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BACKGROUND: Exposure to phthalates during the pubertal window impacts chronic disease risk and temporal trends in exposure can inform public health initiatives. OBJECTIVE: Characterize temporal trends in phthalate metabolite exposure for adolescent girls overall and by sociodemographic characteristics. METHODS: We used the cross-sectional data from each cycle of the National Health and Nutrition Examination Survey from years 2001 to 2018. We restricted participants to ages of 8-14 with at least one urinary measurement of the selected 12 phthalate metabolites within the study period (n=2,063). We used multivariable linear regression to assess temporal trends for selected individual phthalate metabolite concentrations (ng/ml) and source groupings of parent metabolites (sum low and high molecular weight phthalates; ∑LMW and ∑HMW) overall and individually by sociodemographic characteristics (race/ethnicity), nativity, socioeconomic status (SES), intersection of race/ethnicity-SES) to assess for modification. RESULTS: Overall ∑HMW and ∑LMW concentrations declined between 2001 and 2018; however, only ∑LMW consistently differed by all sociodemographic characteristics. Trends in ∑LMW concentration were significantly higher across all racial/ethnic groups, ranging from an average of 35% (Other Hispanic) to 65% (Mexican American and non-Hispanic Black) higher than non-Hispanic White (all p-values<0.0001). Compared to non-Hispanic White, we observed an average decrease of 15% in MiBP for non-Hispanic Black (ßSpline=-0.16, p<0.0001) and 28% for Other Hispanic (ßSpline=-0.33, p=0.01) in 2011-2018 vs. 2001-2010. Summary and individual LMW metabolite phthalate concentrations were 11%-49% higher among low vs. high SES girls. LMW metabolites MBP and MiBP were on average 22% and 35% higher; respectively, among foreign born vs. U.S. born. Compared to non-Hispanic Whites, all racial/ethnic groups had statistically significant higher trends in ∑LMW concentration irrespective of SES status. SIGNIFICANCE: Girls identifying with a historically disadvantaged racial/ethnic group have elevated ∑LMW concentrations irrespective of SES class; suggesting the need for interventions to mitigate exposure among the most historically disadvantaged strata.
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The influence of breast cancer cells on normal cells of the microenvironment, such as fibroblasts and macrophages, has been heavily studied but the influence of normal epithelial cells on breast cancer cells has not. Here using in vivo and in vitro models we demonstrate the impact epithelial cells and the mammary microenvironment can exert on breast cancer cells. Under specific conditions, signals that originate in epithelial cells can induce phenotypic and genotypic changes in cancer cells. We have termed this phenomenon "cancer cell redirection." Once breast cancer cells are redirected, either in vivo or in vitro, they lose their tumor forming capacity and undergo a genetic expression profile shift away from one that supports a cancer profile towards one that supports a non-tumorigenic epithelial profile. These findings indicate that epithelial cells and the normal microenvironment influence breast cancer cells and that under certain circumstances restrict proliferation of tumorigenic cells.
RESUMEN
PURPOSE: Tumor initiation and progression rely on cellular proliferation and migration. Many factors are involved in these processes, including growth factors. Amphiregulin (AREG) is involved in normal mammary development and the development of estrogen receptor (ER)-positive breast cancer. The aim of this project was to determine if AREG is involved in the proliferation and progression of HER2-positive breast cancer. METHODS: Mouse cell lines MMTV-neu, HC-11 and COMMA-D, as well as human cell lines MCF10A, SKBR3, HCC1954 and BT474 were used. Real-time PCR was used to quantify AREG expression and neutralizing antibodies were used to reduce the autocrine/paracrine effects of AREG. Transfections using siRNA and shRNA were used to knockdown AREG expression in the cancer cell lines. Free-floating sphere formation, colony forming, scratch wound and Transwell assays were used to assess the proliferation, tumor forming and migratory capacities of transfected cancer cells. RESULTS: We found AREG expression in both normal epithelial cell lines and tumor-derived cell lines. Knockdown of AREG protein expression resulted in reduced sphere sizes and reduced sphere numbers in both mouse and human cancer cells that overexpress erbB2/HER2. AREG was found to be involved in cancer cell migration and invasion. In addition, we found that AREG expression knockdown resulted in different migration capacities in normal and erbB2/HER2 overexpressing cancer cells. CONCLUSIONS: Based on our results we conclude that AREG is involved in regulating the proliferation and migration of erbB2/HER2-positive breast cancer cells.