The Ubiquitin-Conjugating Enzyme E2-EPF Is Overexpressed in Primary Breast Cancer and Modulates Sensitivity to Topoisomerase II Inhibition

• Main Authors: Donato Tedesco, Jianhuan Zhang, Lan Trinht, Guita Lalehzadeh, Rene Meisner, Ken D. Yamaguchi, Daniel L. Ruderman, Harald Dinter, Deborah A. Zajchowski
• Format: Article
• Language: English
• Published: Elsevier 2007-07-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: E2-EPF; etoposide; doxorubicin; topoisomerase II; breast cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558607800856
• ISSN: 1476-5586; 1522-8002

We identified the ubiquitin-conjugating enzyme E2EPF 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 cycleregulated, suggesting a potential function for E2-EPF in cell cycle progression. However, reduction of E2EPF 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 G2/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 G2 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 IIα protein levels. These data suggest that combined administration of topo II-directed drugs and E2-EPF inhibitors may enhance their clinical effectiveness.