Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms.
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.
Yu
D
D
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Liu
B
B
Tan
M
M
Li
J
J
Wang
S S
SS
Hung
M C
MC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D014162:Transfection; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases