LEVELS OF MULTIDRUG-RESISTANCE (MDR1) P-GLYCOPROTEIN EXPRESSION BY HUMAN BREAST-CANCER CORRELATE WITH IN-VITRO RESISTANCE TO TAXOL AND DOXORUBICIN

To determine whether multidrug resistance (MDR1) P-glycoprotein (Pgp) expression correlated with clinical MDR1-related drug resistance, we e stablished a protocol for quantitative measurement of Pgp expression a nd in vitro drug resistance in doxorubicin resistant MCF7 breast cance r cell lines and 359 freshly resected specimens of breast carcinoma, P gp expression was detected with 4E3, UIC2, and JSB-1 monoclonal antibo dies using flow cytometry and immunohistochemistry (IHC). Pgp function was determined using PSC833 in a drug resistance-reversal assay and w ith a three-dimensional agarose-based extreme drug resistance assay, M CF7 calibrator cell lines expressed Pgp, which was functional and in p roportion to the degree of drug resistance, Flow cytometry, UIC2 shift assays, MC scores, and determination of absorbance products by image analysis were all highly correlated (r > 0.9), Overall Pgp expression increased from 11% in untreated patients to 30% in patients who had pr eviously received chemotherapy, Compared with Pgp-negative tumors, a s ignificant increase in doxorubicin and Taxol resistance was seen for b reast cancers that expressed Pgp, regardless of prior treatment, A str ong correlation between the degree of Pgp expression and in vitro resi stance to Taxol and doxorubicin (but not to 5-fluorouracil) was found when either IHC scores or image analysis-based methods were used to qu antify Pgp expression (n = 185, P < 0.0001), The degree of Pgp express ion strongly correlated with the degree of drug resistance in the clin ical specimens studied, These data suggest that (a) Pgp contributes to clinical MDR1-related drug resistance, and (b) both intrinsic and acq uired expression of Pgp in breast cancer may contribute in part to the rapeutic failure and relapse.