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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 (US)
JournalClinical Cancer Research
Volume12
Issue number3 II
DOIs
StatePublished - Feb 1 2006

Fingerprint

letrozole
Aromatase Inhibitors
Androstenedione
MCF-7 Cells
Estrogen Receptors
Estrogens
Ligands
Aromatase
Chromatin Immunoprecipitation
Genetic Promoter Regions
Therapeutics
Cell Proliferation
Breast Neoplasms
DNA
Genes
ErbB Receptors
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. / Shin, Incheol; Miller, Todd; Arteaga, Carlos L.; Come, Steven; Dowsett, Mitch; Pritchard, Kathleen; Johnston, Stephen; Brown, Myles.

In: Clinical Cancer Research, Vol. 12, No. 3 II, 01.02.2006.

Research output: Contribution to journalArticle

Shin, I, Miller, T, Arteaga, CL, Come, S, Dowsett, M, Pritchard, K, Johnston, S & Brown, M 2006, 'ErbB receptor signaling and therapeutic resistance to aromatase inhibitors', Clinical Cancer Research, vol. 12, no. 3 II. https://doi.org/10.1158/1078-0432.CCR-05-2352
Shin, Incheol ; Miller, Todd ; Arteaga, Carlos L. ; Come, Steven ; Dowsett, Mitch ; Pritchard, Kathleen ; Johnston, Stephen ; Brown, Myles. / ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 3 II.
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