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Ligand-Independent Activation of Arylhydrocarbon Receptor in Breast Cancer Cells

Strategic Insights

— 1 min read

Recent research from Sacramento, California, has shed light on the ligand-independent activation of the arylhydrocarbon receptor (AHR) in certain types of breast tumors. The study, led by Y. Fujisawa and colleagues at the University of California, discovered that estrogen receptor-negative, AHR overexpressing MCF10AT1 human breast cancer cells (designated P20E) showed functional activation of AHR when subjected to serum starvation. This activation was found to be mediated by the tyrosine kinase ETK (Bmx), which up-regulated cytochrome P4501a1 (CYP1A1), a marker of functional activation of AHR.

Key Takeaways:

  • The study found that AHR was functionally activated in estrogen receptor-negative, AHR overexpressing MCF10AT1 human breast cancer cells (P20E) when subjected to serum starvation.
  • The activation of AHR was found to be mediated by the tyrosine kinase ETK (Bmx), which up-regulated CYP1A1, a marker of functional activation of AHR.
  • ETK (Bmx) was identified as the tyrosine kinase responsible for the functional activation of the AHR in these mammary epithelial cells.
  • Artificial overexpression of ETK in P20E cells through transfection with wild-type ETK plasmid caused up-regulation of CYP1A1.
  • Ablation of ETK expression by a specific antisense oligonucleotide or AG879, a specific inhibitor of ETK kinase, suppressed activation of AHR induced by omeprazole.
  • Activation of ETK in those cells conferred them resistance to UVB- and doxorubicin-induced apoptosis, which was reversed by ETK-KQ.

Statistics:

  • 255,000 new cases of breast cancer were diagnosed in the United States in 2011 (Source: American Cancer Society).
  • 40,610 women died of breast cancer in the United States in 2011 (Source: American Cancer Society).
  • ETK (Bmx) tyrosine kinase is responsible for functional activation of AHR in MCF10AT1 breast cancer cells.
  • CYP1A1 is a marker of functional activation of AHR (Source: Biological Chemistry).
  • Omeprazole is a strong ligand-independent activator of AHR (Source: Biological Chemistry).
  • AG879 is a specific inhibitor of ETK kinase (Source: Biological Chemistry).

Sources:

  • Fujisawa Y., et al. (2011). Ligand-independent activation of the arylhydrocarbon receptor by ETK (Bmx) tyrosine kinase helps MCF10AT1 breast cancer cells to survive in an apoptosis-inducing environment. Biological Chemistry, 392(10), 897-908.
  • American Cancer Society. (2011). Breast Cancer Facts & Figures 2011-2012.
  • NewsRx.com. (2011). Gene Therapy Weekly.

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