1. Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway
- Author
-
J. Thomas Sanderson, Rachel Viau, Élyse Caron-Beaudoin, Université de Montréal (UdeM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), This research was funded by a Natural Sciences and Engineering Research Council of Canada Discovery (NSERC, grant no. 313313-2012), a California Breast Cancer Research Program (CBCRP, and grant no. 17UB-8703), and an Alternatives Research and Development Foundation (ARDF) grant to J.T.S. and doctoral studentships from the Fonds de recherche du Québec – Nature et technologies (FRQNT) and Fondation universitaire Armand-Frappier INRS to E.C.-B. This research was conducted in fulfillment of E.C-B.’s PhD requirements at the INRS Institut Armand-Frappier. This study was part of R.V.’s internship that was funded by the Fondation universitaire Armand-Frappier INRS.
- Subjects
0301 basic medicine ,Vascular Endothelial Growth Factor A ,Insecticides ,endocrine system ,Health, Toxicology and Mutagenesis ,[SDV]Life Sciences [q-bio] ,Mammary gland ,Thiazines ,010501 environmental sciences ,01 natural sciences ,03 medical and health sciences ,Neonicotinoids ,Breast cancer ,Aromatase ,Cell Line, Tumor ,medicine ,Humans ,Science Selection ,reproductive and urinary physiology ,0105 earth and related environmental sciences ,Regulation of gene expression ,Messenger RNA ,biology ,urogenital system ,Kinase ,Public Health, Environmental and Occupational Health ,Promoter ,medicine.disease ,Nitro Compounds ,3. Good health ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,biology.protein ,Cancer research ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
International audience; BACKGROUND: Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression.OBJECTIVE: We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved.METHODS: Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay.RESULTS: To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways.CONCLUSIONS: We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer.
- Published
- 2018
- Full Text
- View/download PDF