Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue.
Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue.
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DOI：
10.1038/cddis.2016.302
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发表时间：
2016-10-06
影响因子：
9
通讯作者：
Watson CJ
中科院分区：
文献类型：
--
作者：
Hughes K;Blanck M;Pensa S;Watson CJ
停止哺乳(退缩)时的乳腺退化是一个精心安排的细胞死亡和组织重塑的过程，其中STAT3信号在其中起着至关重要的作用。乳腺的退化微环境被认为是促肿瘤发生的，部分妊娠相关乳腺癌的病例被认为是伴随退化而来的。然而，STAT3在正常乳腺中是细胞死亡所必需的，但与乳腺癌细胞的生存相关，这一明显的悖论尚未得到解决。在此，我们研究了STAT3介导的钙激活氯通道调节蛋白(CLCA)家族成员在退缩和乳腺癌发生过程中的表达调控。利用条件永生的乳腺上皮细胞系Kim-2，以及在哺乳期表现出乳腺上皮细胞特异性的STAT3缺失的小鼠，我们证明了mCLCA1和mCLCA2的表达与STAT3的激活是一致的。相比之下，在STAT3基因敲除的小鼠中，人类CLCA2的小鼠同源基因小鼠CLCA5(MCLCA5)在退化期的24、72和96 h显著上调，表明这些蛋白在体内受到STAT3的相互调节。有趣的是，移植4T1小鼠乳腺肿瘤细胞产生的原位肿瘤同时显示了磷酸化的STAT3和mCLCA5的表达。然而，我们证明，该表达是高度区隔到不同的细胞亚群，并且STAT3对4T1肿瘤细胞中mCLCA5的表达具有抑制作用。这些发现加深了我们对体内和体外CLCA通道表达调控的理解，特别是表明mCLCA1和mCLCA2在退化过程中的表达在很大程度上依赖于STAT3，而mCLCA5和STAT3活性之间的关系是相互作用的，并仅限于不同的细胞亚群。
Mammary gland regression at the cessation of lactation (involution) is an exquisitely orchestrated process of cell death and tissue remodelling in which Stat3 signalling has an essential role. The involution microenvironment of the mammary gland is considered to be pro-tumourigenic and a proportion of cases of pregnancy-associated breast cancer are suggested to originate in tandem with involution. However, the apparent paradox that STAT3 is required for cell death in normal mammary gland, but is associated with breast cancer cell survival, has not been resolved. Herein, we investigate Stat3-mediated regulation of expression of members of the calcium-activated chloride channel regulator (CLCA) family of proteins during involution and mammary carcinogenesis. Using the conditionally immortal mammary epithelial cell line KIM-2, together with mice exhibiting mammary epithelial cell-specific deletion of Stat3 during lactation, we demonstrate that expression of mCLCA1 and mCLCA2 is elevated in concert with activation of Stat3. By contrast, murine CLCA5 (mCLCA5), the murine orthologue of human CLCA2, is significantly upregulated at 24, 72 and 96 h of involution in Stat3 knockout mice, suggesting a reciprocal regulation of these proteins by Stat3 in vivo. Interestingly, orthotopic tumours arising from transplantation of 4T1 murine mammary tumour cells exhibit both phosphorylated Stat3 and mCLCA5 expression. However, we demonstrate that expression is highly compartmentalized to distinct subpopulations of cells, and that Stat3 retains a suppressive effect on mCLCA5 expression in 4T1 tumour cells. These findings enhance our understanding of the regulation of CLCA channel expression both in vitro and in vivo, and in particular, demonstrate that expression of mCLCA1 and mCLCA2 during involution is profoundly dependent upon Stat3, whereas the relationship between mCLCA5 and Stat3 activity is reciprocal and restricted to different subpopulations of cells.
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DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
7.7
作者：
Sala-Rabanal M;Yurtsever Z;Nichols CG;Brett TJ
通讯作者：
Brett TJ
影响因子：
64.8
作者：
Marusyk, Andriy;Tabassum, Doris P.;Altrock, Philipp M.;Almendro, Vanessa;Michor, Franziska;Polyak, Kornelia
通讯作者：
Polyak, Kornelia
影响因子：
10.5
作者：
Chapman, RS;Lourenco, PC;Watson, CJ
通讯作者：
Watson, CJ
影响因子：
3.8
作者：
Callihan, Eryn B.;Gao, Dexiang;Jindal, Sonali;Lyons, Traci R.;Manthey, Elizabeth;Edgerton, Susan;Urquhart, Alexander;Schedin, Pepper;Borges, Virginia F.
通讯作者：
Borges, Virginia F.