Possible Involvement of the Upregulation of ΔNp63 Expression Mediated by HER2-Activated Aryl Hydrocarbon Receptor in Mammosphere Maintenance.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Receptors, Aryl Hydrocarbon*/genetics ; Receptors, Aryl Hydrocarbon*/metabolism ; Breast Neoplasms*/metabolism; Humans ; Female ; Neuregulin-1/metabolism ; Up-Regulation ; RNA, Messenger/genetics ; Luciferases/metabolism ; Chromatin ; Cell Line, Tumor

Cancer stem cells (CSCs) contribute to the drug resistance, recurrence, and metastasis of breast cancers. Recently, we demonstrated that HER2 overexpression increases mammosphere formation via the activation of aryl hydrocarbon receptor (AHR). In this study, the objective was to identify the mechanism underlying mammosphere maintenance mediated by HER2 signaling-activated AHR. We compared the chromatin structure of AHR-knockout (AHRKO) HER2-overexpressing MCF-7 (HER2-5) cells with that of wild-type HER2-5 cells; subsequently, we identified TP63 , a stemness factor, as a potential target gene of AHR. ΔNp63 mRNA and protein levels were higher in HER2-5 cells than in HER2-5/AHRKO cells. Activation of HER2/HER3 signaling by heregulin treatment increased ΔNp63 mRNA levels, and its induction was decreased by AHR knockdown in HER2-5 cells. The results of the chromatin immunoprecipitation assay revealed an interaction between AHR and the intronic region of TP63 , which encodes ΔNp63. A luciferase reporter gene assay with the intronic region of TP63 showed that AHR expression increased reporter activity. Collectively, our findings suggest that HER2-activated AHR upregulates ΔNp63 expression and that this signaling cascade is involved in CSC maintenance in HER2-expressing breast cancers.
Competing Interests: The authors declare no conflict of interest.

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Keywords: aryl hydrocarbon receptor; breast cancer; cancer stem cells; ΔNp63

0 (Receptors, Aryl Hydrocarbon)
0 (Neuregulin-1)
0 (RNA, Messenger)
EC 1.13.12.- (Luciferases)
0 (Chromatin)

Date Created: 20221027 Date Completed: 20221028 Latest Revision: 20221030

20221213

PMC9603582

10.3390/ijms232012095

36292946