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  • 标题:Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer
  • 本地全文:下载
  • 作者:Jun Yang ; Alaa AlTahan ; Dylan T. Jones
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2015
  • 卷号:112
  • 期号:49
  • 页码:15172-15177
  • DOI:10.1073/pnas.1422015112
  • 语种:English
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:SignificanceAbout 1.7 million new cases of breast cancer occur every year, 70% of which are estrogen receptor- (ER) positive. Antiestrogen therapy to block ER function is the most important approach in treatment of ER+ patients. However, resistance eventually will develop for various reasons. Here we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a direct transcriptional target of ER, which may compensate for ER function loss because many other ER targets are also HIF-1 targets. We further show that HIF-1 is able to confer cancer cell resistance to ER antagonists tamoxifen and fulvestrant, and the expression of HIF-1 is associated with poor survival to endocrine therapy in ER+ patients. Our findings thus have revealed a previously unidentified mechanism for antiestrogen resistance. A majority of breast cancers are driven by estrogen via estrogen receptor- (ER). Our previous studies indicate that hypoxia-inducible factor 1 (HIF-1) cooperates with ER in breast cancer cells. However, whether ER is implicated in the direct regulation of HIF-1 and the role of HIF-1 in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1 targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ER in normoxia and hypoxia. Interestingly, the HIF-1 gene itself also bears an estrogen response element, and its expression is directly regulated by ER. Clinical data revealed that expression of the HIF-1 gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ER+ breast cancer. HIF-1 was able to confer endocrine therapy resistance to ER+ breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ER and HIF-1, which might modulate hormone response in treatment.
  • 关键词:ERα ; HIF-1α ; tamoxifen
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