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The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice.乳腺癌中扩增的核受体辅激活因子-1是小鼠中Neu（ErbB2/HER2）激活、信号传导及乳腺肿瘤发生所必需的。
Cancer Res. 2008 May 15;68(10):3697-706. doi: 10.1158/0008-5472.CAN-07-6702.
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FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.叉头框蛋白A1（FoxA1）将表观遗传特征转化为增强子驱动的谱系特异性转录。
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Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients.雌激素受体α在丝氨酸167位点的磷酸化表明乳腺癌患者有更长的无病生存期和总生存期。
Clin Cancer Res. 2007 Oct 1;13(19):5769-76. doi: 10.1158/1078-0432.CCR-07-0822.
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A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.用于研究功能不同癌症亚型的乳腺癌细胞系集合。
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Genome-wide analysis of estrogen receptor binding sites.雌激素受体结合位点的全基因组分析。
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Model-based analysis of tiling-arrays for ChIP-chip.基于模型的染色质免疫沉淀芯片（ChIP-chip）平铺阵列分析
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Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis.PAX2的低甲基化相关激活介导他莫昔芬刺激的子宫内膜癌发生。
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Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.他莫昔芬用于预防乳腺癌：国家外科辅助乳腺和肠道项目P-1研究的现状
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10
Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.HER2阳性乳腺癌辅助化疗后使用曲妥珠单抗。
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雌激素受体-PAX2对ERBB2的调控决定了对他莫昔芬的反应。

Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen.

作者信息

Hurtado Antoni, Holmes Kelly A, Geistlinger Timothy R, Hutcheson Iain R, Nicholson Robert I, Brown Myles, Jiang Jie, Howat William J, Ali Simak, Carroll Jason S

机构信息

Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

出版信息

Nature. 2008 Dec 4;456(7222):663-6. doi: 10.1038/nature07483. Epub 2008 Nov 12.

DOI:10.1038/nature07483
PMID:19005469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2920208/
Abstract

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.

摘要

雌激素受体（ER）与ERBB2/HER-2信号通路之间的串扰长期以来一直被认为与乳腺癌的病因及药物反应有关，但尚未发现转录水平上的直接联系。在此，我们表明雌激素-ER和他莫昔芬-ER复合物通过人细胞系中ERBB2基因内的顺式调控元件直接抑制ERBB2转录。我们发现配对盒2基因产物（PAX2）在之前未被认识的作用中，作为抗癌药物他莫昔芬对ERBB2进行ER抑制的关键介质。我们表明PAX2与ER共激活因子AIB-1/SRC-3竞争对ERBB2转录的结合与调控，其结果决定了乳腺癌细胞对他莫昔芬的反应。ER-PAX2对ERBB2的抑制将这两种乳腺癌亚型联系起来，表明侵袭性ERBB2阳性肿瘤可能通过规避这种抑制机制源自ER阳性管腔型肿瘤。这些数据为乳腺癌内分泌耐药的分子基础提供了机制性见解。