ArticleToxicological sciences : an official journal of the Society of Toxicology2018
Cadmium Exposure Inhibits Branching Morphogenesis and Causes Alterations Consistent With HIF-1α Inhibition in Human Primary Breast Organoids.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Animal organoids as models for integrated One Health research.One health (Amsterdam, Netherlands) · 2026Review
- Cd stabilizes HIF-1α under normoxic conditions via lysine-63-linked ubiquitination and induces ER stress and cell proliferation.Toxicological research · 2025Article
- Insoluble HIFa protein aggregates by cadmium disrupt hypoxia-prolyl hydroxylase (PHD)-hypoxia inducible factor (HIFa) signaling in renal epithelial (NRK-52E) and interstitial (FAIK3-5) cells.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2024Article
- Applications of 3D organoids in toxicological studies: a comprehensive analysis based on bibliometrics and advances in toxicological mechanisms.Archives of toxicology · 2024Review
- Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures.bioRxiv : the preprint server for biology · 2024Article
- Innovative explorations: unveiling the potential of organoids for investigating environmental pollutant exposure.Environmental science and pollution research international · 2024Review
- AI-enabled organoids: Construction, analysis, and application.Bioactive materials · 2024Review
- The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity.Archives of toxicology · 2023Review
- Toxic metals in the regulation of epithelial-mesenchymal plasticity: demons or angels?Cancer cell international · 2022Review
- Vulnerability of HIF1α and HIF2α to damage by proteotoxic stressors.Toxicology and applied pharmacology · 2022Article
- Organoids for toxicology and genetic toxicology: applications with drugs and prospects for environmental carcinogenesis.Mutagenesis · 2022Article
- Activation of multiple proteolysis systems contributes to acute cadmium cytotoxicity.Molecular and cellular biochemistry · 2022Article
- Next-generation cancer organoids.Nature materials · 2022Review
- Identifying the link between chemical exposures and breast cancer in African American women via integrated in vitro and exposure biomarker data.Toxicology · 2021Article
- The roles of inducible chromatin and transcriptional memory in cellular defense system responses to redox-active pollutants.Free radical biology & medicine · 2021Review
- Environmental exposures, stem cells, and cancer.Pharmacology & therapeutics · 2019Review
- Radial Profile Analysis of Epithelial Polarity in Breast Acini: A Tool for Primary (Breast) Cancer Prevention.Frontiers in medicine · 2019Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Developmental cadmium exposure in vivo disrupts mammary gland differentiation, while exposure of breast cell lines to cadmium causes invasion consistent with the epithelial-mesenchymal transition (EMT). The effects of cadmium on normal human breast stem cells have not been measured. Here, we quantified the effects of cadmium exposure on reduction mammoplasty patient-derived breast stem cell proliferation and differentiation. Using the mammosphere assay and organoid formation in 3D hydrogels, we tested 2 physiologically relevant doses of cadmium, 0.25 and 2.5 µM, and tested for molecular alterations using RNA-seq. We functionally validated our RNA-seq findings with a hypoxia-inducible factor (HIF)-1α activity reporter line and pharmaceutical inhibition of HIF-1α in organoid formation assays. 2.5 µM cadmium reduced primary mammosphere formation and branching structure organoid formation rates by 33% and 87%, respectively. Despite no changes in mammosphere formation, 0.25 µM cadmium inhibited branching organoid formation in hydrogels by 73%. RNA-seq revealed cadmium downregulated genes associated with extracellular matrix formation and EMT, while upregulating genes associated with metal response including metallothioneins and zinc transporters. In the RNA-seq data, cadmium downregulated HIF-1α target genes including LOXL2, ZEB1, and VIM. Cadmium significantly inhibited HIF-1α activity in a luciferase assay, and the HIF-1α inhibitor acriflavine ablated mammosphere and organoid formation. These findings show that cadmium, at doses relevant to human exposure, inhibited human mammary stem cell proliferation and differentiation, potentially through disruption of HIF-1α activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.