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Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen [Letter]

Hurtado, Antoni, Holmes, Kelly A., Geistlinger, Timothy R., Hutcheson, Iain Robert, Nicholson, Robert Ian, Brown, Myles, Jiang, Jie, Howat, William J., Ali, Simak and Carroll, Jason S. 2008. Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen [Letter]. Nature 456 (7222) , pp. 663-666. 10.1038/nature07483

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Abstract

Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response1, 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: Nature Publishing Group
ISSN: 0028-0836
Last Modified: 04 Jun 2017 04:52
URI: http://orca-mwe.cf.ac.uk/id/eprint/46005

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