Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifen

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Abstract
Tamoxifen is commonly used for breast cancer therapy, but a proportion of patients become resistant to the treatment, and their cancer is more likely to return. A study of the relationship between the oestrogen receptor and ERBB2/HER-2 pathways in breast cancer throws light on the mechanism of tamoxifen action and on the basis of tamoxifen-resistance. The new work shows that Pax2 is required for active repression of ErbB2 in breast cancer and that reduction of Pax2 causes ErbB2-driven tamoxifen-resistant cell growth. Tamoxifen is commonly used for breast cancer therapy. This paper shows that the transcriptional repression of the ERBB2 oncogene by tamoxifen in breast cancer cells is affected by an antagonistic interaction between the transcriptional regulators PAX2 and AIB-1. This affects the ability of tamoxifen to inhibit cancer cell proliferation. The relative levels of PAX2 and AIP1 in breast cancer patients treated with tamoxifen correlates with relapse-free survival. 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.