Overexpression of both p185c-erbB2 and p170mdr-1 renders breast cancer cells highly resistant to taxol.
We recently found that overexpression of p185c-erbB2 in c-erbB2 transfected MDA-MB-435 breast cancer cells (435.eB transfectants) confers a 5-9-fold increase in Taxol resistance. To examine whether Taxol resistance is a common phenomenon in other c-erbB2 overexpressing breast cancer cell lines, we tested a panel of human breast cancer cell lines established from different patients and expressing pl85c-erbB2 at different levels for their sensitivity to Taxol and Taxotere, a synthetic taxoid. Higher expression of p185c-erbB2 in these breast cancer cell lines indeed correlated well with resistance to Taxol and Taxotere, and the degree of resistance was about 100-fold that in c-erbB2-overexpressing 435.eB transfectants, demonstrating that these breast cancer cells are highly resistant to Taxol. Since mdr-1-encoded p-glycoprotein (p170mdr-1) has been implicated in Taxol resistance, we next examined the p170mdr-1 levels in these breast cancer cell lines that are highly resistant to Taxol. Higher levels of p170mdr-1 expression were found in several breast cancer cell lines that are highly resistant to Taxol. Since these same breast cancer cell lines also expressed higher levels of p185c-erbB2, we sought to determine the relative contribution of p185c-erbB2 and p170mdr-1 overexpression to Taxol resistance. We first specifically down-regulated cell surface p185c-erbB2 using anti-p185c-erbB2 monoclonal antibodies and assayed sensitivity of these cells to Taxol. We next specifically inactivated p170mdr-1 function using p170mdr-1 blockers (thioridazine or verapamil) and again assayed Taxol sensitivity. Both p185c-erbB2 down-regulation and p170mdr-1 blockade significantly sensitized the breast cancer cell lines to Taxol. The results indicate that overexpression of either p185c-erbB2 or p170mdr-1 renders human breast cancer cells resistant to Taxol. Furthermore, p185c-erbB2 synergizes with p170mdr-1 conferring higher degrees of Taxol resistance. Finally, combination therapy (down-regulation of p185c-erbB2 plus blocking p170mdr-1 plus administration of Taxol) may be beneficial to breast cancer patients whose tumors express high levels of both p185c-erbB2 and p170mdr-1.
Yu
D
D
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Liu
B
B
Jing
T
T
Sun
D
D
Price
J E
JE
Singletary
S E
SE
Ibrahim
N
N
Hortobagyi
G N
GN
Hung
M C
MC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids