Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFß.
Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFß.
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DOI：
10.1371/journal.pone.0061125
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Green JE
中科院分区：
文献类型：
--
作者：
Chu IM;Lai WC;Aprelikova O;El Touny LH;Kouros-Mehr H;Green JE
转化生长因子（β 1 TGF β 1）可促进晚期癌症的增殖，但在正常上皮细胞和早期癌症中充当肿瘤抑制因子。虽然，TGF β通路已被证明在肿瘤发生和转移中发挥关键作用，但只有有限数量的模型被开发出来以了解这一过程。在这里，我们提出了一种新的模型系统，以辨别这种矛盾的作用，TGF β 1使用MDA-MB-231（MB-231）细胞系。MB-231三阴性乳腺癌细胞系已被广泛表征，并已显示在TGF β 1刺激后继续增殖并经历上皮向间充质转化（EMT）。我们先前通过微阵列分析表明，MB-231细胞中GATA 3的表达导致这些细胞从基底亚型重编程为管腔亚型，这与作为异种移植物植入时转移和肿瘤发生的减少有关。我们现在证明，在这些细胞中GATA 3过表达导致TGF β 1反应的降低、EMT的逆转，最重要的是，恢复对TGF β 1增殖抑制作用的敏感性。微阵列分析显示，TGF β 1处理导致231-GATA 3细胞中几种细胞周期效应物的减少，但在对照细胞中没有。此外，我们的微阵列分析揭示了231-GATA 3细胞中BMP 5的显著增加。我们证明用TGF β 1和BMP 5联合处理MB-231对照细胞导致细胞增殖的显著降低。因此，该模型提供了一种进一步研究潜在的新机制的方法，所述机制涉及通过GATA 3转录因子对三阴性乳腺癌细胞系的重编程而响应于TGF β 1从肿瘤启动子到肿瘤抑制子的转换。
Transforming growth factor (ß1TGFß1) can promote proliferation in late stage cancers but acts as a tumor suppressor in normal epithelial cells and in early stage cancers. Although, the TGFß pathway has been shown to play a key role in tumorigenesis and metastasis, only a limited number of models have been developed to understand this process. Here, we present a novel model system to discern this paradoxical role of TGFß1 using the MDA-MB-231 (MB-231) cell line. The MB-231 triple-negative breast cancer cell line has been extensively characterized and has been shown to continue to proliferate and undergo epithelial-to-mesenchymal transition (EMT) upon TGFß1 stimulation. We have previously shown by microarray analysis that expression of GATA3 in MB-231 cells results in reprogramming of these cells from a basal to a luminal subtype associated with a reduction of metastasis and tumorigenesis when implanted as xenografts. We now demonstrate that GATA3 overexpression in these cells results in a reduction of TGFß1 response, reversal of EMT, and most importantly, restoration of sensitivity to the inhibitory effects on proliferation of TGFß1. Microarray analysis revealed that TGFß1 treatment resulted in reduction of several cell cycle effectors in 231-GATA3 cells but not in control cells. Furthermore, our microarray analysis revealed a significant increase of BMP5 in 231-GATA3 cells. We demonstrate that combined treatment of MB-231 control cells with TGFß1 and BMP5 results in a significant reduction of cellular proliferation. Thus, this model offers a means to further investigate potentially novel mechanisms involved in the switch in response to TGFß1 from tumor promoter to tumor suppressor through the reprogramming of a triple-negative breast cancer cell line by the GATA3 transcription factor.
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影响因子：
8
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.
通讯作者：
Green, J. E.
影响因子：
11.2
作者：
Onder, Tamer T.;Gupta, Piyush B.;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
11.2
作者：
Buijs, Jeroen T.;Henriquez, Nico V.;Van der Pluijm, Gabri
通讯作者：
Van der Pluijm, Gabri
影响因子：
9.7
作者：
Alarmo, Emma-Leena;Parssinen, Jenita;Kallioniemi, Anne
通讯作者：
Kallioniemi, Anne