T29C and TGF β receptor type 1 (TGFBR1) 6A/9A polymorphisms have been implicated in the modulation of risk for breast cancer in Caucasian women. We analyzed these polymorphisms and combinations of their genotypes, in pre menopausal breast cancer patients (N = 182) and healthy women (N = 236) from western India as well as in breast cancer patients and healthy women from the Parsi community (N = 48 & 171, respectively). Western Indian women were characterized by a higher frequency of TGFB1*C allele of the TGF β T29C polymorphism (0.48 vs 0.44) and a significantly lower frequency of TGFBR1*6A allele of the TGFBR1 6A/9A polymorphism (0.02 vs 0.068, p<0.01) as compared to healthy Parsi women. A strong protective effect of TGFB1*29C allele was seen in younger western Indian women (<40 yrs; OR = 0.45, 95% CI 0.25–0.81). Compared to healthy women, the strikingly higher frequencies of low or intermediate TGF β signalers in patients suggested a strong influence of the combination of these genotypes on the risk for breast cancer in Parsi women (for intermediate signalers, OR = 4.47 95%CI 1.01–19.69). The frequency of low signalers in Parsi healthy women, while comparable to that reported in Europeans and Americans, was three times higher than that in healthy women from western India (10.6% vs 3.3%, p<0.01). These observations, in conjunction with the low incidence rate of breast cancer in Indian women compared to White women, raise a possibility that the higher frequency of TGFB1*29C allele and lower frequency of TGFBR1*6A allele may represent important genetic determinants that together contribute to a lower risk of breast cancer in western Indian women.

A genetic variant in a PP2A regulatory subunit encoded by the PPP2R2B gene associates with altered breast cancer risk and recurrence

A recent candidate gene association study identified a single nucleotide polymorphism (SNP) in the PPP2R2B gene (rs319217, A/G) that manifests allelic differences in the cellular responses to treatment with chemotherapeutic agents (Vazquez et al., Nat Rev Drug Discov 2008;7:979-87). This gene encodes a regulatory subunit of protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases implicated in the negative control of cell growth and division. Given the tumor suppressor activities of PP2A, here we evaluate whether this genetic variant associates with the age of diagnosis and recurrence of breast cancer in women. To investigate the linkage disequilibrium in the vicinity of this SNP, PPP2R2B haplotypes were analyzed using HapMap data for 90 Caucasians. It is found that the A variant of rs319217 tags a haplotype that appears tobe under positive selection in the Caucasian population, implying that this SNP is functional. Subsequently, associations with cellular responses were investigated using data reported by the NCI anticancer drug screen and associations with breast cancer clinical variables were analyzed in a cohort of 819 Caucasian women. The A allele associates with a better response of tumor derived cell lines, lower risk of breast cancer recurrence, later time to recurrence, and later age of diagnosis of breast cancer in Caucasian women. Taken together these results indicate that the A variant of the rs319217 SNP is a marker of better prognosis in breast cancer.

Polymorphisms of the endothelial nitric oxide synthase gene in breast cancer

Nitric oxide (NO) is known to be critically involved in breast carcinogenesis. Genetic polymorphisms of the gene encoding for endothelial nitric oxide synthase (Nos3), the enzyme catalyzing the production of the NO, are known to predispose to malignant disease. Whether these polymorphisms also influence breast cancer risk is unknown. In the present case-control study, we ascertained 2 polymorphisms of the Nos3 gene cluster (Nos3 exon 7 Glu298Asp and a 27-base pair repeat in intron 4 of Nos3) in 269 Caucasian patients with breast cancer and 244 healthy controls using pyrosequencing and PCR, respectively. Presence of the exon 7 Nos3 polymorphism predisposed women to breast cancer (p=0.03, Odds ratio [95% Confidence Intervals]=1.9 [1.1-3.6]), but was not associated with any clinico-pathological parameters. No significant associations were ascertained with respect to the intron 4 Nos3 polymorphism. In our series, presence of the mutant exon7 Nos3 polymorphism was associated with an increased risk for breast cancer in Caucasian women.

Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women

Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

Polymorphisms XRCC1-R399Q and XRCC3-T241M and the Risk of Breast Cancer at the Ontario Site of the Breast Cancer Family Registry

Abstract This study investigates the role of two nonsynonymous single nucleotide polymorphisms in DNA repair genes, X-ray repair cross-complementing group 1 (XRCC1)-R399Q and X-ray repair cross-complementing group 3 (XRCC3)-T241M, in breast cancer. Incident cases of invasive breast cancer in Caucasian women [n = 402, mean age = 45.7 (SD = 6.2) years] and female Caucasian controls [n = 402, mean age = 45.2 (6.5) years] frequency matched on 5-year age intervals were identified from the Ontario Familial Breast Cancer Registry. No evidence for a main effect of the XRCC1-R399Q genotype on breast cancer risk was observed. Estimates of risk for a family history (FH) of breast cancer compared with no FH differed by XRCC1-R399Q genotype (P value for interaction = 0.001). Homozygote XRCC1-399 R/R individuals and FH+ were at a 2.92-fold [95% confidence interval (95% CI) = 1.47–5.79] increased risk of disease compared with FH− individuals; the estimate of risk increased for R/Q heterozygotes with FH+ [odds ratio (OR) = 3.85, 95% CI = 1.94–7.65] but not for Q/Q homozygotes with FH+ (OR = 0.54, 95% CI = 0.20–1.47) compared with homozygous R/R and FH− individuals. A marginal positive association for XRCC3-241 M/M compared with T/T genotype was found (OR = 1.44, 95% CI = 0.94–2.19), but the heterozygous T/M was not associated with an increase in risk (OR = 0.96, 95% CI = 0.71–1.32). There was also some evidence for a combined effect of body mass index and XRCC3-T241M on estimates of risk. Our results suggest that these polymorphisms may influence breast cancer risk by modifying the effect of risk factors such as FH. There is a need for further study into the role of these polymorphisms as effect modifiers.

Genetic variants of GPX1 and SOD2 and breast cancer risk at the Ontario site of the Breast Cancer Family Registry.

There are several genes that code for enzymes, including various forms of superoxide dismutase and glutathione peroxidase, that protect the cell against oxidative damage that, in turn, can lead to carcinogenesis. There are a few common genetic polymorphisms in these genes that lead to altered proteins. Three that have been identified are SOD2 Val-9Ala, GPX1 Pro198Leu, and the GPX1 GCG repeat (three alleles with four, five, or six repeats). The SOD2 variant has been associated with increased breast cancer risk in two studies. The GPX1 variants have not been studied with respect to breast cancer, but Pro198Leu has been associated with lung cancer. We conducted a case-control study of these three polymorphisms in incident, invasive breast cancer in Caucasian women under 55. There were 399 cases and 372 controls genotyped, of whom 488 were premenopausal, 208 postmenopausal, and 75 of unknown menopausal status. We were unable to replicate the previously observed association with SOD2 Val-9Ala and also found no association between breast cancer and GPX1 Pro198Leu. However, the allele of GPX1 containing four GCG repeats was significantly associated with breast cancer risk in premenopausal women (odds ratio, 1.55; 95% confidence interval, 1.04-2.30 for carriers versus noncarriers). There is a significant trend of increasing risk with increasing number of alleles with four GCG repeats (P = 0.03). This variant has not previously been reported to be associated with breast cancer.

Plasma sex steroid hormones and breast cancer risk in Chinese women.

Estrogens regulate the growth and differentiation of mammary cells and play an important role in the development of breast cancer. High circulating levels of estrogens are associated with increased risk of breast cancer in Caucasian women. Because Asian women have low estrogens in the circulation compared with their Caucasian counterparts, the effect of estrogens on breast cancer risk in populations with low circulating estrogens remains to be elucidated. We conducted a population-based case-control study in China to evaluate the association of sex steroid hormones with breast cancer risk in Chinese women. Our study included 300 incident cases with primary breast cancer and 300 age- and menopausal status-matched healthy controls randomly selected from the general population in Shanghai. Fasting blood samples were collected from cases prior to any treatment and from their matched controls. Commercial immunoassays were used to measure plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, progesterone, dehydroepiandrosteindian sulfate (DHEA-S) and steroid hormone-binding globulin (SHBG). Conditional logistic regression analysis was performed to examine the association between steroid hormones and breast cancer risk. The results showed that breast cancer risk was elevated with increasing levels of estrone and testosterone (p for trend < 0.05) but not with DHEA-S, estradiol, estrone sulfate, progesterone or SHBG. The estimated relative risks between upper and lower tertiles were 2.07 (95% confidence interval [CI] 0.97-4.41) for estrone in postmenopausal women, 2.01 (95% CI 0.96-4.21) for testosterone in premenopausal women, and 2.40 (95% CI 1.11-5.21) for testosterone in postmenopausal women, after adjusting for age at first live birth, waist-to-hip ratio, total calorie intake, a history of fibroadenoma, a family history of breast cancer and SHBG. These results, in general, are consistent with the findings in Caucasian women and indicate that high sex steroid hormones in the circulation, both androgen and estrogen, are associated with increased risk of breast cancer even in populations with relatively low sex hormones.