Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB-231 human breast cancer cell line

Gennifer D. Goode, Billy R. Ballard, H. Charles Manning, Michael L. Freeman, Yibin Kang, Sakina E. Eltom

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that belongs to the basic-helix-loop-helix (bHLH)-Per-ARNT-Sim (PAS) superfamily of transcription factors, mediates toxic response induced by environmental chemicals such as polycyclic aromatic hydrocarbons (PAH). AhR is expressed at high levels in several human breast carcinoma cell lines in direct correlation with the degree of their malignancy. Recent studies suggest a possible role for AhR in cancer independent of PAH. Therefore, we established stable AhR knockdown cells of the human breast cancer cell line MDA-MB-231 and analyzed their tumorigenic properties in in vitro and in vivo model systems. In addition we analyzed their response to radiation and chemotherapeutic treatment. AhR knockdown attenuated these cells tumorigenic properties in vitro including proliferation, anchorage independent growth, migration and apoptosis and reduced orthotopic xenograft tumor growth and lung metastasis in vivo. Notably, we observed that AhR knockdown enhanced radiation-induced apoptosis as well as significantly decreased cell clonogenic survival. Furthermore, AhR knockdown in MDA-MB-231 cells sensitized them to paclitaxel treatment, evident by a decrease in the required cytotoxic dose. Subsequent analysis revealed AhR knockdown significantly reduced phosphorylation of AKT, which impacts cell proliferation and survival. Apoptosis-focused gene expression analyses revealed an altered expression of genes regulating apoptosis in MDA-MB-231 cells. Collectively, our data identify AhR as a potential novel therapeutic target in the treatment of metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)2769-2780
Number of pages12
JournalInternational Journal of Cancer
Volume133
Issue number12
DOIs
StatePublished - Dec 15 2013

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Aryl Hydrocarbon Receptors
Breast Neoplasms
Neoplasm Metastasis
Cell Line
Growth
Neoplasms
Apoptosis
Polycyclic Aromatic Hydrocarbons
Cell Survival
Transcription Factors
Radiation
Gene Expression
Poisons
Paclitaxel
Heterografts
Phosphorylation
Cell Proliferation
Ligands
Lung

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Goode, Gennifer D. ; Ballard, Billy R. ; Manning, H. Charles ; Freeman, Michael L. ; Kang, Yibin ; Eltom, Sakina E. / Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB-231 human breast cancer cell line. In: International Journal of Cancer. 2013 ; Vol. 133, No. 12. pp. 2769-2780.
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Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB-231 human breast cancer cell line. / Goode, Gennifer D.; Ballard, Billy R.; Manning, H. Charles; Freeman, Michael L.; Kang, Yibin; Eltom, Sakina E.

In: International Journal of Cancer, Vol. 133, No. 12, 15.12.2013, p. 2769-2780.

Research output: Contribution to journalArticle

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