Search

Simple Summary: Breast cancer is a major global issue, ranking as the second most common cancer among women. Various factors such as genetics, epigenetics, obesity, sedentary lifestyle, tobacco use, and vitamin D deficiency have been implicated in its prevalence. Toll-like receptor 9 (TLR9) has emerged as a potential key factor, yet its role in breast cancer has not been fully explored. TLR9, a component of the innate immune system, recognizes unmethylated CpG motifs, thus initiating immune responses. Understanding TLR9 expression and function in breast tissue, particularly in distinguishing between normal and cancerous tissue, is crucial. This review examines the existing literature on TLR9 expression in both normal and cancerous breast tissue, aiming to identify knowledge gaps and enhance our understanding of TLR9's role in breast cancer. The ultimate goal is to enhance our understanding of TLR9's involvement in breast cancer pathogenesis, which could potentially lead to novel diagnostic markers or therapeutic targets, thereby improving patient outcomes and advancing breast cancer treatment strategies. Breast cancer is a significant global issue, ranking as the second most common cancer among women worldwide and a leading cause of cancer-related deaths. Although the exact causes of this increase remain unclear, factors such as genetics, epigenetics, obesity, sedentary lifestyle, tobacco use, and vitamin D deficiency have been implicated. The Toll-like receptor 9 (TLR9) is recognized for its role in inflammation and innate immunity; however, its specific involvement in breast cancer pathogenesis requires further investigation. This study aims to systematically review the existing literature on TLR9 expression in normal and cancerous breast tissue, providing current knowledge and identifying gaps. Relevant articles in English were from PubMed, Scopus, and Google Scholar, with the inclusion criteria focusing on studies evaluating TLR9 mRNA and protein expression. The review found that TLR9 mRNA and protein exhibit variable expressions in both normal and cancerous breast tissue, highlighting the need for further research to clarify TLR9's role in breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: We have previously shown that the glucocorticoid receptor (GCR) protein was reduced in invasive breast carcinoma compared to normal breast tissue. Here, we evaluated the level of serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2) levels in the corresponding primary breast cancer tissue. SGK1 was higher and Bcl-2 was lower in breast cancer tissue compared to normal breast tissue. Similar to previous reports, we found that the expression of the Bcl-2 protein was associated with longer survival. We observed a correlation between the expression of the GCR and the Bcl-2 protein. The expression of the Bcl-2 protein was higher among cases who self-reported their race and ethnicity as non-Hispanic Black people. It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression. [ABSTRACT FROM AUTHOR]

Purpose: Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings. Methods: We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software. Results: BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001). Conclusion: Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer. [ABSTRACT FROM AUTHOR]

Zinc is an essential dietary element that has been implicated in the pathogenesis of prostate cancer, a cancer that disproportionately affects men of African descent. Studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. Furthermore, very little is known about the relationship between zinc intake and prostate cancer among African Americans. We examined the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study of African Americans. We then compared our results with previous studies by performing a meta-analysis to summarize the evidence regarding the association between zinc and prostate cancer. Newly diagnosed African American men with histologically confirmed prostate cancer (n = 127) and controls (n = 81) were recruited from an urban academic urology clinic in Washington, DC. Controls had higher zinc intake, with a mean of 14 mg/day versus 11 mg/day for cases. We observed a non-significant, non-linear increase in prostate cancer when comparing tertiles of zinc intake (OR <6.5 vs 6.5–12.5mg/day 1.8, 95% CI: 0.6,5.6; OR <6.5 vs >12.5mg/day 1.3, 95% CI: 0.2,6.5). The pooled estimate from 17 studies (including 3 cohorts, 2 nested case-control, 11 case-control studies, and 1 randomized clinical trial, with a total of 111,199 participants and 11,689 cases of prostate cancer) was 1.07hi vs lo 95% CI: 0.98–1.16. Using a dose-response meta-analysis, we observed a non-linear trend in the relationship between zinc intake and prostate cancer (p for nonlinearity = 0.0022). This is the first study to examine the relationship between zinc intake in black men and risk of prostate cancer and systematically evaluate available epidemiologic evidence about the magnitude of the relationship between zinc intake and prostate cancer. Despite of the lower intake of zinc by prostate cancer patients, our meta-analysis indicated that there is no evidence for an association between zinc intake and prostate cancer. [ABSTRACT FROM AUTHOR]

