E2F1 drives chemotherapeutic drug resistance via ABCG2

Rosenfeldt, M.T., Bell, L.A., Long, J.S., O'Prey, J., Nixon, C., Roberts, F., Dufès, C. and Ryan, K.M. (2014) E2F1 drives chemotherapeutic drug resistance via ABCG2. Oncogene, 33(32), pp. 4164-4172. (doi:10.1038/onc.2013.470)

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Abstract

Multidrug resistance is a major barrier against successful chemotherapy, and this has been shown in vitro to be often caused by ATP-binding cassette (ABC) transporters. These transporters are frequently overexpressed in human cancers and confer an adverse prognosis in many common malignancies. The genetic factors, however, that initiate their expression in cancer are largely unknown. Here we report that the major multidrug transporter ABCG2 (BCRP/MXR) is directly and specifically activated by the transcription factor E2F1—a factor perturbed in the majority of human cancers. E2F1 regulates ABCG2 expression in multiple cell systems, and, importantly, we have identified a significant correlation between elevated E2F1 and ABCG2 expression in human lung cancers. We show that E2F1 causes chemotherapeutic drug efflux both in vitro and in vivo via ABCG2. Furthermore, the E2F1–ABCG2 axis suppresses chemotherapy-induced cell death that can be restored by the inhibition of ABCG2. These findings therefore identify a new axis in multidrug resistance and highlight a radical new function of E2F1 that is relevant to tumor therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Long, Dr Jaclyn and Roberts, Dr Fiona and Ryan, Professor Kevin and Nixon, Mr Colin and Rosenfeldt, Dr Mathias and O'Prey, Mr James and Bell, Miss Laura
Authors: Rosenfeldt, M.T., Bell, L.A., Long, J.S., O'Prey, J., Nixon, C., Roberts, F., Dufès, C., and Ryan, K.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
Publisher:Nature Publishing Group
ISSN:0950-9232
ISSN (Online):1476-5594
Copyright Holders:Copyright © 2014 Macmillan Publishers Limited
First Published:First published in Oncogene 33(32):4164-4172
Publisher Policy:Reproduced under a Creative Commons License

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