三苯氧胺常用于乳腺癌治疗，但一部分患者会变得对治疗方法产生抵抗力，她们的癌症更可能复发。对乳腺癌中雌激素受体与ERBB2/HER-2通道之间的关系所做的一项研究，为了解三苯氧胺的作用机制及三苯氧胺抗药性的基础提供了线索。这项新的研究工作表明，乳腺癌中ErbB2的主动抑制需要Pax2，Pax2的减少引起由ErbB2驱动的抗三苯氧胺细胞的生长。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 456, 663-666 (4 December 2008) | doi:10.1038/nature07483
Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifen
Antoni Hurtado1, Kelly A. Holmes1, Timothy R. Geistlinger2, Iain R. Hutcheson3, Robert I. Nicholson3, Myles Brown2, Jie Jiang4, William J. Howat1, Simak Ali4 & Jason S. Carroll1
1 Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
2 Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
3 Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, UK
4 Imperial College London, Hammersmith Hospital, London W12 0NN, UK
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.
