HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.
HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.
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DOI：
10.1371/journal.pone.0063419
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Resar LM
中科院分区：
文献类型：
--
作者：
Shah SN;Cope L;Poh W;Belton A;Roy S;Talbot CC Jr;Sukumar S;Huso DL;Resar LM
新出现的证据表明，肿瘤细胞通过增选干细胞转录网络进行转移，尽管这一过程的分子基础尚不清楚。在这里，我们首次证明了高迁移率组A1(HMGA1)基因通过将癌细胞重新编程到干细胞样状态来驱动三阴性乳腺癌细胞(MDA-MB-231，Hs578T)的转移进展。抑制HMGA1在侵袭性乳腺癌细胞中的表达可显著阻止细胞生长，并导致从间充质样、纺锤形细胞到立方上皮样细胞的显著形态变化。间充质基因(Vimentin、Snail)被抑制，而E-钙粘附素在敲除细胞中被诱导。沉默HMGA1还可以阻止致癌特性，包括增殖、迁移、侵袭和原位肿瘤形成。在HMGA1基因敲除细胞中，植入乳房后的转移进展几乎完全被消除。此外，沉默HMGA1会抑制干细胞的三维乳房形成特性，包括初级、二级和三级球体。此外，HMGA1基因的敲除可以耗尽癌症启动者/癌症干细胞，并在有限的稀释度下防止肿瘤的发生。我们还在三阴性乳腺癌细胞中发现了HMGA1信号，这种信号在胚胎干细胞中高度丰富。总之，这些发现表明，HMGA1通过干细胞转录网络对癌细胞进行重新编程，是乳腺癌肿瘤进展的主要调节因子。需要进一步的研究来确定如何在治疗中靶向HMGA1。
Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail) are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.
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影响因子：
8
作者：
Dhar, A;Hu, J;Colburn, NH
通讯作者：
Colburn, NH
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Liau, Siong-Seng;Jazag, Amarsanaa;Whang, Edward E.
通讯作者：
Whang, Edward E.
DOI：
10.1158/1541-7786.mcr-08-0336
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Hillion J;Wood LJ;Mukherjee M;Bhattacharya R;Di Cello F;Kowalski J;Elbahloul O;Segal J;Poirier J;Rudin CM;Dhara S;Belton A;Joseph B;Zucker S;Resar LM
通讯作者：
Resar LM
影响因子：
11.2
作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
通讯作者：
Resar LM