Inflammatory breast cancer: Activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression
Inflammatory breast cancer: Activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression
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DOI：
10.1016/j.jare.2018.11.006
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发表时间：
2019-03-01
影响因子：
10.7
通讯作者：
Mohamed, Mona M.
中科院分区：
文献类型：
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作者：
Mohamed, Hossam T.;Gadalla, Ramy;Mohamed, Mona M.
本研究旨在探讨芳香烃受体(AHR)及其靶基因CYP1B1在炎症性乳腺癌(IBC)和非IBC患者中的表达水平及其与Wnt5a/b-β-catenin、CD44(+)/CD24(-/low)肿瘤干细胞(CSC)亚群及预后不良因素的关系。采用实时定量聚合酶链式反应、Western blotting、免疫组织化学和流式细胞术等方法进行分析。与非IBC组织相比，IBC组织中AHR及其靶基因/蛋白CYP1B1过表达。AHR和CYP1B1mRNA水平与肿瘤分级、淋巴血管侵犯、细胞增殖和淋巴结转移有关。此外，AHR的表达与Wnt5a/b和β-catenin信号分子的表达有关，抑制AHR后，Wnt5a在SUM149人IBC细胞系和MDA-MB-231非IBC细胞系中的表达下调。AHR基因敲除(CRISPR-Cas9)可抑制IBC细胞系中CYP1B1和Wnt5a的表达。CD44(+)/CD24(-/low)亚群与IBC组织中AHR、CYP1B1、Wnt5a/b和β-catenin的表达显著相关。AHR及其靶细胞色素P1B1的过度表达与Wnt5a/b、β-连环蛋白、CSCs的表达及临床预后因素有关。因此，靶向AHR和/或其下游靶分子CYP1B1和WNT5a/b可能代表了一种治疗IBC的方法。(C)2018年作者。由Elsevier B.V.代表开罗大学出版。
The aim of the present study was to evaluate the expression levels of the aryl hydrocarbon receptor (AHR) and its target gene CYP1B1 and to correlate their expression withWnt5a/b-beta-catenin, the CD44(+)/CD24((-/low)) cancer stem cell (CSC) subset and factors associated with poor prognosis in inflammatory breast cancer (IBC) and non-IBC patients. The methods of analysis used were quantitative real-time PCR, western blotting, immunohistochemistry and flow cytometry. Compared to non-IBC tissues, IBC tissues exhibited the overexpression of AHR and its target gene/protein CYP1B1. AHR and CYP1B1 mRNA levels were associated with the poor clinical prognosis markers tumour grade, lymphovascular invasion, cell proliferation and lymph node metastasis. Furthermore, AHR expression correlated with the expression of Wnt5a/b and beta-catenin signalling molecules, and Wnt5a mRNA expression was downregulated in the SUM149 human IBC cell line and the MDA-MB-231 non-IBC cell line upon inhibition of AHR. AHR gene knockout (CRISPR-Cas9) inhibits CYP1B1 and Wnt5a expression in the IBC cell line. The CD44(+)/CD24((-/low)) subset was significantly correlated with the expression of AHR, CYP1B1, Wnt5a/b and beta-catenin in IBC tissues. The overexpression of AHR and its target CYP1B1 correlated with the expression of Wnt5a/b and beta-catenin, CSCs, and poor clinical prognostic factors of IBC. Thus, targeting AHR and/or its downstream target molecules CYP1B1 and Wnt5a/b may represent a therapeutic approach for IBC. (C) 2018 The Authors. Published by Elsevier B.V. on behalf of Cairo University.