Suppression of c-myc expression and c-Myc function in response to sustained DNA damage in MCF-7 breast tumor cells

Kj. Magnet et al., Suppression of c-myc expression and c-Myc function in response to sustained DNA damage in MCF-7 breast tumor cells, BIOCH PHARM, 62(5), 2001, pp. 593-602
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
0006-2952 → ACNP
Year of publication
593 - 602
SICI code
The topoisomerase II inhibitors teniposide (VM-26), doxorubicin, and amsacr ine (m-AMSA), as well as ionizing radiation, induce a transient suppression of c-myc mRNA, which correlates with growth inhibition of MCF-7 breast tum or cells. To further assess the involvement of c-myc in the DNA damage-indu ced signal transduction pathways of the breast tumor cell, we determined th e influence of sustained DNA damage on c-myc expression, c-Myc protein leve ls and c-Myc function. Continuous exposure of MCF-7 breast tumor cells to V M-26 induced DNA strand breaks that were sustained for at least 9 hr. DNA s trand breakage was accompanied by a decline in c-myc transcripts and c-Myc protein levels by >90% after VM-26 exposure for 24 hr. The activity of a tr anscriptional target of the c-Myc protein, ornithine decarboxylase, was red uced by approximately 75% within 9 hr of DNA damage, in parallel to the dec lines in c-myc mRNA and protein levels. Extended exposure to VM-26 resulted in an initial loss of approximately 35% of the cell population followed by the death of additional cells such that by 72 hr only 50% of the cells wer e viable. Although apoptosis was evident 72 hr after initiating drug exposu re [based on cell cycle analysis, terminal deoxynucleotidyl transferase-med iated dUTP nick end-labeling (TUNEL) assays, and an assessment of cell morp hology], the primary phase of cell killing, which occurred during the first 24 hr was non-apoptotic. These studies indicate that non-apoptotic, pathwa ys can also mediate cell death in the breast tumor cell and support the rol e of c-myc expression, c-Myc protein, and c-Myc function as elements of the DNA damage response pathway in the breast tumor cell. (C) 2001 Elsevier Sc ience Inc. All rights reserved.