Intrinsic multidrug class 1 and 2 gene expression and localization in rat and human mammary tumors

Abstract

P-glycoproteins (P-gp), the protein products of the multidrug resistant (mdr) genes, are often overexpressed in tumors that are resistant to chemotherapy. In this study, we measured intrinsic (preexisting) mdr1a, -1b, and -2 gene expression in N-nitroso-N-methylurea-induced rat mammary tumors. Using immunohistochemistry and in situ hybridization, we determined the localization of mdr1b mRNA and P-gp. We compared these results with a similar morphologic analysis of untreated human breast carcinomas. The predominantly expressed member of the mdr gene family in normal rat mammary tissue was mdr2. In rat mammary tumors, mdr2 expression was only inconsistently and slightly increased (1.4-fold on average). In contrast, expression of the class 1 genes (mdr1a and mdr1b) were consistently increased to a much greater extent. The average increase of mdr1b gene expression was greater than that of mdr1a (on average, 12.9 compared with 2.4, respectively). This indicated a differential regulation of these two closely related genes in these tumors. Immunostaining and in situ analysis showed that mdr mRNA and P-gp were expressed in a minority of neoplastic epithelial cells located in defined areas of the tumor, often on the interface of the neoplastic epithelium and stroma. Single epithelial cells that had invaded the stroma also expressed P-gp. In human breast carcinomas, the patterns of mdr mRNA and P-gp expression were similar to those in rat N-nitroso-N-methylurea-induced mammary tumors.