The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition.
We identified the ubiquitin-conjugating enzyme E2-EPF mRNA as differentially expressed in breast tumors relative to normal tissues and performed studies to elucidate its putative role in cancer. We demonstrated that overexpression of E2-EPF protein correlated with estrogen receptor (ER) negativity in breast cancer specimens and that its expression is cell cycle-regulated, suggesting a potential function for E2-EPF in cell cycle progression. However, reduction of E2-EPF protein levels by > 80% using RNAi had no significant effects on the proliferation of HeLa cervical cancer cells or ER(-) MDA-MB-231 or MDA-MB-453 breast cancer cells. Because E2-EPF protein levels were elevated during the G(2)/M phase of the cell cycle and because E2-EPF mRNA in tumor specimens was frequently coexpressed with genes involved in cell cycle control, spindle assembly, and mitotic surveillance, the possibility that E2-EPF might have a function in the cellular response to agents that induce a G(2) checkpoint or an M checkpoint was investigated. E2-EPF knockdown sensitized HeLa cells to the topoisomerase (topo) II inhibitors etoposide and doxorubicin and also increased topo IIalpha protein levels. These data suggest that combined administration of topo II-directed drugs and E2-EPF inhibitors may enhance their clinical effectiveness.
Tedesco
Donato
D
Department of Cancer Research, Berlex Biosciences, Richmond, CA 94804, USA.
Zhang
Jianhuan
J
Trinh
Lan
L
Lalehzadeh
Guita
G
Meisner
Rene
R
Yamaguchi
Ken D
KD
Ruderman
Daniel L
DL
Dinter
Harald
H
Zajchowski
Deborah A
DA
D001943:Breast Neoplasms / Q000201:enzymology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D015533:Transcriptional Activation; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; C544962:Ube2S protein, human; D044763:Ubiquitin-Conjugating Enzymes
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