Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer.
Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer.
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DOI：
10.1186/bcr3609
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发表时间：
2014-01-29
期刊：
影响因子：
--
通讯作者：
Brodie AH
中科院分区：
文献类型：
--
作者：
Kazi AA;Gilani RA;Schech AJ;Chumsri S;Sabnis G;Shah P;Goloubeva O;Kronsberg S;Brodie AH
虽然芳香酶抑制剂（AI;例如，来曲唑）在治疗雌激素受体阳性（ER+）乳腺癌方面非常有效，但相当大比例的患者对AI没有反应或对其产生耐药性。先前的研究表明，对AI的获得性耐药性涉及从依赖ER信号传导到依赖生长因子介导的途径（如人表皮生长因子受体2（HER 2））的转变。然而，HER 2的作用以及可用作生物标志物或治疗靶点的其他相关因子的身份仍然未知。本研究探讨了转录因子缺氧诱导因子1（HIF-1）在获得性AI抗性中的潜在作用及其受HER 2的调节。使用AI（来曲唑或阿司美坦）抗性和AI敏感性细胞进行体外研究以研究HIF-1在AI抗性中的调节和作用。Western blot和RT-PCR分析分别比较AI耐药和AI敏感细胞中ERα、HER 2和HIF-1α（诱导型HIF-1亚基）的蛋白和mRNA表达。还进行了类似的表达分析，沿着染色质免疫沉淀（ChIP），以鉴定先前已知的HIF-1靶基因，如乳腺癌耐药蛋白（BCRP），其也可能在AI耐药中起作用。用HER 2、激酶通路和ERα抑制剂处理来曲唑耐药细胞，以阐明HIF-1和BCRP的调节。最后，用HIF-1α的抑制剂或诱导剂处理细胞以确定其重要性。在非缺氧条件下，AI抵抗和HER 2转染的细胞中基础HIF-1α蛋白和BCRP mRNA和蛋白高于AI敏感和HER 2亲本细胞。HIF-1α在AI耐药细胞中的表达可能受HER 2激活的磷脂酰肌醇-3-激酶/Akt蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI 3 K/Akt/mTOR）通路的调节，因为其表达被HER 2抑制剂和激酶通路抑制剂抑制。HIF-1α的抑制或上调部分通过BCRP影响乳腺癌细胞BCRP的表达; AI反应性;以及癌症干细胞特征的表达。AI耐药的机制之一可能是通过调节与化疗耐药有关的非缺氧HIF-1靶基因，如BCRP。因此，HIF-1作为肿瘤生物标志物和治疗靶点的潜力值得进一步研究。
Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERα, HER2, and HIF-1α (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERα to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1α to determine its importance. Basal HIF-1α protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1α expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1α affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.
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影响因子：
3.8
作者：
Burks, Scott R.;Macedo, Luciana F.;Kao, Joseph P. Y.
通讯作者：
Kao, Joseph P. Y.
影响因子：
4.8
作者：
Krishnamurthy, P;Ross, DD;Schuetz, JD
通讯作者：
Schuetz, JD
DOI：
10.1016/j.jsbmb.2007.05.019
发表时间：
2007-08-01
影响因子：
4.1
作者：
Johnston, Stephen R. D.;Martin, Lesley-Ann;Dowsett, Mitch
通讯作者：
Dowsett, Mitch
DOI：
10.1016/j.jsbmb.2006.03.002
发表时间：
2006-07-01
影响因子：
4.1
作者：
Cho, Jungyoon;Bahn, Jae-Jun;Lee, Young Joo
通讯作者：
Lee, Young Joo
影响因子：
3.9
作者：
Feng, Yadong;Zhu, Hong;Shi, Ruihua
通讯作者：
Shi, Ruihua