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COUP-TFII inhibits NFkappaB activation in endocrine-resistant breast cancer cells

Lacey M Litchfield1, Savitri N Appana2, Susmita Datta2

  • 1Department of Biochemistry & Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.

Molecular and Cellular Endocrinology
|October 22, 2013
PubMed

Insights

Reduced COUP-TFII expression promotes endocrine resistance in breast cancer by increasing nuclear factor kappa B (NFκB) activity. Restoring COUP-TFII suppresses NFκB, offering a potential therapeutic target for endocrine-resistant breast cancer.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Endocrine resistance is a major challenge in breast cancer treatment.
  • Nuclear factor kappa B (NFκB) signaling is implicated in endocrine resistance.
  • The role of COUP-TFII in endocrine resistance and NFκB regulation is unclear.

Purpose of the Study:

  • To investigate the role of COUP-TFII in modulating NFκB activity in breast cancer.
  • To determine if COUP-TFII expression is inversely correlated with NFκB activity in endocrine-resistant cells and patient samples.

Main Methods:

  • Comparison of NFκB activity in endocrine-sensitive (MCF-7) and resistant (LCC9) breast cancer cells.
  • Overexpression of COUP-TFII in LCC9 cells via transient transfection.
  • Co-immunoprecipitation assays to assess protein-protein interactions between COUP-TFII and NFκB subunits.
  • In vitro assays to evaluate NFκB DNA binding and transactivation.

Main Results:

  • Endocrine-resistant LCC9 cells exhibit significantly higher basal NFκB activity compared to MCF-7 cells.
  • Overexpression of COUP-TFII in LCC9 cells suppressed NFκB activation and target gene expression.
  • COUP-TFII and NFκB showed an inverse correlation in breast cancer patient samples.
  • COUP-TFII directly interacted with NFκB subunits (RelB, NFκB1) and inhibited NFκB DNA binding and transactivation.

Conclusions:

  • COUP-TFII acts as a novel suppressor of NFκB activity in breast cancer.
  • Reduced COUP-TFII expression contributes to endocrine resistance by enhancing NFκB signaling.
  • Targeting COUP-TFII or NFκB may represent a therapeutic strategy for endocrine-resistant breast cancer.
Keywords:
4-OHT4-hydroxytamoxifenA20/TNFAIP3AntiestrogensCOUP-TFIIDrug resistanceERαICAM1IL6NFκB/NFkappa BNuclear receptorsRESERDSERMTAMTNFαTNFα-induced protein 3TamoxifenTranscription factorschicken ovalbumin upstream promoter transcription factor IIestrogen receptorintercellular adhesion molecule 1interleukin 6 (IL6)nuclear factor κBqPCRquantitative real-time PCRresponse elementselective estrogen receptor downregulatorselective estrogen receptor modulatortamoxifentumor necrosis factor

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