GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells.
GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells.
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DOI：
10.1038/onc.2011.382
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发表时间：
2012-04-19
期刊：
影响因子：
8
通讯作者：
Green, J. E.
中科院分区：
文献类型：
--
作者：
Chu, I. M.;Michalowski, A. M.;Hoenerhoff, M.;Szauter, K. M.;Luger, D.;Sato, M.;Flanders, K.;Oshima, A.;Csiszar, K.;Green, J. E.
发现阻碍人基底三阴性型乳腺癌（BTNBC）的侵袭性和转移性表型的机制可以为这种具有相对较差预后的乳腺癌形式的治疗提供新的靶点。先前的研究已经证明，GATA 3（乳腺腔分化的主要转录调节因子）的表达可以降低人BTNBC MDA-MB-231细胞系（MB 231）的致瘤性和转移倾向，尽管尚未阐明减少转移的机制。我们证明，通过基因表达谱，GATA 3在231细胞中的表达导致赖氨酰氧化酶（LOX），转移促进基质重塑蛋白的表达显着减少，部分通过LOX启动子的甲基化。在BTNBC Hs 578 T细胞系中进一步证实了GATA 3对LOX表达的抑制。相反，在Luminal BT474细胞中通过siRNA减少GATA 3表达增加LOX表达。231-GATA 3细胞中LOX表达的重建恢复了转移倾向。在一组51个人乳腺癌细胞系中证实了LOX高表达和GATA 3低表达之间的强负相关。类似地，人乳腺癌微阵列数据表明，高LOX/低GATA 3表达与乳腺癌的BTNBC亚型和患者预后不良相关。GATA 3的表达将BTNBC重编程为侵袭性较低的表型，并通过抑制LOX抑制转移的主要机制。在BTNBC细胞中诱导GATA 3或抑制LOX表达或活性的新方法可能是治疗BTNBC的重要策略。
Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative type breast cancers (BTNBC) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that the expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although the mechanism for reduced metastases was not elucidated. We demonstrate through gene expression profiling that GATA3 expression in 231 cells resulted in the dramatic reduction in the expression of Lysyl oxidase (LOX), a metastasis-promoting matrix remodeling protein, in part, through methylation of the LOX promoter. Suppression of LOX expression by GATA3 was further confirmed in the BTNBC Hs578T cell line. Conversely, reduction of GATA3 expression by siRNA in luminal BT474 cells increased LOX expression. Reconstitution of LOX expression in 231-GATA3 cells restored metastatic propensity. A strong inverse association between high LOX and low GATA3 expression was confirmed in a panel of 51 human breast cancer cell lines. Similarly, human breast cancer microarray data demonstrated that high LOX/low GATA3 expression is associated with the BTNBC subtype of breast cancer and poor patient prognosis. Expression of GATA3 reprograms BTNBC to a less aggressive phenotype and inhibits a major mechanism of metastasis through inhibition of LOX. Induction of GATA3 in BTNBC cells or novel approaches that inhibit LOX expression or activity could be important strategies for treating BTNBC.
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影响因子：
8
作者：
Hoenerhoff, M. J.;Chu, I.;Barkan, D.;Liu, Z-y;Datta, S.;Dimri, G. P.;Green, J. E.
通讯作者：
Green, J. E.
影响因子：
4
作者：
Grimsby, Jessica L.;Lucero, Hector A.;Trackman, Philip C.;Ravid, Katya;Kagan, Herbert M.
通讯作者：
Kagan, Herbert M.
影响因子：
11.2
作者：
Barkan D;Kleinman H;Simmons JL;Asmussen H;Kamaraju AK;Hoenorhoff MJ;Liu ZY;Costes SV;Cho EH;Lockett S;Khanna C;Chambers AF;Green JE
通讯作者：
Green JE
影响因子：
3.7
作者：
Bondareva A;Downey CM;Ayres F;Liu W;Boyd SK;Hallgrimsson B;Jirik FR
通讯作者：
Jirik FR
影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena