Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells

Int J Oncol. 2008 Mar;32(3):683-8.


The combination of trastuzumab with paclitaxel (PTX) is an important option for the treatment of HER2-positive breast cancer. Dexamethasone (Dex) premedication is routinely used in the treatment with PTX. The interactions among Dex, PTX and trastuzumab were evaluated in BT-474 cells. Dex interfered with trastuzumab-induced cell growth inhibition without clear effects on PTX-induced cytotoxicity. Trastuzumab dephosphorylated retinoblastoma protein (pRB). Dex restored this trastuzumab-induced dephosphorylation of pRB and released trastuzumab-induced G1 arrest. Trastuzumab suppressed AKT activity without affecting ERK activity. A specific inhibitor for the phosphatidylinositol 3-kinase/AKT pathway, LY294002, inhibited cell growth and AKT and pRB phosphorylation. Dex restored the trastuzumab-induced suppression of AKT without affecting ERK activity. It was concluded that Dex interferes with trastuzumab-induced cell growth inhibition, at least partially, through the restoration of trastuzumab-induced AKT suppression and subsequent pRB dephosphorylation in BT-474 breast cancer cells. These observations support the development of new chemotherapeutic regimens without glucocorticoid premedication.

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / antagonists & inhibitors
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Dexamethasone / adverse effects
  • Dexamethasone / pharmacology*
  • Down-Regulation / drug effects
  • Drug Combinations
  • Drug Evaluation, Preclinical
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Oncogene Protein v-akt / metabolism*
  • Oncogene Protein v-akt / physiology
  • Paclitaxel / pharmacology
  • Phosphorylation / drug effects
  • Trastuzumab
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Drug Combinations
  • Dexamethasone
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Trastuzumab
  • Paclitaxel