C-MYC Correlates with Expression of Multidrug Transporters ABCC1 and ABCC4.

Abstract C-MYC is an oncogene with protean effects and there is some speculation that aberrant overexpression in cancer may be associated with drug resistance by increased expression of the Multi-Drug Resistance Transporters, for example ABCC4 (MRP4) and ABCC1 (MRP1). A relationship between N-MYC and these transporters has been established in the limited context of childhood neuroblastoma and it would be tantalising to extrapolate this to the wider scope of adult tumours. The corollory would be that modulating the levels of C-MYC might have a beneficial secondary effect of making a tumour more sensitive to chemotherapeutic treatments. We have determined that the ABCC4 promoter directly responds in vitro to C-MYC and N-MYC contransfection and that this effect can be abolished by the progressive disruption of the C-MYC binding sites i.e. mutation of the E-boxes. Transient or stable overexpression of C-MYC or N-MYC did not increase multidrug transporter protein expression in 5 tumour cell lines, possibly due to the methylation status of the E-boxes or that the transporters present are already maximally expressed. However, knocking-down C-MYC by shRNA results in a concomitant reduction in ABCC1 and ABCC4. Together, these results suggest both direct and indirect regulation may be important in the functional control of these transporters. A survey was performed of Chronic Myeloid Leukaemias (CML, n=26) and Myelomas (n=23), assessing the expression of C-MYC, ABCC4 and ABCC1 by quantitative RT-PCR. The genes of interest were normalised to housekeeping genes and linear regression applied to examine the relationship of C-MYC levels to transporter expression. In CML, a direct relationship was seen between C-MYC and both ABCC4 and ABCC1. In Myeloma, a correlation was noted between C-MYC and ABCC1 but was not seen with ABCC4, as the levels detected were very low. The inference is that high levels of C-MYC may be associated with elevated multidrug transporter levels in other tumours and may be of use in predicting transporter-mediated drug resistance.