NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen

Ann Oncol. 2004 Jun;15(6):885-90. doi: 10.1093/annonc/mdh232.


Studies show that high Akt activity in breast carcinoma is associated with endocrine therapy resistance. Breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions, and are resistant to the growth inhibitory effects of tamoxifen. Understanding the targets of Akt signaling mediating tamoxifen resistance is of clinical significance. One possible target is nuclear factor kappa B (NF-kappa B), a transcription factor that plays a critical role in resistance to apoptosis and the induction of angiogenesis and invasion. In the present study, we found that Akt activity correlated with phosphorylation of I kappa B (the negative regulator of NF-kappa B), NF-kappa B DNA binding and tamoxifen resistance in vivo. Importantly, we found that co-treatment with the NF-kappa B inhibitor, parthenolide, or overexpression of I kappa B superrepressor restored tamoxifen sensitivity to our refractory Akt MCF-7 cells. These data suggest that activation of NF-kappa B via the PI3K/Akt signaling pathway may be a significant mechanism for development of endocrine therapy resistance in breast cancer, and that inhibition of NF-kappa B may be an effective treatment strategy to limit the progression of this disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • I-kappa B Proteins / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Sesquiterpenes / pharmacology
  • Signal Transduction
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • I-kappa B Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Sesquiterpenes
  • Tamoxifen
  • parthenolide
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt