Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer.

Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues-2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and mirex-assayed by high resolution gas chromatography were abundant in breast tissue. p,p'-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p'-DDE and HCB were significantly correlated (P < .001) with patient age at mastectomy, and levels of p,p'-DDE were correlated (P < .05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.

Outcome Disparities in African American Compared with European American Women with ER+HER2- Tumors Treated within an Equal-Access Health Care System.

PURPOSE: Breast cancer mortality rates are higher for African American women (AAW) than for any other ethnic group in the United States. Recent reports suggest that outcome disparities between AAW and European American women (EAW) are present in the ER+HER2- subtype. To improve our understanding, pathological characteristics, mortality and molecular profiles from women treated within an equal-access health care system were evaluated. PROCEDURES: All AAW (n=90) and EAW (n=308) with ER+HER2- tumors were identified. Gene expression profiles were generated from primary breast tumors from 57 AAW and 181 EAW. Pathological characteristics, survival and gene expression analysis were evaluated using chi-square analysis, log-rank tests and ANOVA. RESULTS: Tumors from AAW were significantly more likely to be PR-, Ki67+ and of higher grade. Tumor stage, size and lymph node status did not differ significantly, nor did mortality rates (P=.879). At the molecular level, genes PSPHL and CRYBB2P1 were expressed at significantly higher levels in tumor tissues as well as normal stroma and blood from AAW. Polymorphisms controlling expression of each gene were identified with minor allele frequencies differing significantly between populations but not between cases and controls within each population. CONCLUSIONS: Survival disparities were not detected in patients with ER+HER2- tumors treated within an equal-access health care system and molecular differences in tumors were not causal. Thus, outcome disparities in AAW with ER+HER2- tumors are largely attributable to socioeconomic factors affecting access to screening and treatment, rather than reflecting underlying biological differences.

Effect of obesity on molecular characteristics of invasive breast tumors: gene expression analysis in a large cohort of female patients.

BACKGROUND: Obesity is a risk factor for breast cancer in postmenopausal women and is associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade, and poor prognosis, regardless of menopausal status. Despite the negative impact of obesity on clinical outcome, molecular mechanisms through which excess adiposity influences breast cancer etiology are not well-defined. METHODS: Affymetrix U133 2.0 gene expression data were generated for 405 primary breast tumors using RNA isolated from laser microdissected tissues. Patients were classified as normal-weight (BMI < 25), overweight (BMI 25-29.9) or obese (BMI ≥ 30). Statistical analysis was performed by ANOVA using Partek Genomics Suite version 6.6 using a false discovery rate <0.05 to define significance. RESULTS: Obese patients were significantly more likely to be diagnosed ≥50 years or with African American ancestry compared to lean or overweight women. Pathological characteristics including tumor stage, size or grade, lymph node status, intrinsic subtype, and breast cancer mortality did not differ significantly between groups. No significant gene expression differences were detected by BMI in a non-stratified analysis which included all subtypes or within luminal B, HER2-enriched or basal-like subtypes. Within luminal A tumors, however, 44 probes representing 42 genes from pathways such as cell cycle, p53 and mTOR signaling, DNA repair, and transcriptional misregulation were differentially expressed. CONCLUSIONS: Identification of transcriptome differences in luminal A tumors from normal-weight compared to obese women suggests that obesity alters gene expression within ER+ tumor epithelial cells. Alterations of pathways involved in cell cycle control, tumorigenesis and metabolism may promote cellular proliferation and provide a molecular explanation for less favorable outcome of obese women with breast cancer. Targeted treatments, such as mTOR inhibitors, may allow for improved treatment and survival of obese women, especially African American women, who are more likely to be obese and suffer outcome disparities.

Molecular Heterogeneity in Primary Breast Carcinomas and Axillary Lymph Node Metastases Assessed by Genomic Fingerprinting Analysis.

Molecular heterogeneity within primary breast carcinomas and among axillary lymph node (LN) metastases may impact diagnosis and confound treatment. In this study, we used short tandem repeated sequences to assess genomic heterogeneity and to determine hereditary relationships among primary tumor areas and regional metastases from 30 breast cancer patients. We found that primary carcinomas were genetically heterogeneous and sampling multiple areas was necessary to adequately assess genomic variability. LN metastases appeared to originate at different time periods during disease progression from different sites of the primary tumor and the extent of genomic divergence among regional metastases was associated with a less favorable patient outcome (P = 0.009). In conclusion, metastasis is a complex process influenced by primary tumor heterogeneity and variability in the timing of dissemination. Genomic variation in primary breast tumors and regional metastases may negatively impact clinical diagnostics and contribute to therapeutic resistance.

Importance of substantial weight loss for altering gene expression during cardiovascular lifestyle modification.

OBJECTIVE: To examine relationships between weight loss through changes in lifestyle and peripheral blood gene expression profiles. METHODS: A prospective nonrandomized trial was conducted over 1 year in participants undergoing intensive lifestyle modification to reverse or stabilize progression of coronary artery disease. Cardiovascular risk factors, inflammatory biomarkers, and gene expression as a function of weight loss were assessed in 89 lifestyle participants and 71 retrospectively matched controls undergoing usual care. RESULTS: Substantial weight loss (-15.2 ± 3.8%) in lifestyle participants (n = 33) was associated with improvement in selected cardiovascular risk factors and significant changes in peripheral blood gene expression from pre- to post-intervention: 132 unique genes showed significant expression changes (false discovery rate corrected P-value <0.05 and fold-change ≥1.4). Altered molecular pathways were related to immune function and inflammatory responses involving endothelial activation. In contrast, participants losing minimal weight (-3.1 ± 2.5%, n = 32) showed only minor changes in cardiovascular risk factors and markers of inflammation and no changes in gene expression compared to non intervention controls after 1 year. CONCLUSIONS: Weight loss (≥10%) during lifestyle modification is associated with down-regulation of genetic pathways governing interactions between circulating immune cells and the vascular endothelium and may be required to successfully reduce CVD risk.

Abundance and distribution of polychlorinated biphenyls (PCBs) in breast tissue.

Many environmental chemicals accumulate in human tissues and may contribute to cancer risk. Polychlorinated biphenyls (PCBs) are associated with adverse health effects, but relationships between PCB exposure and breast cancer are unclear. In this study, we sought to determine whether bioaccumulation of PCBs differs within regions of the human breast and whether PCB levels are associated with clinical and pathological characteristics in breast cancer patients. Tissue sections (n=245) were collected from breast quadrants from 51 women with a diagnosis ranging from disease-free to metastatic breast cancer. Ninety-seven PCB congeners were assayed by high resolution gas chromatography. ANOVA was used to examine PCB distribution within the breast and relationships with clinical/pathological variables. Pearson product-moment correlations assessed relationships between age at mastectomy and PCB levels. PCBs were abundant in breast tissues with a median concentration of 293.4ng/g lipid (range 15.4-1636.3ng/g). PCB levels in breast tissue were significantly different (p<0.001) among functional groupings of congeners defined by structure-activity properties: Group I (28.2ng/g), Group II (96.6ng/g), Group III (166.0ng/g). Total PCB concentration was highly correlated with age at mastectomy, but the distribution of PCBs did not differ by breast quadrant. PCB levels were not associated with patient status or tumor characteristics. In conclusion, PCB congeners with carcinogenic potential were present at high levels in the human breast, but were not associated with clinical or pathological characteristics in breast cancer patients.