Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin.
Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin.
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DOI：
10.1186/bcr2586
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Janatpour MJ
中科院分区：
文献类型：
--
作者：
Vanderlaag KE;Hudak S;Bald L;Fayadat-Dilman L;Sathe M;Grein J;Janatpour MJ
前向梯度蛋白2（AGR 2）是一种雌激素应答性分泌蛋白。它的上调已经在许多癌症中得到了很好的证明，特别是乳腺癌，对于这些癌症，存在关于AGR 2表达的预后意义的混合数据。尽管新出现的证据表明AGR 2与预后不良相关，但其对癌症相关通路的功能和影响尚未在乳腺癌中阐明。为了研究AGR 2在乳腺癌中的生物学作用，通过使用siRNA瞬时敲除T47 D和ZR-75-1（雌激素受体-α（ER）阳性）和MDA-MB-231和SK-BR-3（ER阴性）人乳腺癌细胞系中的AGR 2。在锚定依赖性和锚定非依赖性生长（软琼脂，球状体）测定中评估沉默AGR 2的影响。用BrdU掺入法测定ER阳性细胞系的细胞周期分布，用Annexin V、JC-1和F7-26染色法测定细胞死亡。在短暂沉默AGR 2或用重组AGR 2刺激后，用Western印迹评估生长和存活途径的关键调节因子的调节。进行了AGR 2敲低与抗雌激素他莫昔芬和氟维司群的联合研究，并在锚定依赖性生长抑制和靶点调节（细胞周期蛋白D1，ER）水平进行了评估。AGR 2敲低抑制生长的锚定依赖性和锚定非依赖性测定，ER阳性细胞系中的效果更明显。细胞周期蛋白D1的水平和BrdU掺入减少AGR 2敲低。相反，细胞周期蛋白D1诱导与重组AGR 2。AGR 2基因敲减诱导ZR-75-1和T47 D细胞死亡，并下调生存素和c-Myc。AGR 2-ER串扰的证据通过短暂沉默AGR 2后ER在蛋白质水平上的减少来证明。AGR 2基因敲除与氟维司群或他莫昔芬联合使用并不妨碍抗雌激素的疗效，但增强了它。此外，与他莫昔芬耐药性有关的p-Src基因在AGR 2基因敲除后下调。短暂沉默ER阳性乳腺癌细胞系中的AGR 2抑制细胞生长和细胞周期进展并诱导细胞死亡。乳腺癌驱动因子（ER和细胞周期蛋白D1）以及癌症信号传导节点（pSrc，c-Myc和生存素）被证明是AGR 2的下游。总的来说，所提供的数据支持抗AGR 2治疗在ER阳性乳腺癌中的效用，因为其对癌症相关途径的影响。
Anterior-gradient 2 (AGR2) is an estrogen-responsive secreted protein. Its upregulation has been well documented in a number of cancers, particularly breast cancer, for which mixed data exist on the prognostic implications of AGR2 expression. Although emerging evidence indicates that AGR2 is associated with poor prognosis, its function and impact on cancer-relevant pathways have not been elucidated in breast cancer. To investigate the biologic role of AGR2 in breast cancer, AGR2 was transiently knocked down, by using siRNA, in T47 D and ZR-75-1 (estrogen receptor-α (ER)-positive) and MDA-MB-231 and SK-BR-3 (ER-negative) human breast cancer cell lines. The impact of silencing AGR2 was evaluated in both anchorage-dependent and anchorage-independent growth (soft agar, spheroid) assays. Cell-cycle profiles in ER-positive cell lines were determined with BrdU incorporation, and cell death was measured with Annexin V, JC-1, and F7-26 staining. After transiently silencing AGR2 or stimulating with recombinant AGR2, modulation of key regulators of growth and survival pathways was assessed with Western blot. Combination studies of AGR2 knockdown with the antiestrogens tamoxifen and fulvestrant were carried out and assessed at the level of anchorage-dependent growth inhibition and target modulation (cyclin D1, ER). AGR2 knockdown inhibited growth in anchorage-dependent and anchorage-independent assays, with a more-pronounced effect in ER-positive cell lines. Cyclin D1 levels and BrdU incorporation were reduced with AGR2 knockdown. Conversely, cyclin D1 was induced with recombinant AGR2. AGR2 knockdown induced cell death in ZR-75-1 and T47 D cells, and also downregulated survivin and c-Myc. Evidence of AGR2-ER crosstalk was demonstrated by a reduction of ER at the protein level after transiently silencing AGR2. AGR2 knockdown in combination with fulvestrant or tamoxifen did not preclude the efficacy of the antiestrogens, but enhanced it. In addition, p-Src, implicated in tamoxifen resistance, was downregulated with AGR2 knockdown. Transiently silencing AGR2 in ER-positive breast cancer cell lines inhibited cell growth and cell-cycle progression and induced cell death. Breast cancer drivers (ER and cyclin D1) as well as cancer-signaling nodes (pSrc, c-Myc, and survivin) were demonstrated to be downstream of AGR2. Collectively, the data presented support the utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways.
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蛋白质二硫键异构酶 AGR2 对于肠粘液的产生至关重要
DOI：
10.1073/pnas.0808722106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Park, Sung-Woo;Zhen, Guohua;Erle, David J.
通讯作者：
Erle, David J.
影响因子：
7.3
作者：
Kristiansen, G;Pilarsky, C;Rosenthal, A
通讯作者：
Rosenthal, A
影响因子：
11.5
作者：
Mita, Alain C.;Mita, Monica M.;Giles, Francis J.
通讯作者：
Giles, Francis J.
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1023/b:jomg.0000023586.69263.0b
发表时间：
2004-01-01
影响因子：
2.5
作者：
Jamerson, MH;Johnson, MD;Dickson, RB
通讯作者：
Dickson, RB