Background: We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA). Results: DNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African- American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/ PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity. Conclusions: Higher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples. [ABSTRACT FROM AUTHOR]

Background: Breast cancer formation is associated with frequent changes in DNA methylation but the extent of very early alterations in DNA methylation and the biological significance of cancer-associated epigenetic changes need further elucidation.Methods: Pyrosequencing was done on bisulfite-treated DNA from formalin-fixed, paraffin-embedded sections containing invasive tumor and paired samples of histologically normal tissue adjacent to the cancers as well as control reduction mammoplasty samples from unaffected women. The DNA regions studied were promoters (BRCA1, CD44, ESR1, GSTM2, GSTP1, MAGEA1, MSI1, NFE2L3, RASSF1A, RUNX3, SIX3 and TFF1), far-upstream regions (EN1, PAX3, PITX2, and SGK1), introns (APC, EGFR, LHX2, RFX1 and SOX9) and the LINE-1 and satellite 2 DNA repeats. These choices were based upon previous literature or publicly available DNA methylome profiles. The percent methylation was averaged across neighboring CpG sites.Results: Most of the assayed gene regions displayed hypermethylation in cancer vs. adjacent tissue but the TFF1 and MAGEA1 regions were significantly hypomethylated (p ≤0.001). Importantly, six of the 16 regions examined in a large collection of patients (105 - 129) and in 15-18 reduction mammoplasty samples were already aberrantly methylated in adjacent, histologically normal tissue vs. non-cancerous mammoplasty samples (p ≤0.01). In addition, examination of transcriptome and DNA methylation databases indicated that methylation at three non-promoter regions (far-upstream EN1 and PITX2 and intronic LHX2) was associated with higher gene expression, unlike the inverse associations between cancer DNA hypermethylation and cancer-altered gene expression usually reported. These three non-promoter regions also exhibited normal tissue-specific hypermethylation positively associated with differentiation-related gene expression (in muscle progenitor cells vs. many other types of normal cells). The importance of considering the exact DNA region analyzed and the gene structure was further illustrated by bioinformatic analysis of an alternative promoter/intron gene region for APC.Conclusions: We confirmed the frequent DNA methylation changes in invasive breast cancer at a variety of genome locations and found evidence for an extensive field effect in breast cancer. In addition, we illustrate the power of combining publicly available whole-genome databases with a candidate gene approach to study cancer epigenetics. [ABSTRACT FROM AUTHOR]

Introduction: Non-Hispanic (nH) Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors. Methods: We used a panel of 100 ancestry informative markers (AIMs) to estimate individual genetic ancestry in 656 women from the “Breast Cancer Care in Chicago” study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities. Results: As expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54–0.92) among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56–0.95) among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02) and higher grade (p = 0.012) in nH Whites and later stage (p = 0.03) in nH Blacks. Conclusion: Non-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups. [ABSTRACT FROM AUTHOR]

Functional polymorphisms in endogenous antioxidant defense genes including manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX-1) have been linked with risk of cancer at multiple sites. Although it is presumed that these germline variants impact disease risk by altering the host's ability to detoxify mutagenic reactive oxygen species, very few studies have directly examined this hypothesis. Concentrations of 8-isoprostane F2α (8-iso-PGF2α) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxoxdG)-sensitive indicators of lipid peroxidation and DNA oxidation, respectively-were measured in 24-h urine samples obtained from 93 healthy, premenopausal women participating in a dietary intervention trial. In addition, DNA was extracted from blood for genotyping of MnSOD Val16Ala, CAT-262 C > T, and GPX1 Pro198Leu genotypes by Taqman assay. Although geometric mean concentrations of 8-iso-PGF2 and 8-oxoxdG varied across several study characteristics including race, education level, body mass index, and serum antioxidant levels, there was little evidence that these biomarkers differed across any of the examined genotypes. In summary, functional polymorphisms in endogenous antioxidant defense genes do not appear to be strongly associated with systemic oxidative stress levels in young, healthy women. [ABSTRACT FROM AUTHOR]

