Transcription factors and drug resistance Kimitoshi Kohno a, * , Takeshi Uchiumi a , Ichiro Niina a , Tetsuro Wakasugi a , Tomonori Igarashi a , Yasutomo Momii a , Takeshi Yoshida a , Ken-ichi Matsuo b , Naoya Miyamoto a , Hiroto Izumi a a Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka 807-8555, Japan b Hanno Research Center, Taiho Pharmaceutical Company Ltd., Hanno, Saitama 357-8527, Japan Available online 4 October 2005 Abstract Intrinsic or acquired resistance to anticancer agents is a major obstacle to the success of chemotherapy. Anticancer agents are known to modulate signal transduction pathways and alter expression of genes that play an important role in drug resistance. Emerging evidence suggests that the complexity of genomic response against anticancer agents arise from elaborate gene expression by multiple transcription factors. Here, we briefly describe the development of solid tumours and the appearance of drug-resistant cells. We also review what is known of the transcription factors that are involved in resistance to drugs, particularly cisplatin. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Transcription; DNA damage; Drug resistance; DNA repair; Cisplatin 1. Introduction The transcriptional regulation of gene expression requires the participation of a large and diverse collec- tion of nuclear factors, such as sequence-specific DNA-binding proteins, transcriptional cofactors, chro- matin-remodelling factors, modifying enzymes and basal transcription factors [1–3]. These factors interact in a complex fashion. Cancer is a genomic disease that is thought to arise from the accumulation of mutations leading to immortal cell proliferation. Either the activation of protooncoge- nes or the inactivation of tumour suppressor genes is responsible for this activity. Many protooncogenes and tumour-suppressor genes encode transcription-related factors and modulate cellular sensitivity to anticancer agents. However, little is known about those that affect responses to anticancer agents. Both intrinsic and acquired drug-resistance hinder the treatment of solid tumours. Anticancer agents activate a variety of signal transduction pathways and trigger genome-wide re- sponses. Transcription factors contribute to drug-in- duced responses and can induce either transient or acquired drug resistance. Molecular dissection of the functions of transcription factors allows the complexi- ties of solid tumour development and drug resistance to be elucidated. Our research has focused on factors affecting the sensitivity of solid tumours to anticancer agents. The post-genomic approach has enabled us to analyse the com- plexity of genetic responses to anticancer agents. This is likely to reflect the activity of transcriptional networks that control the expression of many different genes and depend on the combinatorial action of numerous tran- scription-related factors. Investigation of the interac- tions between factors that are activated in response to anticancer agents is therefore essential for understand- ing the complexity of the genomic response. Moreover, these factors and molecular interactions constitute potential targets for chemotherapy. It is well-known 0959-8049/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2005.08.007 * Corresponding author. Tel.: +81 93 691 7423; fax: +81 93 692 2766. E-mail address: k-kohno@med.uoeh-u.ac.jp (K. Kohno). www.ejconline.com European Journal of Cancer 41 (2005) 2577–2586 European Journal of Cancer