The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells

Kanae Bekki, Helena Vogel, Wen Li, Tomohiro Ito, Colleen A Sweeney, Thomas Haarmann-Stemmann, Fumio Matsumura, Christoph F A Vogel

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR) is well known as a ligand binding transcription factor regulating various biological effects. Previously we have shown that long-term exposure to estrogen in breast cancer cells caused not only down regulation of estrogen receptor (ER) but also overexpression of AhR. The AhR interacts with several cell signaling pathways associated with induction of tyrosine kinases, cytokines and growth factors which may support the survival roles of AhR escaping from apoptosis elicited by a variety of apoptosis inducing agents in breast cancer. In this study, we studied the anti-apoptotic role of AhR in different breast cancer cells when apoptosis was induced by exposure to UV light and chemotherapeutic agents. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-. p-dioxin (TCDD) in AhR overexpressing breast cancer cells effectively suppressed the apoptotic response induced by UV-irradiation, doxorubicin, lapatinib and paclitaxel. The anti-apoptotic response of TCDD was uniformly antagonized by the treatment with 3'methoxy-4'nitroflavone (MNF), a specific antagonist of AhR. TCDD's survival action of apoptosis was accompanied with the induction of well-known inflammatory genes, such as cyclooxygenase-2 (COX-2) and NF-κB subunit RelB. Moreover, TCDD increased the activity of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine (Kyn) and mediates tumor immunity. Kyn also acts as an AhR ligand like TCDD, and kyn induced an anti-apoptotic response in breast cancer cells. Accordingly, our present study suggests that AhR plays a pivotal role in the development of breast cancer via the suppression of apoptosis, and provides an idea that the use of AhR antagonists with chemotherapeutic agents may effectively synergize the elimination of breast cancer cells.

Original languageEnglish (US)
Pages (from-to)5-13
Number of pages9
JournalPesticide Biochemistry and Physiology
Volume120
DOIs
StatePublished - May 1 2015

Keywords

  • AhR
  • Apoptosis
  • Breast cancer
  • IDO
  • NF-κB
  • TCDD

ASJC Scopus subject areas

  • Agronomy and Crop Science
  • Health, Toxicology and Mutagenesis

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