Regulation of multidrug resistance genes in mammary tumours.

Intrinsic or acquired multidrug resistance is a major impediment to the successful treatment of cancer by chemotherapy. One biochemical mechanism by which such multidrug resistance may develop is via the overexpression of the membrane transport protein P-glycoprotein (P-gp). P-gp is coded for by the multidrug resistance (mdr) genes that constitute a small conserved gene family. These genes are separated into two classes. Only the class 1 genes can confer a multidrug resistance phenotype, and are often over-expressed in a variety of tumours. Breast cancer is the highest incident cancer amongst women in western society, where, despite radical surgery, about 35% patients die from this disease due to a failure of chemotherapy. Although an association of P-gp expression with a poor prognosis has been shown in clinical studies, the mechanism which results in P-gp expression in breast cancer is not known. In vitro, cells selected for a multidrug resistance phenotype, by high concentration anticancer drugs, often have an mdr gene amplification and increased gene transcription rate. However, this does not appear to be a general mechanism of increasing mdr expression in tumours. To date, there have been no studies that have investigated regulation of mdr genes in an in vivo model of mammary tumourigenesis. In this study, differential expression of mdr genes and P-gp was characterised in chemical (N-methyl-N-nitrosourea) induced rat mammary tumours. It was found that expression of the class 1 genes (mdr1a and mdr1b) were consistently increased in the tumours, with the mdr1b gene being most highly induced. The expression of P-gp was located in a minority of neoplastic epithelial cells, often on the epithelial / stroma interface and surrounding necrotic areas. Single epithelial cells that had invaded the stroma also expressed P-gp, suggesting a possible association with invasive potential. Increased mdr1b gene expression in rat mammary tumours was due to an increased gene transcription rate measured by a RT-PCR based nuclear run-on assay. A specific mammary tumour nuclear factor (MTNF) was found to bind to the mdr1b promoter upstream of the transcription initiation site. It is likely that MTNF is responsible for increased the mdr1b gene transcription in rat mammary tumours. The relevance of this factor in human breast cancer need to be further investigated.