Objective: A recent Monographs Working Group of the International Agency for Research on Cancer (IARC) concluded that there is sufficient evidence for a causal association between exposure to asbestos and ovarian cancer. We performed a meta-analysis to quantitatively evaluate this association. Data sources: Searches of PubMed and unpublished data yielded a total of 18 cohort studies of women occupationally exposed to asbestos. Data extraction: Two authors independently abstracted data; any disagreement was resolved by consulting a third reviewer. Data synthesis: All but one study reported standardized mortality ratios (SMRs) comparing observed numbers of deaths with expected numbers for the general population; the exception was a study that reported standardized incidence ratios. For simplicity, we refer to all effect estimates as SMRs. The overall pooled SMR estimate for ovarian cancer was 1.77 (95% confidence interval, 1.37-2.28), with a moderate degree of heterogeneity among the studies (I2 = 35.3%, p = 0.061). Effect estimates were stronger for cohorts compensated for asbestosis, cohorts with estimated lung cancer SMRs > 2.0, and studies conducted in Europe compared with other geographic regions. Effect estimates were similar for studies with and without pathologic confirmation, and we found no evidence of publication bias (Egger’s test p-value = 0.162). Conclusions: Our study supports the IARC conclusion that exposure to asbestos is associated with increased risk of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer, one of the leading causes of death among women, is a complex disease in which several factors, such as psychosocial stress, have been implicated in its initiation and progression. The glucocorticoid receptor (GCR) is one of the molecules that transfers the stress signal into the body. We measured the genetic variation and protein expression of GCR and the genes that regulate GCR function or response and examined whether these variations were associated with breast cancer. We found several genetic variants of functionally important SNPs associated with later disease stage, higher grade, and hormone receptor-negative status. The GCR protein expression was reduced in breast cancer tissue and correlated with the basal cell marker CK5/6. Background: Glucocorticoid, one of the primary mediators of stress, acts via its receptor, the glucocorticoid receptor (GCR/NR3C1), to regulate a myriad of physiological processes. We measured the genetic variation and protein expression of GCR, and the genes that regulate GCR function or response and examined whether these alterations were associated with breast cancer clinicopathological characteristics. Method: We used samples from a multiracial cohort of breast cancer patients to assess the association between breast cancer characteristics and the genetic variants of single nucleotide polymorphisms (SNPs) in GCR/NR3C1, FKBP5, Sgk1, IL-6, ADIPOQ, LEPR, SOD2, CAT, and BCL2. Results: Several SNPs were associated with breast cancer characteristics, but statistical significance was lost after adjustment for multiple comparisons. GCR was detected in all normal breast tissues and was predominantly located in the nuclei of the myoepithelial cell layer, whereas the luminal layer was negative for GCR. GCR expression was significantly decreased in all breast cancer tissue types, compared to nontumor tissue, but was not associated with breast cancer characteristics. We found that high nuclear GCR expression was associated with basal cell marker cytokeratin 5/6 positivity. Conclusion: GCR expression is reduced in breast cancer tissue and correlates with the basal cell marker CK5/6. [ABSTRACT FROM AUTHOR]

The authors discuss the association between allergies and adult gliomas. The article makes reference to the research of F.C.F. Calboli and colleagues published in the issue titled "Prediagnostic plasma IgE levels and risk of adult glioma in four prospective cohort studies." The authors suggest a larger sample size for borderline levels of prediagnostic plasma immunoglobulin E (IgE). They also suggest case-control studies to determine the response to the use of the drug temozolomide.