EGFR-mediated G1/S transition contributes to the multidrug resistance in breast cancer cells

• DOI: 10.1007/s11033-011-1347-4
• Publication Date: 2011-12-16T05:21:47Z
• Authors: Shu-Jun Chen; Jing Luan; Hai-Shi Zhang; Can-Ping Ruan; Xin-Yun Xu; Qing-Quan Li; Nian-Hong Wang
• Keywords: G1 Phase; Cyclin-Dependent Kinase 4; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Multiple; Neoplasm Proteins; S Phase; Up-Regulation; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Inhibitory Concentration 50; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Drug Resistance, Neoplasm; Cell Line, Tumor; ATP Binding Cassette Transporter, Subfamily G, Member 2; Humans; ATP-Binding Cassette Transporters; Cyclin D1; Female; RNA, Messenger

Despite the improvement of strategies against cancer therapy, the multidrug resistance (MDR)is the critical problem for successful cancer therapy. Recurrent cancers after initial treatment with chemotherapy are generally refractory to second treatments with these anticancer therapies. Therefore, it is necessary to elucidate the therapy-resistant mechanism for development of effective therapeutic modalities against tumors. Here we demonstrate a phase-specific chemotherapy resistance due to epidermal growth factor receptor (EGFR) in human breast cancer cells. Thymidine-induced G1-arrested cultures showed upregulated chemosensitivity, whereas S-phase arrested cells were more resistant to chemotherapeutic agents. Overexpression of EGFR promoted the MDR phenotypes in breast cancer cells via accelerating the G1/S phase transition, whereas depletion of EGFR exerted the opposite effects. Furthermore, CyclinD1, a protein related to cell cycle, was demonstrated to be involved in above EGFR-mediated effects since EGFR increased the expression of CyclinD1, and the specific RNA interference against CyclinD1 could primarily abolish the EGFR-induced MDR phenotypes. These data provide new insights into the mode by which MDR breast cancers evade cytoxic attacks from chemotherapeutic agents and also suggest a role for EGFR-CyclinD1 axis in this process.