Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells.
DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIalpha (Topo IIalpha) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIalpha is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIalpha-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIalpha inhibitors. Here we show that Metnase interacts with Topo IIalpha in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIalpha inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIalpha-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIalpha inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIalpha inhibitors, specifically in anthracycline-resistant breast cancer.
Wray
Justin
J
Division of Hematology-Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico, United States of America.
Williamson
Elizabeth A
EA
Royce
Melanie
M
Shaheen
Montaser
M
Beck
Brian D
BD
Lee
Suk-Hee
SH
Nickoloff
Jac A
JA
Hromas
Robert
R
D018943:Anthracyclines / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D059005:Topoisomerase II Inhibitors
D018943:Anthracyclines; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D004250:DNA Topoisomerases, Type II