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

Hossam T Mohamed; Ramy Gadalla; Noura El-Husseiny; Hebatallah Hassan; Zhongyan Wang; Sherif A Ibrahim; Mohamed El-Shinawi; David H Sherr; Mona M Mohamed

doi:10.1016/j.jare.2018.11.006

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

J Adv Res. 2018 Dec 8:16:75-86. doi: 10.1016/j.jare.2018.11.006. eCollection 2019 Mar.

Authors

Hossam T Mohamed¹, Ramy Gadalla¹, Noura El-Husseiny¹, Hebatallah Hassan¹, Zhongyan Wang², Sherif A Ibrahim¹, Mohamed El-Shinawi³, David H Sherr², Mona M Mohamed¹

Affiliations

¹ Department of Zoology, Faculty of Science, Cairo University, Cairo University, Giza 12613, Egypt.
² Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
³ Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.

Abstract

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 with Wnt5a/b-β-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 β-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 β-catenin in IBC tissues. The overexpression of AHR and its target CYP1B1 correlated with the expression of Wnt5a/b and β-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.

Keywords: Aryl hydrocarbon receptor; CD44+/CD24(−/low) subset and lymphovascular invasion; CYP1B1; Inflammatory breast cancer; Wnt5a/b and β-catenin.