Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms

Oncogene. 1996 Sep 19;13(6):1359-65.


It has been reported that breast tumors that overexpress c-erbB-2/neu are less responsive to certain adjuvant chemotherapy regimens than those that express a normal amount of the gene product. To investigate whether overexpression of the c-erbB-2/neu-encoded p185 can indeed lead to increased chemoresistance in breast cancers, we introduced the human c-erbB-2/neu gene into the very low p185-expressing MDA-MB435 human breast cancer cells and examined Taxol sensitivities among the parental MDA-MB-435 cells and stable transfectants which express increased levels of p185. The p185-overexpressing MDA-MB-435 transfectants were more resistant to Taxol than the parental cells. The increased Taxol resistance was not accompanied by changes in doubling time and S-phase fraction. The increased Taxol resistance was independent from oncogenic transformation since it was observed only in c-erbB-2/neu-transformed cells and not ras-transformed cells when oncogene-transformed NIH3T3 cells were examined. To study whether p185 induced Taxol resistance through the mdr-1 pathway, we examined the mdr-l-encoded p170 levels in these transfectants. The MDA-MB-435 cells expressed very low levels of p170 and there was no increase of p170 expression in the p185-overexpressing MDA-MB-435 transfectants. Furthermore, these transfectants were not sensitized to Taxol treatment by mdr-1 blocker thioradazine. These data demonstrated that overexpression of c-erbB-2/neu can lead to intrinsic Taxol resistance independent from mdr-1 mechanisms.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Cell Cycle / physiology
  • Cell Transformation, Neoplastic
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Neoplasm
  • Humans
  • Paclitaxel / pharmacology*
  • Receptor, ErbB-2 / biosynthesis*
  • Transfection
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Receptor, ErbB-2
  • Paclitaxel