Adipocyte-derived kynurenine stimulates malignant transformation of mammary epithelial cells through the aryl hydrocarbon receptor.

Autor: Diedrich JD; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA., Gonzalez-Pons R; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA., Medeiros HCD; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA., Ensink E; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA., Liby KT; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA., Wellberg EA; Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA., Lunt SY; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824 USA., Bernard JJ; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA; Department of Medicine, Michigan State University, East Lansing, MI 48824 USA. Electronic address: jbernard@msu.edu.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2023 Oct; Vol. 216, pp. 115763. Date of Electronic Publication: 2023 Aug 23.
DOI: 10.1016/j.bcp.2023.115763
Abstrakt: Anti-hormone therapies are not efficacious for reducing the incidence of triple negative breast cancer (TNBC), which lacks both estrogen and progesterone receptors. While the etiology of this aggressive breast cancer subtype is unclear, visceral obesity is a strong risk factor for both pre- and post-menopausal cases. The mechanism by which excessive deposition of visceral adipose tissue (VAT) promotes the malignant transformation of hormone receptor-negative mammary epithelial cells is currently unknown. We developed a novel in vitro system of malignant transformation in which non-tumorigenic human breast epithelial cells (MCF-10A) grow in soft agar when cultured with factors released from VAT. These cells, which acquire the capacity for 3D growth, show elevated aryl hydrocarbon receptor (AhR) protein and AhR target genes, suggesting that AhR activity may drive malignant transformation by VAT. AhR is a ligand-dependent transcription factor that generates biological responses to exogenous carcinogens and to the endogenous tryptophan pathway metabolite, kynurenine. The serum kynurenine to tryptophan ratio has been shown to be elevated in patients with obesity. Herein, we demonstrate that AhR inhibitors or knockdown of AhR in MCF-10A cells prevents VAT-induced malignant transformation. Specifically, VAT-induced transformation is inhibited by Kyn-101, an inhibitor for the endogenous ligand binding site of AhR. Mass spectrometry analysis demonstrates that adipocytes metabolize tryptophan and release kynurenine, which is taken up by MCF-10A cells and activates the AhR to induce CYP1B1 and promote malignant transformation. This novel hormone receptor-independent mechanism of malignant transformation suggests targeting AhR for TNBC prevention in the context of visceral adiposity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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