Aberrant regulation of the BST2 (Tetherin) promoter enhances cell proliferation and apoptosis evasion in high grade breast cancer cells.
Aberrant regulation of the BST2 (Tetherin) promoter enhances cell proliferation and apoptosis evasion in high grade breast cancer cells.
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DOI：
10.1371/journal.pone.0067191
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dairkee SH
中科院分区：
文献类型：
--
作者：
Sayeed A;Luciani-Torres G;Meng Z;Bennington JL;Moore DH;Dairkee SH
在肿瘤发生过程中具有致癌功能的正常细胞表型是癌症靶向药物的潜在候选者。在侵袭性原发性乳腺癌的一个亚群中，我们观察到相对丰富的Tetherin表达，Tetherin是一种由骨髓基质细胞抗原（BST2）编码的细胞表面蛋白，已知在宿主感染免疫细胞的病毒释放中起抑制作用。我们使用来自低和中等组织病理学级别侵袭性原发肿瘤的乳腺癌细胞系，这些肿瘤维持生长抑制tgf - β信号，我们证明上皮细胞中的BST2受到tgf - β轴的负调控。通过抑制TGFβ通路，转录因子AP2与BST2启动子的结合减弱，从而增加BST2在肿瘤细胞中的表达。相反，高级别乳腺肿瘤固有的TGFβ耐药特性是BST2调控受损的关键因素，因此BST2在非恶性乳腺上皮和大多数中低级别肿瘤细胞中的组成性过表达。在二维和三维生长条件下，与BST2过表达的肿瘤细胞相比，BST2沉默的肿瘤细胞在他莫昔芬或司陶孢素诱导的凋亡细胞死亡中表现出增强，同时s期分数减少。在接受促凋亡激素治疗的乳腺癌患者亚群中，BST2表达与不良临床结果的趋势相关，进一步支持其在赋予抗凋亡表型中的作用。与基因操作类似，植物抗毒素-白藜芦醇诱导内源性BST2水平下降，恢复细胞凋亡功能，抑制细胞增殖。我们提供了一种直接的方法，可以减少癌细胞中异常的BST2表达，作为一种早期靶向策略，以帮助克服对促凋亡治疗的耐药性。
Normal cellular phenotypes that serve an oncogenic function during tumorigenesis are potential candidates for cancer targeting drugs. Within a subset of invasive primary breast carcinoma, we observed relatively abundant expression of Tetherin, a cell surface protein encoded by the Bone Marrow Stromal Cell Antigen (BST2) known to play an inhibitory role in viral release from infected immune cells of the host. Using breast cancer cell lines derived from low and intermediate histopathologic grade invasive primary tumors that maintain growth-suppressive TGFβ signaling, we demonstrate that BST2 is negatively regulated by the TGFβ axis in epithelial cells. Binding of the transcription factor AP2 to the BST2 promoter was attenuated by inhibition of the TGFβ pathway thereby increasing BST2 expression in tumor cells. In contrast, inherent TGFβ resistance characteristic of high grade breast tumors is a key factor underlying compromised BST2 regulation, and consequently its constitutive overexpression relative to non-malignant breast epithelium, and to most low and intermediate grade cancer cells. In both 2-dimensional and 3-dimensional growth conditions, BST2-silenced tumor cells displayed an enhancement in tamoxifen or staurosporine-induced apoptotic cell death together with a reduction in the S-phase fraction compared to BST2 overexpressing counterparts. In a subset of breast cancer patients treated with pro apoptotic hormonal therapy, BST2 expression correlated with a trend for poor clinical outcome, further supporting its role in conferring an anti apoptotic phenotype. Similar to the effects of gene manipulation, declining levels of endogenous BST2 induced by the phytoalexin – resveratrol, restored apoptotic function, and curbed cell proliferation. We provide evidence for a direct approach that diminishes aberrant BST2 expression in cancer cells as an early targeting strategy to assist in surmounting resistance to pro apoptotic therapies.
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影响因子：
3.8
作者：
Cai D;Cao J;Li Z;Zheng X;Yao Y;Li W;Yuan Z
通讯作者：
Yuan Z
影响因子：
11.2
作者：
Schild-Hay LJ;Leil TA;Divi RL;Olivero OA;Weston A;Poirier MC
通讯作者：
Poirier MC
影响因子：
--
作者：
Buck, MB;Pfizenmaier, K;Knabbe, C
通讯作者：
Knabbe, C
DOI：
10.1016/j.biocel.2008.09.028
发表时间：
2009-04-01
影响因子：
4
作者：
Jhumka, Ziyad;Pervaiz, Shazib;Clement, Marie-Veronique
通讯作者：
Clement, Marie-Veronique
影响因子：
6.7
作者：
Bartee E;McCormack A;Früh K
通讯作者：
Früh K