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

Mol Biol Rep. 2012 May;39(5):5465-71. doi: 10.1007/s11033-011-1347-4. Epub 2011 Dec 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Drug Resistance, Multiple* / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • ErbB Receptors / metabolism*
  • Female
  • G1 Phase* / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • S Phase* / drug effects
  • Up-Regulation / drug effects

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • CCND1 protein, human
  • Neoplasm Proteins
  • RNA, Messenger
  • Cyclin D1
  • EGFR protein, human
  • ErbB Receptors
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4