Nature, 2008-12, Vol.456 (7222), p.663-666
2008
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- Autor(en) / Beteiligte
- Titel
- Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen
- Ist Teil von
- Nature, 2008-12, Vol.456 (7222), p.663-666
- Ort / Verlag
- London: Nature Publishing Group
- Erscheinungsjahr
- 2008
- Quelle
- Psychology & Behavioral Sciences Collection
- Beschreibungen/Notizen
- Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response, yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product (PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti-cancer drug tamoxifen. We show that PAX2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2-positive tumours can originate from ER-positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687, 1476-4679DOI: 10.1038/nature07483Titel-ID: cdi_proquest_miscellaneous_19568116
- Format
- –
- Schlagworte
- Antineoplastic agents, Binding sites, Biological and medical sciences, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - genetics, Breast Neoplasms - pathology, Cancer, Care and treatment, Cell growth, Cell Line, Cell Line, Tumor, Cells, Chromatin Immunoprecipitation, Competition, Dosage and administration, Drug Resistance, Neoplasm - genetics, Drug therapy, Estrogen, Estrogens - metabolism, Gene Expression Regulation, Neoplastic - drug effects, Gene Silencing, General aspects, Genes, erbB-2 - genetics, Genetic aspects, Gynecology. Andrology. Obstetrics, Health aspects, Histone Acetyltransferases, Humans, Mammary gland diseases, Medical sciences, Nuclear Receptor Coactivator 3, Oncogenes, Oncology, Experimental, PAX2 Transcription Factor - deficiency, PAX2 Transcription Factor - genetics, PAX2 Transcription Factor - metabolism, Pharmacology. Drug treatments, Physiological aspects, Proteins, Receptor, ErbB-2 - genetics, Receptors, Receptors, Estrogen - metabolism, Regression analysis, Regulatory Sequences, Nucleic Acid - genetics, Repressor Proteins - metabolism, RNA polymerase, Tamoxifen, Tamoxifen - metabolism, Tamoxifen - pharmacology, Trans-Activators, Tumors