ErbB receptor signaling and therapeutic resistance to aromatase inhibitors.
We have investigated the effect of HER-2 overexpression on resistance to the aromatase inhibitor letrozole in MCF-7 breast cancer cells stably expressing cellular aromatase (MCF-7/CA). MCF-7/CA cells overexpressing HER-2 showed a >2-fold increase in estrogen receptor (ER)-mediated transcriptional reporter activity upon treatment with androstenedione compared with vector-only control MCF-7/CA cells. Co-treatment with letrozole did not abrogate androstenedione-induced transcription and cell proliferation in HER-2-overexpressing cells. Chromatin immunoprecipitation assays using cross-linked protein-DNA from MCF-7/CA/HER-2 cells indicated ligand-independent association of the ERalpha coactivators AIB-1 and CBP to the promoter region of the estrogen-responsive pS2 gene. Upon treatment with androstenedione, there were increased associations of AIB1 and CBP with the pS2 promoter in the HER-2-overexpressing compared with control MCF-7/CA cells. These results suggest that ligand-independent recruitment of coactivator complexes to estrogen-responsive promoters as a result of HER-2 overexpression may play a role in the development of letrozole resistance.
Shin
Incheol
I
Department of Cancer Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, USA.
Miller
Todd
T
Arteaga
Carlos L
CL
D000123:Acetyltransferases / Q000187:drug effects / Q000378:metabolism; D000735:Androstenedione / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003345:Corticosterone; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D051548:Histone Acetyltransferases; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000494:pharmacology; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
D000123:Acetyltransferases; D000735:Androstenedione; D047072:Aromatase Inhibitors; D002352:Carrier Proteins; D003345:Corticosterone; D051548:Histone Acetyltransferases; D000077289:Letrozole; D009570:Nitriles; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014230:Triazoles; C538866:NCOA3 protein, human