IMMUNOCYTOCHEMICAL DETECTION OF THE P170 MULTIDRUG-RESISTANCE (MDR) AND THE P53 TUMOR-SUPPRESSOR GENE PROTEINS IN HUMAN BREAST-CANCER CELLS- CLINICAL AND THERAPEUTIC SIGNIFICANCE

The phenomenon of multidrug resistance (MDR) is characterized by resis tance to several unrelated cytotoxic agents, such as anthracyclines, v inca alkaloids and epipodophylline derivatives. MDR has been described frequently in human breast carcinoma (BC) as has the alteration of th e p53 gene, responsible for ensuring the integrity of the genome. The most well known type of MDR is associated with the overexpression of a 170kD glycoprotein (p170). This mechanism of MDR is the result of inc reased transcription of the mdr1 gene. The p170 glycoprotein in normal cells with excretory functions is a permanent component of a membrane transport system and an increase in its expression, such as that whic h occurs in neoplastically transformed cells, results in ina-eased dru g efflux and decreased intracellular drug concentration. The present i mmunocytochemical study was carried out on routine, formalin fixed par affin-wax embedded, 3-4 mu m thick tissue sections of 15 breast carcin omas, treated at the University of Southern California. The immunopero xidase antigen detection protocol, developed by Hsu et al (1981) was e mployed using three anti-p170 monoclonal antibodies (MoABs), JSB-1, C- 219 and C-494 (Signet Laboratories, Dedham, MA, USA), and the anti-p53 MoAB PAb1801 (NeoMarkers, Inc., Fremont, CA, USA). 14/15 BCs containe d large proportions of cells which displayed the characteristic transm embrane localized expression of p170. All 15 BCs were comprised of dis tinct groups of cells which accumulated p53 in their nucleus and occas ionally in their cytoplasm. A distinct, heterogeneous immunophenotype (IF) of the cells comprising the tumor microenvironment and different grades of neoplastic differentiation was also observed In 5/15 BC case s intense immunoreactivity, correlating with p170 overexpression was d etected. The 15 BCs exhibited different staining patterns typical for each anti-p170 MoAB. MoAB JSB-1 reacted strongly with the transmembran ic antigen epitope, as did MoAB C-494, the long incubation time employ ed with MoAB C-219, on the other hand, resulted in inhomogeneous cytop lasmic staining. Previous reports suggest a direct correlation between the presence of the p170 glycoprotein in human cancer cells and the p oor response to chemotherapy. Furthermore, the genetic instability, wh ich is the consequence of the loss of wild-type p53 function, may be t he underlying property which allows highly malignant cells to amplify the mdr1 gene and thus become resistant to a wide spectrum of cytotoxi c drugs.