ErbB receptor signaling and therapeutic resistance to aromatase inhibitors

Incheol Shin, Todd Miller, Carlos L. Arteaga, Steven Come, Mitch Dowsett, Kathleen Pritchard, Stephen Johnston, Myles Brown

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38 Scopus citations

Abstract

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. Cotreatment 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 ERα 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.

Original languageEnglish
Pages (from-to)1008s-1012s
JournalClinical Cancer Research
Volume12
Issue number3 II
DOIs
StatePublished - 2006 Feb 1

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    Shin, I., Miller, T., Arteaga, C. L., Come, S., Dowsett, M., Pritchard, K., Johnston, S., & Brown, M. (2006). ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. Clinical Cancer Research, 12(3 II), 1008s-1012s. https://doi.org/10.1158/1078-0432.CCR-05-2352