DEHP mediates drug resistance by directly targeting AhR in human breast cancer

Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and fo...

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Autores principales:	Tsung-Hua Hsieh, Chia-Yi Hsu, Pei-Jing Yang, Chien-Chih Chiu, Shih-Shin Liang, Fu Ou-Yang, Jung-Yu Kan, Ming-Feng Hou, Tsu-Nai Wang, Eing-Mei Tsai
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	DEHP Drug Resistance AhR Breast Cancer Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/00d3b1c688a74a52aca908b280671cb2
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spelling	oai:doaj.org-article:00d3b1c688a74a52aca908b280671cb22021-11-20T04:55:50ZDEHP mediates drug resistance by directly targeting AhR in human breast cancer0753-332210.1016/j.biopha.2021.112400https://doaj.org/article/00d3b1c688a74a52aca908b280671cb22022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011860https://doaj.org/toc/0753-3322Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that Σ4MEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0.018) in the recurrent breast cancer group compared with non-recurrent patients. Σ4MEHP-High was positively and significantly correlated with tumor stage (P = 0.005), lymph node status (P = 0.001), estrogen receptor status (P = 0.010), Her2/Neu status (P = 0.004), recurrence (P = 0.000) and tumor size (P = 0.002), as well as an independent prognostic marker (OR = 1.868; 95% CI = 1.424–2.451; P < 0.000) associated with poor survival rates based on a positive Her2/Neu status (P = 0.035). In addition, we found that DEHP inhibited paclitaxel and doxorubicin effects in breast cancer cell lines MCF-7 and MDA-MB-231 and in zebrafish and mouse tumor initiation models. DEHP induced trefoil factor 3 (TFF3) expression through the vinculin/aryl hydrocarbon receptor (AhR)/ERK signaling pathway and induced CYP2D6, CYP2C8 and CYP3A4 expression through the AhR genomic pathway to increase the epithelial-mesenchymal transition (EMT) and doxorubicin metabolism, respectably. DEHP mediated AhR-related alterations in estrogen receptor expression through the ubiquitination system, which decreased tamoxifen effects in AhR knockout mice. These findings suggest a novel therapeutic avenue by targeting AhR in drug-resistant and recurrent breast cancer.Tsung-Hua HsiehChia-Yi HsuPei-Jing YangChien-Chih ChiuShih-Shin LiangFu Ou-YangJung-Yu KanMing-Feng HouTsu-Nai WangEing-Mei TsaiElsevierarticleDEHPDrugResistanceAhRBreast CancerTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112400- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	DEHP Drug Resistance AhR Breast Cancer Therapeutics. Pharmacology RM1-950
spellingShingle	DEHP Drug Resistance AhR Breast Cancer Therapeutics. Pharmacology RM1-950 Tsung-Hua Hsieh Chia-Yi Hsu Pei-Jing Yang Chien-Chih Chiu Shih-Shin Liang Fu Ou-Yang Jung-Yu Kan Ming-Feng Hou Tsu-Nai Wang Eing-Mei Tsai DEHP mediates drug resistance by directly targeting AhR in human breast cancer
description	Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that Σ4MEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0.018) in the recurrent breast cancer group compared with non-recurrent patients. Σ4MEHP-High was positively and significantly correlated with tumor stage (P = 0.005), lymph node status (P = 0.001), estrogen receptor status (P = 0.010), Her2/Neu status (P = 0.004), recurrence (P = 0.000) and tumor size (P = 0.002), as well as an independent prognostic marker (OR = 1.868; 95% CI = 1.424–2.451; P < 0.000) associated with poor survival rates based on a positive Her2/Neu status (P = 0.035). In addition, we found that DEHP inhibited paclitaxel and doxorubicin effects in breast cancer cell lines MCF-7 and MDA-MB-231 and in zebrafish and mouse tumor initiation models. DEHP induced trefoil factor 3 (TFF3) expression through the vinculin/aryl hydrocarbon receptor (AhR)/ERK signaling pathway and induced CYP2D6, CYP2C8 and CYP3A4 expression through the AhR genomic pathway to increase the epithelial-mesenchymal transition (EMT) and doxorubicin metabolism, respectably. DEHP mediated AhR-related alterations in estrogen receptor expression through the ubiquitination system, which decreased tamoxifen effects in AhR knockout mice. These findings suggest a novel therapeutic avenue by targeting AhR in drug-resistant and recurrent breast cancer.
format	article
author	Tsung-Hua Hsieh Chia-Yi Hsu Pei-Jing Yang Chien-Chih Chiu Shih-Shin Liang Fu Ou-Yang Jung-Yu Kan Ming-Feng Hou Tsu-Nai Wang Eing-Mei Tsai
author_facet	Tsung-Hua Hsieh Chia-Yi Hsu Pei-Jing Yang Chien-Chih Chiu Shih-Shin Liang Fu Ou-Yang Jung-Yu Kan Ming-Feng Hou Tsu-Nai Wang Eing-Mei Tsai
author_sort	Tsung-Hua Hsieh
title	DEHP mediates drug resistance by directly targeting AhR in human breast cancer
title_short	DEHP mediates drug resistance by directly targeting AhR in human breast cancer
title_full	DEHP mediates drug resistance by directly targeting AhR in human breast cancer
title_fullStr	DEHP mediates drug resistance by directly targeting AhR in human breast cancer
title_full_unstemmed	DEHP mediates drug resistance by directly targeting AhR in human breast cancer
title_sort	dehp mediates drug resistance by directly targeting ahr in human breast cancer
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/00d3b1c688a74a52aca908b280671cb2
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DEHP mediates drug resistance by directly targeting AhR in human breast cancer

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