OVEREXPRESSION OF BOTH P185(C-ERBB2) AND P170(MDR-1) RENDERS BREAST-CANCER CELLS HIGHLY RESISTANT TO TAXOL

We recently found that overexpression of p185(c-erbB2) in c-erbB2 tran sfected MDA-MB-435 breast cancer cells (435.eB transfectants) confers a 5-9-fold increase in Taxol resistance. To examine whether Taxol resi stance is a common phenomenon in other c-erbB2 overexpressing breast c ancer cell lines, we tested a panel of human breast cancer cell lines established from different patients and expressing p185(c-erbB2) at di fferent levels for their sensitivity to Taxol and Taxotere, a syntheti c taxoid. Higher expression of p185(c-erbB2) in these breast cancer ce ll Lines indeed correlated well with resistance to Taxol and Taxotere, and the degree of resistance was about 100-fold that in c-erbB2-overe xpressing 435.eB transfectants, demonstrating that these breast cancer cells are highly resistant to Taxol, Since mdr-1-encoded p-glycoprote in (p170(mdr-1)) has been implicated in Taxol resistance, we next exam ined the p170(mdr-1) levels in these breast cancer cell lines that are highly resistant to Taxol, Higher levels of p170(mdr-1) expression we re found in several breast cancer cell lines that are highly resistant to Taxol, Since these same breast cancer cell lines also expressed hi gher levels of p185(c-erbB2), we sought to determine the relative cont ribution of p185(c-erbB2) and p170(mdr-1) overexpression to Taxol resi stance. We first specifically down-regulated cell surface p185(c-erbB2 ) using anti-p185(c-erbB2) monoclonal antibodies and assayed sensitivi ty of these cells to Taxol, We next specifically inactivated p170(mdr- 1) function using p170(mdr-1) blockers (thioridazine or verapamil) and again assayed Taxol sensitivity. Both p185(c-erbB2) down-regulation a nd p170(mdr-1) blockade significantly sensitized the breast cancer cel l lines to Taxol, The results indicate that overexpression of either p 185(c-erbB2) or p170(mdr-1) renders human breast cancer cells resistan t to Taxol. Furthermore, p185(c-erbB2) synergizes with p170(mdr-1) con ferring higher degrees of Taxol resistance. Finally, combination thera py (down-regulation of p185(c-erbB2) plus blocking p170(mdr-1) plus ad ministration of Taxol) may be beneficial to breast cancer patients who se tumors express high levels of both p185(c-erbB2) and p170(mdr-1).