Cumulative environmental quality is associated with breast cancer incidence differentially by summary stage and urbanicity.

Individual environmental contaminants have been associated with breast cancer; however, evaluations of multiple exposures simultaneously are limited. Herein, we evaluated associations between breast cancer summary stages and the Environmental Quality Index (EQI), which includes a range of environmental factors across five domains. The EQI (2000-2005) was linked to county-level age-standardized incidence rates (SIRs) obtained from the North Carolina Central Cancer Registry (2010-2014). Incidence rates and SIRs of total, in situ, localized, regional, and distant breast cancers were evaluated stratified by rural-urban status. In counties with poor environmental quality compared to those with good environmental quality, total breast cancer incidence was higher by 10.82 cases per 100,000 persons (95% CI 2.04, 19.60, p = 0.02). This association was most pronounced for localized breast cancer (ß = 5.59, 95% CI 0.59, 10.58, p = 0.03). Higher incidence of early-stage disease (carcinoma in situ ß = 5.25, 95% CI 2.34, 8.16, p = 0.00 and localized breast cancer ß = 6.98, 95% CI 2.24, 11.73, p = 0.00) and total breast cancer (ß = 11.44, 95% CI 3.01, 19.87, p = 0.01) occurred in counties with poor land quality, especially urban counties. Our analyses indicate significant associations between environmental quality and breast cancer incidence, which differ by breast cancer stage and urbanicity, identifying a critical need to assess cumulative environmental exposures in the context of cancer stage.

Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.

Aggressive breast cancer variants, like triple negative and inflammatory breast cancer, contribute to disparities in survival and clinical outcomes among African American (AA) patients compared to White (W) patients. We previously identified the dominant role of anti-apoptotic protein XIAP in regulating tumor cell adaptive stress response (ASR) that promotes a hyperproliferative, drug resistant phenotype. Using The Cancer Genome Atlas (TCGA), we identified 46-88 ASR genes that are differentially expressed (2-fold-change and adjusted p-value < 0.05) depending on PAM50 breast cancer subtype. On average, 20% of all 226 ASR genes exhibited race-related differential expression. These genes were functionally relevant in cell cycle, DNA damage response, signal transduction, and regulation of cell death-related processes. Moreover, 23% of the differentially expressed ASR genes were associated with AA and/or W breast cancer patient survival. These identified genes represent potential therapeutic targets to improve breast cancer outcomes and mitigate associated health disparities.

Analysis of polycyclic aromatic hydrocarbon intake in the US adult population from NHANES 2005-2014 identifies vulnerable subpopulations, suggests interaction between tobacco smoke exposure and sociodemographic factors.

Polycyclic aromatic hydrocarbons (PAHs) are a toxic and ubiquitous class of environmental chemicals, products of fuel combustion from human and natural sources. The objective of this study was to identify vulnerable populations for high PAH exposure and variability, to better understand where to target PAH exposure reduction initiatives. Urinary metabolite data were collected from 9517 individuals from the U.S. CDC National Health and Nutrition Examination Survey years 2005-2014 for four parental PAHs naphthalene, fluorene, phenanthrene, and pyrene. We utilized these urinary biomarkers to estimate PAH intake, and regression models were fit for multiple demographic and lifestyle variables, to determine variable effects, interactions, odds of high versus low PAH intake. Smoking and secondhand smoke exposure accounted for the largest PAH intake rate variability (25.62%), and there were strongest interactions between race/ethnicity and smoking or SHS exposure, reflected in a much greater contribution of smoking to PAH intake in non-Hispanic Whites as compared to other races/ethnicities. Increased odds of high PAH intake were seen in older age groups, obese persons, college graduates, midrange incomes, smokers, and those who were SHS exposed. Among the non-smoking population, effects of other demographic factors lessened, suggesting a highly interactive nature. Our results suggest that there are demographic subpopulations with high PAH intake as a result of different smoking behaviors and potentially other exposures. This has human health, environmental justice, and regulatory implications wherein smoking cessation programs, SHS exposure regulations, and public health initiatives could be better targeted towards vulnerable subpopulations to meaningfully reduce PAH exposures.

A polycyclic aromatic hydrocarbon-enriched environmental chemical mixture enhances AhR, antiapoptotic signaling and a proliferative phenotype in breast cancer cells.

Emerging evidence suggests the role of environmental chemicals, in particular endocrine-disrupting chemicals (EDCs), in progression of breast cancer and treatment resistance, which can impact survival outcomes. However, most research tends to focus on tumor etiology and the effect of single chemicals, offering little insight into the effects of realistic complex mixture exposures on tumor progression. Herein, we investigated the effect of a polycyclic aromatic hydrocarbon (PAH)-enriched EDC mixture in a panel of normal and breast cancer cells and in a tumor organoid model. Cells or organoids in culture were treated with EDC mixture at doses estimated from US adult intake of the top four PAH compounds within the mixture from the National Health and Nutrition Examination Survey database. We demonstrate that low-dose PAH mixture (6, 30 and 300 nM) increased aryl hydrocarbon receptor (AhR) expression and CYP activity in estrogen receptor (ER) positive but not normal mammary or ER-negative breast cancer cells, and that upregulated AhR signaling corresponded with increased cell proliferation and expression of antiapoptotic and antioxidant proteins XIAP and SOD1. We employed a mathematical model to validate PAH-mediated increases in AhR and XIAP expression in the MCF-7 ER-positive cell line. Furthermore, the PAH mixture caused significant growth increases in ER-negative breast cancer cell derived 3D tumor organoids, providing further evidence for the role of a natural-derived PAH mixture in enhancing a tumor proliferative phenotype. Together, our integrated cell signaling, computational and phenotype analysis reveals the underlying mechanisms of EDC mixtures in breast cancer progression and survival.

Environmental Quality and Invasive Breast Cancer.

Background: Breast cancer is a complex and multifactorial disease, and environmental factors have been suggested to increase its risk. However, prior research has largely focused on studying exposures to one factor/contaminant at a time, which does not reflect the real-world environment.Methods: Herein, we investigate associations between breast cancer and the environmental quality index (EQI), a comprehensive assessment of five domains of environmental quality (air, water, land, sociodemographic, and built environments) at the county level. Breast cancer diagnoses for North Carolina women were obtained from the North Carolina Central Cancer Registry (2009-2014) and the county of residence at the time of diagnosis was linked with the EQI. We evaluated the odds of localized, regional, or distant metastatic breast cancer in categories of environmental quality using women with carcinoma in situ as registry-based controls.Results: Overall environmental quality was generally not associated with invasive breast cancer; however, all breast cancer types tended to be inversely associated with land quality, particularly in more rural communities [distant metastatic breast cancer was 5%-8% more likely (OR, 1.08; 95% confidence interval, 1.02-1.14; P = 0.02) compared with carcinoma in situ].Conclusions: Cumulatively, our results suggest that some broad measures of environmental quality are associated with invasive breast cancer but that associations vary by environmental domain, cancer stage, subtype, and urbanicity.Impact: Our findings suggest that components of land quality (e.g., pesticide applications and animal facilities) warrant additional investigation in relation to invasive breast cancer.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment.

The epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-ß, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational-experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.

Assessing Cancer Risk Associated with Aquatic Polycyclic Aromatic Hydrocarbon Pollution Reveals Dietary Routes of Exposure and Vulnerable Populations.

Polycyclic aromatic hydrocarbon (PAH) exposure is widespread, and many PAHs are considered carcinogenic. The PAH-contaminated AWI Superfund site in Virginia provides a model for studying a complex PAH mixture and its extrapolation to cancer risk and PAH exposure in the general population. We examined cancer risk at the Superfund site due to sediment-derived PAHs and then evaluated PAH sources in the general population and potentially vulnerable subpopulations upon PAH mixture exposure. The PAH mixture was assessed for potential carcinogenicity using the US EPA's OncoLogic™ ranking tool and the US EPA list of priority PAHs. Cancer risk due to PAH exposure was calculated for Superfund site users and compared to the US EPA assessment. Human intake and health endpoints of PAHs within the mixture were extracted from USEtox® chemical fate database, while mean intake exposure was calculated for U.S. adults for select PAHs using NHANES database urinary biomarkers. Eleven PAH compounds within the mixture were of carcinogenic concern, and seven PAHs conveyed significant excess cancer risk at the Superfund site and in the general population, wherein PAH-contaminated seafood ingestion was a main contributor. Other dietary sources of PAHs derived from PAH-contaminated soil or water could also play a role in total exposure. Vulnerable populations to PAH exposure and coinciding increased cancer risk may include, in addition to smokers, children and non-Hispanic blacks, which is a public health concern.

Estimated tris(1,3-dichloro-2-propyl) phosphate exposure levels for US infants suggest potential health risks.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been widely used as a flame retardant and is commonly detected in environmental samples. Biomonitoring studies relying on urinary metabolite levels (i.e. bis(1,3-dichloro-2-propyl) phosphate (BDCIPP)) demonstrate widespread exposure, but TDCIPP intake is unknown. Intake data area critical component of meaningful risk assessments and are needed to elucidate the potential health impacts of TDCIPP exposure. Using biomonitoring data, we estimated TDCIPP intake for infants. Infants aged 2-18 months were recruited from central, North Carolina (n=43, recruited 2014-2015), and spot urine samples were analyzed for BDCIPP. TDCIPP intake rates were estimated using daily urine excretion and the fraction of TDCIPP excreted as BDCIPP in urine. Daily TDCIPP intake estimates ranged from 0.01-15.03 µg/kg-day for children included in our assessment, with some variation depending on model assumptions. The U.S. Consumer Products Safety Commission (CPSC) previously established an acceptable daily intake of 5µg/kg-day for non-cancer health risks. Depending on modeling assumptions, we found that 2-9% percent of infants had TDCIPP intake estimates above this threshold. Our results indicate that current TDCIPP exposure levels could pose health risks for highly exposed infants.