title: Nuclear translocation of epidermal growth factor receptor by Akt-dependent phosphorylation enhances breast cancer-resistant protein expression in gefitinib-resistant cells.
abstract: Epidermal growth factor receptor (EGFR), an aberrantly overexpressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for non-small cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ABCG2 expression.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan. whuang@mail.cmu.edu.tw
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Wei
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Hsu
authors.forename: Shing-Ling
authors.initials: SL
authors.lastname: Tsai
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chiu
authors.forename: Wei-Pang
authors.initials: WP
authors.lastname: Huang
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Andy Jer-En
authors.initials: AJ
authors.lastname: Chen
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib