GPER mediates the angiocrine actions induced by IGF1 through the HIF-1α/VEGF pathway in the breast tumor microenvironment.
GPER mediates the angiocrine actions induced by IGF1 through the HIF-1α/VEGF pathway in the breast tumor microenvironment.
复制标题
DOI：
10.1186/s13058-017-0923-5
复制
发表时间：
2017-12-06
期刊：
影响因子：
--
通讯作者：
Clarke RB
中科院分区：
文献类型：
--
作者：
De Francesco EM;Sims AH;Maggiolini M;Sotgia F;Lisanti MP;Clarke RB
G蛋白雌激素受体GPER/GPR30介导乳腺癌细胞和乳腺癌相关成纤维细胞（CAFs）中的雌激素作用，这是驱动肿瘤进展的微环境的关键组成部分。GPER是缺氧诱导因子1α (hypoxia inducible factor 1α, HIF-1α)的转录靶点，在低氧乳腺肿瘤微环境中激活VEGF的表达和血管生成。此外，具有血管生成作用的IGF1/IGF1R信号已被证明可激活乳腺癌细胞中的GPER。我们分析了来自近5000名乳腺癌患者的已发表研究的基因表达数据，以研究GPER和IGF1信号是否在乳腺癌患者中建立了血管分泌基因特征。接下来，我们使用来自患者乳腺肿瘤和SKBR3乳腺癌细胞的GPER阳性但雌激素受体（ER）阴性的原代CAF细胞来研究GPER在调节IGF1触发的VEGF表达和血管生成中的作用。我们通过基因表达和启动子研究、免疫印迹和免疫荧光分析、基因沉默策略和内皮管形成实验来评估HIF-1α/GPER/VEGF信号通路在IGF1生物学反应中的作用。我们首先确定GPER在人乳腺肿瘤中与IGF1R和血管标志物CD34共表达（n = 4972）。接下来，我们确定IGF1/IGF1R信号参与ERK1/2和AKT转导通路，诱导HIF-1α及其靶点GPER和VEGF的表达。我们发现HIF-1α和GPER之间的功能合作对于IGF1诱导的VEGF转录激活至关重要。最后，利用IGF1刺激的CAFs和SKBR3细胞的条件培养基，我们确定了HIF-1α和GPER都是vegf诱导的人血管内皮细胞管形成所必需的。这些发现揭示了GPER在诱导乳腺肿瘤血管生成的IGF1/IGF1R信号传导中所起的重要作用。靶向GPCRs和生长因子受体参与的癌细胞与肿瘤微环境的多方面相互作用，在未来的联合抗癌治疗中具有潜力。本文的在线版本（doi:10.1186/s13058-017-0923-5）包含补充材料，仅供授权用户使用。
The G protein estrogen receptor GPER/GPR30 mediates estrogen action in breast cancer cells as well as in breast cancer-associated fibroblasts (CAFs), which are key components of microenvironment driving tumor progression. GPER is a transcriptional target of hypoxia inducible factor 1 alpha (HIF-1α) and activates VEGF expression and angiogenesis in hypoxic breast tumor microenvironment. Furthermore, IGF1/IGF1R signaling, which has angiogenic effects, has been shown to activate GPER in breast cancer cells. We analyzed gene expression data from published studies representing almost 5000 breast cancer patients to investigate whether GPER and IGF1 signaling establish an angiocrine gene signature in breast cancer patients. Next, we used GPER-positive but estrogen receptor (ER)-negative primary CAF cells derived from patient breast tumours and SKBR3 breast cancer cells to investigate the role of GPER in the regulation of VEGF expression and angiogenesis triggered by IGF1. We performed gene expression and promoter studies, western blotting and immunofluorescence analysis, gene silencing strategies and endothelial tube formation assays to evaluate the involvement of the HIF-1α/GPER/VEGF signaling in the biological responses to IGF1. We first determined that GPER is co-expressed with IGF1R and with the vessel marker CD34 in human breast tumors (n = 4972). Next, we determined that IGF1/IGF1R signaling engages the ERK1/2 and AKT transduction pathways to induce the expression of HIF-1α and its targets GPER and VEGF. We found that a functional cooperation between HIF-1α and GPER is essential for the transcriptional activation of VEGF induced by IGF1. Finally, using conditioned medium from CAFs and SKBR3 cells stimulated with IGF1, we established that HIF-1α and GPER are both required for VEGF-induced human vascular endothelial cell tube formation. These findings shed new light on the essential role played by GPER in IGF1/IGF1R signaling that induces breast tumor angiogenesis. Targeting the multifaceted interactions between cancer cells and tumor microenvironment involving both GPCRs and growth factor receptors has potential in future combination anticancer therapies. The online version of this article (doi:10.1186/s13058-017-0923-5) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
--
作者：
Avino S;De Marco P;Cirillo F;Santolla MF;De Francesco EM;Perri MG;Rigiracciolo D;Dolce V;Belfiore A;Maggiolini M;Lappano R;Vivacqua A
通讯作者：
Vivacqua A
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
GPR30 作为激素依赖性乳腺癌他莫昔芬耐药的引发剂。
DOI：
10.1186/bcr3581
发表时间：
2013-11-29
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Mo Z;Liu M;Yang F;Luo H;Li Z;Tu G;Yang G
通讯作者：
Yang G
影响因子：
8
作者：
De Marco, P.;Bartella, V.;Maggiolini, M.
通讯作者：
Maggiolini, M.