TRANSCRIPTIONAL DOWN-REGULATION OF C-MYC EXPRESSION IN THE MCF-7 BREAST-TUMOR CELL-LINE BY THE TOPOISOMERASE-II INHIBITOR, VM-26

In the MCF-7 human breast tumor cell line, the topoisomerase II inhibi tor, VM-26, produces a concentration dependent reduction in expression of the oncogene c-myc which parallels growth inhibition. Down-regulat ion of c-myc expression was examined at transcriptional and post-trans criptional levels. VM-26, at 10 mu M, produced a reduction in the tran scription rate of both sense and antisense strands of c-myc as determi ned by nuclear run-off analysis. In contrast, in the presence of the R NA synthesis inhibitor, actinomycin D, VM-26 failed to alter the half- life of the c-myc message. The capacity of VM-26 to reduce c-myc expre ssion was not abrogated in cells pretreated with the protein synthesis inhibitor, cycloheximide (despite superinduction of c-myc expression in both control and VM-26 treated cells); this observation suggests th at de novo protein synthesis may not be required to mediate the effect s of VM-26 on steady state c-myc transcript levels. An extended analys is of the time course of c-myc expression demonstrated that the declin e of steady state c-myc mRNA levels induced by VM-26 was biphasic. 6 h after the initial reduction in c-myc expression to approx. 30% of con trol levels, c-myc levels rebounded to 70% of control; after 74 h, c-m yc expression declined gradually and remained at depressed levels (40% of control) at 48 and 72 h. These observations suggest that the initi al transient reduction in c-myc expression associated with inhibition of transcription may represent a component of an early signalling path way leading to growth arrest in MCF-7 breast tumor cells exposed to VM -26.