ErbB receptor signaling and therapeutic resistance to aromatase inhibitors.

Shin I, Miller T, Arteaga CL
Clin Cancer Res. 2006 12 (3 Pt 2): 1008s-1012s

PMID: 16467117 · DOI:10.1158/1078-0432.CCR-05-2352

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.

MeSH Terms (22)

Acetyltransferases Androstenedione Aromatase Inhibitors Breast Neoplasms Carrier Proteins Cell Line, Tumor Corticosterone Drug Resistance, Neoplasm Female Histone Acetyltransferases Humans Letrozole Nitriles Nuclear Receptor Coactivator 3 Oncogene Proteins Promoter Regions, Genetic Receptor, ErbB-2 Receptors, Estrogen Signal Transduction Trans-Activators Transcriptional Activation Triazoles

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