Phthalates stimulate the epithelial to mesenchymal transition through an HDAC6-dependent mechanism in human breast epithelial stem cells

Toxicological Sciences : an Official Journal of the Society of Toxicology
Tsung-Hua HsiehEing-Mei Tsai

Abstract

Phthalates are environmental hormone-like molecules that are associated with breast cancer risk and are involved in metastasis, a process that requires the epithelial-mesenchymal transition (EMT). However, few studies have addressed the potential effects of phthalates on stem cells. Here we tested the hypothesis that phthalates such as butyl benzyl phthalate and di-n-butyl phthalate induce EMT in R2d cells, a stem cell-derived human breast epithelial cell line that is responsive to estradiol for tumor development. We observed that phthalates induced EMT as evidenced by morphological changes concomitant with increased expression of mesenchymal markers and decreased expression of epithelial markers. Molecular mechanism studies revealed that histone deacetylase 6 (HDAC6) is required for phthalate-induced cell migration and invasion during EMT in vitro and metastasis into the lungs of nude mice. We also constructed a series of mutant HDAC6 promoter fragments and found that the transcription factor AP-2a plays a novel role in regulating the HDAC6 promoter. Furthermore, phthalates stimulated estrogen receptors and triggered the downstream EGFR-PKA signaling cascade, leading to increased expression of AP-2a in the nucleus. We also obs...Continue Reading

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Citations

Nov 28, 2013·Endocrine-related Cancer·Elizabeth KoprasSusan Kasper
Nov 16, 2013·Climacteric : the Journal of the International Menopause Society·F-P Chen, M-H Chien
Aug 20, 2014·BioMed Research International·Laura ContiStefania Lanzardo
Dec 23, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tsung-Hua HsiehEing-Mei Tsai
Jan 4, 2017·Taiwanese Journal of Obstetrics & Gynecology·Fang-Ping ChenIngrid Ying-Yu Chern
Jun 1, 2015·Seminars in Cell & Developmental Biology·Frances XinMarisa S Bartolomei
Sep 12, 2012·Molecular Oncology·Bruna Barneda-Zahonero, Maribel Parra
Jan 11, 2019·Journal of the National Cancer Institute·Katherine W ReevesAntonia M Calafat
Sep 19, 2012·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Naisana S Asli, Richard P Harvey
Jul 30, 2020·British Journal of Pharmacology·Erica BuosoMarco Racchi
Jan 22, 2019·Molecular Medicine Reports·Chin-Hu WuEing-Mei Tsai
Nov 19, 2020·Environmental Health : a Global Access Science Source·Meriem KoualXavier Coumoul
May 1, 2013·Journal of Medicinal Chemistry·Jay H Kalin, Joel A Bergman

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