Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids

Rocco, Sabrina; Koneva, Lada A.; Middleton, Lauren Y. M.; Thong, Tasha; Solanki, Sumeet; Karram, Sarah; Nambunmee, Kowit; Harris, Craig; Rozek, Laura S.; Sartor, Maureen A.; Shah, Yatrik M.; Colacino, Justin A.

doi:10.1101/208157

Cited by 1 publication

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“…A recent study found that chemotherapy induced HIF-1A controlled pathway led to epigenetic activation of pluripotency factor transcription (Lu et al ., 2020), suggesting that this pathway can be activated by stressor exposures. We previously showed that HIF-1A is required for stem cell proliferation from normal human mammary gland in vitro , including both spheroid formation and organoid growth (Rocco et al ., 2018). Determining which chemicals can push cells into a stemness phenotype can help in testing prioritization as well as identify novel mechanisms by which chemical exposures can promote the development of aggressive breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Polemi

Nguyen

Heidt

et al. 2021

Preprint

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Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40% higher in African American women compared to European American women in the US. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is approximately three times higher in non-Hispanic Black women (NHBW) compared to non-Hispanic White women (NHWW). The drivers of these differences in breast cancer incidence and mortality are still poorly understood, and likely lie in an interaction between genetic and environmental factors. Here, we aimed to identify chemical exposures which may play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPA’s ToxCast program, we assessed the toxicological profiles of chemicals with higher biomarker concentrations in US NHBW. We conducted a literature search to identify a gene set of breast cancer targets included in ToxCast to analyze the response of prioritized chemicals in these assays. Forty-four chemical biomarkers are significantly higher in NHBW. Investigation of these chemicals in ToxCast resulted in a total of 33,645 assays for analysis, 5,301 of which contained nonzero values for ACC (modl_acc: the concentration at which the dose-response fitted model reaches the cutoff considered “active”) and modl_tp (scaled top value of dose response curve) data. Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in NHBW and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in NHBW. Through this integrated analysis, we have identified that multiple chemicals, including thiram, propylparaben, and p,p’ DDE, with disproportionate exposures in NHBW, have breast cancer associated biological activity at human exposure relevant doses.

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Section: Discussionmentioning

confidence: 99%

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Polemi

Nguyen

Heidt

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids

Abstract: Background: Developmental cadmium exposure in vivo disrupts mammary gland

Cited by 1 publication

References 48 publications

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

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