Immunocytochemical detection of the p170 multidrug resistance (MDR) and the p53 tumor suppressor gene proteins in human breast cancer cells: Clinical and therapeutical significance

The phenomenon of multidrug resistance (MDR) is characterized by resistance to several unrelated cytotoxic agents, such as anthracyclines, vinca alkaloids and epipodophylline derivatives. MDR has been described frequently in human breast carcinoma (BC) as has the alteration of the 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 increased 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 which occurs in neoplastically transformed cells, results in ina-eased drug efflux and decreased intracellular drug concentration. The present immunocytochemical study was carried out on routine, formalin fixed paraffin-wax embedded, 3-4 mu m thick tissue sections of 15 breast carcinomas, treated at the University of Southern California. The immunoperoxidase antigen detection protocol, developed by Hsu et al (1981) was employed 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 contained large proportions of cells which displayed the characteristic transmembrane localized expression of p170. All 15 BCs were comprised of distinct groups of cells which accumulated p53 in their nucleus and occasionally 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 cases intense immunoreactivity, correlating with p170 overexpression was detected. The 15 BCs exhibited different staining patterns typical for each anti-p170 MoAB. MoAB JSB-1 reacted strongly with the transmembranic antigen epitope, as did MoAB C-494, the long incubation time employed with MoAB C-219, on the other hand, resulted in inhomogeneous cytoplasmic staining. Previous reports suggest a direct correlation between the presence of the p170 glycoprotein in human cancer cells and the poor response to chemotherapy. Furthermore, the genetic instability, which is the consequence of the loss of wild-type p53 function, may be the underlying property which allows highly malignant cells to amplify the mdr1 gene and thus become resistant to a wide spectrum of cytotoxic drugs.