Projects per year
Abstract
Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.
Original language | English |
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Journal | Biochemical Pharmacology |
Volume | 222 |
Pages (from-to) | 116095 |
ISSN | 0006-2952 |
DOIs | |
Publication status | Published - Apr 2024 |
Keywords
- Adipogenesis
- Adipose Tissue/metabolism
- Aromatase/genetics
- Breast Neoplasms/drug therapy
- Estrogens/metabolism
- Female
- Humans
- PPAR gamma/genetics
Fingerprint
Dive into the research topics of 'PPARγ antagonists induce aromatase transcription in adipose tissue cultures'. Together they form a unique fingerprint.Projects
- 2 Active
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Fornyet Fokus på Kemisk Arbejdsmiljø 2
Vogel, U. B., Hougaard, K. S., Madsen, A. M., Andrup, L., Hadrup, N., Sørli, J. B., Saber, A. T., Nøjgaard, J. N. K., Frederiksen, M. & Jensen, K. A.
30/03/2023 → 31/12/2026
Project: Research
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FFIKA: Fornyet fokus på forskning i kemisk arbejdsmiljø
Vogel, U. B., Jensen, K. A., Jensen, A. C. Ø., Berthing, T., Andersen, M. H. G., Hougaard, K. S., Clausen, P. A., Frederiksen, M., Mortensen, A., Saber, A. T., Jacobsen, N. R., Akhtar, Y., Asp, A., Abildtrup, A., Tegner, U., Terrida, E. B., Guldbrandsen, M., Kembouche, Y., Kofoed-Sørensen, V., Nielsen, S. H., Sahlgren, N. M., Fonseca, A. S., Danielsen, P. H., Sørli, J. B., Hadrup, N., Ardenkjær-Skinnerup, J., Nøjgaard, J. N. K., Jørgensen, A. K. & Gutierrez, C. A. T.
01/01/2020 → 31/12/2026
Project: Research
Research output
- 1 Journal article
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Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay
Ardenkjær-Skinnerup, J., Nissen, A. C. V. E., Nikolov, N. G., Hadrup, N., Ravn-Haren, G., Wedebye, E. B. & Vogel, U., Jan 2024, In: Environmental Toxicology and Pharmacology. 105, p. 104347Research output: Contribution to journal › Journal article › Research › peer-review
Open Access